Clinical trial NCT03019289
Conditions: Health Volunteers, Huntington Disease
Sponsor: Prilenia
Start date: 2017-04-19; Completion date: 2018-02-09
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to demonstrate engagement of pridopidine with S1R and D2R (optional) in the living human brain. No formal statistical analysis will be conducted

Detailed description:

Arms: arm 1: Pridopidine (TV-7820) capsules
Interventions: intervention 1: pridopidine (90 mg)
Intervention descriptions: intervention 1: single dose will be administered in Cohort 1. Other optional cohorts 2 and 3 may include single dose 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 22.5 mg, 45 mg, or 90 mg. The dose will be selected based on the results obtained from Cohorts 1 and 2.

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine 
and [18F]fallypride Positron Emission Tomography Study to Evaluate Sigma-1 and 
Dopamine-2 Receptor Occupancy by Pridopidine in the Human Brain of Healthy 
Volunteers and in Patients with Huntington’s Disease 
NCT Number: NCT03019289 
Document Date: 2 May 2016 


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TITLE PAGE
Clinical Study Protocol with Amendment 02
Study Number TV7820-IMG-10082
A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine and [18F]fallypride 
Positron Emission Tomography Study to Evaluate Sigma-1 and Dopamine-2 Receptor 
Occupancy by Pridopidine in the Human Brain of Healthy Volunteers and in Patients with 
Huntington’s Disease
Phase 1
IND number: 77,419;
NDA number: N/A; EudraCT number: 2016-001757-41
Protocol Approval Date: 02 May 2016
Protocol with Amendment 01 Approval Date: 11 November 2016
Protocol with Amendment 02 Approval Date: 06 October 2017
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Council for Harmonisation (ICH); United States (US) Code of Federal Regulations 
(CFR), and European Union (EU) Directives (as applicable in the region of the study); national 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.
© 2017 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for study TV7820-IMG-10082 (original protocol dated 02 May 2016) has been 
amended and reissued as follows:
Amendment 02
06 October 2017
18 subjects and no patients have been 
enrolled to date
Amendment 01
11 November 2016
No subjects or patients have been enrolled 
to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 17.


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INVESTIGATOR AGREEMENT
Original Protocol Dated 02 May 2016
Clinical Study Protocol with Amendment 02 06 October 2017
IND Number: 77,419;
NDA Number: N/A; EudraCT Number: 2016-001757-41
A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine and [18F]fallypride 
Positron Emission Tomography Study to Evaluate Sigma-1 and Dopamine-2 Receptor 
Occupancy by Pridopidine in the Human Brain of Healthy Volunteers and in Patients with 
Huntington’s Disease
Principal Investigator: Osama Sabri, MD, PhD
Title: Director and Chairman, Department of Nuclear Medicine, University of Leipzig 
Address of Investigational Center: 
I have read the protocol with Amendment 02 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes approval of this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the drug that were furnished to me by 
the sponsor to all physicians and other study personnel responsible to me who participate in this 
study and will discuss this material with them to ensure that they are fully informed regarding the 
drug and the conduct of the study. I agree to keep records on all subject information, study drug 
shipment and return forms, and all other information collected during the study, in accordance 
with national and local Good Clinical Practice (GCP) regulations.
Principal Investigator
Osama Sabri, MD, PhD
Signature
Date


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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
 
Sponsor’s Representative of Global Patient Safety and Pharmacovigilance
Contract Research Organization and Image Core Laboratory


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Screening and Follow-up
Screening MRIs
Treatment Period
 
Central Clinical Laboratory
Virology Testing
Bioanalysis of Pridopidine and TV-45065 in Plasma


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Pharmacogenetic/Biomarker Evaluation (Sponsor)
Biorepository for Pharmacogenetic and Biomarker Samples
Pharmacogenetic Analysis


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below:
For operational issues, contact the operational lead listed below:
For protocol clinical issues, contact the study leader listed below:
 
For serious adverse events:
Send by email to the local safety officer (LSO)
 The email address 
will also be provided in the serious adverse event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel identified above for further 
instruction.


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CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV7820-IMG-10082
Title of Study: A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine and [18F]fallypride Positron 
Emission Tomography Study to Evaluate Sigma-1 and Dopamine-2 Receptor Occupancy by Pridopidine in the 
Human Brain of Healthy Volunteers and in Patients with Huntington’s Disease
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 77,419 New Drug Application (NDA) Number: N/A
EudraCT Number: 2016-001757-41
Name of Active Ingredient: 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride
Name of Investigational Product: Pridopidine (TV-7820) capsules
Phase of the Study: 1
Number of Investigational Centers Planned: 1
Countries Planned: Germany
Planned Study Period: Q1 2017 to Q1 2018
Number of Patients Planned: Up to 45 subjects are planned to be enrolled in this study to ensure up to 
38 evaluable subjects (20 subjects in Part A, 15 subjects in Part B, 3 subjects in Part 0 [test-retest])
Study Population: This study will recruit healthy non-smoking men between 25 and 55 years of age (inclusive) and 
(optional) men aged ≥25 years with Huntington’s disease (HD). Healthy subjects and HD patients who are poor 
cytochrome P450 (CYP) 2D6 metabolizers will be excluded from participation in this study.
Primary Objective: The primary objectives of this study are:

To demonstrate target engagement, receptor binding/occupancy (RO) of pridopidine to sigma-1 
receptors (S1R) in the brain (whole brain, cortical and subcortical regions) of healthy subjects and 
(optional) Huntington’s disease (HD) patients after single oral dose administration; 

To establish the relationship between the plasma pridopidine concentrations and the S1R occupancy in 
the brain of healthy subjects and (optional) HD patients following a single oral dose of pridopidine. 
Secondary Objectives: The secondary objectives of this study are:

To establish test-retest variability of (S)-(-)-[18F]fluspidine positron emission tomography (PET) 
imaging of S1R in healthy subjects;

To evaluate the pharmacokinetics of pridopidine following single oral administration in healthy 
subjects and (optional) HD patients;

To assess safety of pridopidine in healthy subjects and (optional) HD patients. 
Exploratory Objectives: The exploratory objectives of the study are:


To explore target engagement, RO of pridopidine to the dopamine-2 receptors (D2R) in the brain of 
healthy subjects and (optional) HD patients;

To explore the relationship between the plasma pridopidine concentrations and D2R occupancy in the 
brain of healthy subjects and (optional) HD patients following a single oral dose of pridopidine;

To establish the relationship between the plasma metabolite TV-45065 concentrations and the S1R 
occupancy in the brain following a single oral dose of pridopidine to healthy subjects and (optional) 
HD patients;


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
To evaluate the relationship between plasma pridopidine concentration and brain activity using 
functional magnetic resonance imaging (MRI-based Attenuation Correction [MR-AC], T1-weighted 
rapid 3-dimensional gradient-echo technique [T1 MPRAGE 3D]. Arterial Spin Labeling [ASL], 2D 
multi-voxel Magnetic Resonance Spectroscopy [MRS], and resting state functional Magnetic 
Resonance Imaging [rs-fMRI]); 

To evaluate the relationship between S1R and D2 receptor occupancy in vivo by pridopidine and brain 
activity using functional magnetic resonance imaging (MR-AC, T1 MPRAGE 3D, ASL, 2D MRS, and 
rs-fMRI);

To explore any effects of pridopidine on brain activity, and link it to the occupancy of S1R and D2R;

 
 
Study Endpoints:
Pharmacodynamic Endpoints
The PET acquisition, as well as advanced magnetic resonance imaging (MRI) protocols (MR-AC, T1 MPRAGE 3D, 
ASL, 2D MRS, and rs-fMRI) will be detailed in dedicated imaging manuals. These will also contain an analysis plan 
for the image data. Imaging manuals will be provided prior to initiating the study.
Pharmacokinetic Endpoints
Blood samples for analysis of pridopidine and the metabolite TV-45065 will be obtained up to 24 hours after dosing. 
Pharmacokinetic parameters will be calculated.
Safety and Tolerability Endpoints
The safety and tolerability endpoints are:

occurrence of adverse events during the study

clinical laboratory (serum chemistry, hematology, and urinalysis) test results

vital signs (blood pressure [BP], respiratory rate, body temperature, and pulse) measurements at each 
visit

electrocardiogram (ECG) findings

physical examination findings, including body weight measurements,

use of concomitant medication during the study

number (%) of subjects who did not complete the study (end of study)

number (%) of subjects who did not complete the study due to adverse events
Biomarker Endpoints
Blood samples for biomarker analysis in serum, plasma, and ribonucleic acid (RNA) will be collected up to 24 hours 
after pridopidine dosing. 
Pharmacogenetic Endpoints
A pharmacogenetic blood sample will be collected at screening for genetic analyses of the CYP2D6 metabolizer 
status and S1R polymorphs.
General Design and Methods: This is a Phase 1, single-dose, open-label, adaptive design (S)-(-)-[18F]fluspidine 
PET study in healthy subjects and (optional) in patients with HD designed to demonstrate target engagement and to 
assess the occupancy of the S1R by pridopidine. PET with the tracer (S)-(-)-[18F]fluspidine will be used to quantify 


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changes in S1R availability following the administration of pridopidine (Part A). Binding of pridopidine to D2R 
may be assessed using PET imaging with [18F]fallypride (Part B, optional). 
The test-retest variability of (S)-(-)-[18F]fluspidine PET will be determined in up to 6 healthy subjects in parallel 
(Part 0).
In addition, plasma corticoid levels will be assessed immediately before each (S)-(-)-[18F]fluspidine or 
[18F]fallypride injection in all subjects.
Pharmacogenetic samples will be collected at screening for CYP2D6 and exploratory genotyping. Biomarker 
pharmacodynamic samples will be collected at visit 3, prior to dosing and 4, 8, and 24 hours post pridopidine dose.
Up to 45 subjects are planned to be enrolled in this study to ensure up to 38 evaluable subjects. The study will 
consist of a screening period of up to 8 weeks prior to first dosing, including a T1 MPRAGE 3D MRI scan (visit 1), 
a study period of up to 4 weeks (including visits 2 and 3), and a follow-up visit (visit 4). During the study period, the 
subjects will undergo a baseline PET investigation (PET session 1) at visit 2, and subsequently a post-treatment PET 
investigation (PET session 2) following a single oral dose of pridopidine at visit 3. Each dose cohort will comprise 
up to 4 subjects. It is expected that each dose cohort within Part A or Part B will receive a different dose of 
pridopidine; however, subjects within each cohort will be administered the same dose (deviation will also be 
allowed). It is possible that subjects in different cohorts within Part A or Part B may receive the same dose of 
pridopidine if timing of the PET imaging is changed or unchanged (eg, cohort with HD patients).
Subjects in Part A and B may receive the same dose of pridopidine for different tracers or different populations 
(healthy volunteers or patients with HD). The maximal dose of pridopidine administered will not exceed 90 mg in 
healthy subjects or 112.5 mg in HD patients (the highest dose investigated in the PRIDE-HD study).
Up to 20 subjects may be evaluated in Part A, although it is expected that study objectives may be achieved with 
fewer subjects (more subjects will also be allowed). At the day of each PET session, prior to PET imaging, a cubital 
or forearm vein will be cannulated to inject (S)-(-)-[18F]fluspidine and (at visit 3 only) to obtain venous blood 
samples for quantification of pridopidine and its metabolite TV-45065, and also for other exploratory biomarker 
analysis. The subject’s radial artery on the other arm (or the same arm if this cannot be achieved) will be cannulated 
to obtain arterial blood samples during PET imaging for the quantification of plasma radioactivity associated with 
(S)-(-)-[18F]fluspidine, in order to estimate a metabolite-corrected arterial plasma input function for PET data 
analysis.
The PET imaging will consist of subsets of PET scans that will be acquired in list mode: 4 blocks with breaks in 
between. The first PET acquisition block of 90 minutes duration (0 to 90 minutes) will be started together with the 
intravenous injection of 300±30 MBq (S)-(-)-[18F]fluspidine; the following acquisition blocks of 30 minutes 
duration each will be started at 2, 3, and 6 hours post-injection of the PET tracer. Each PET acquisition block will be 
acquired in list mode in order to allow variable subdivision into multiple time frames as detailed in the imaging 
manual. In an effort to facilitate easier PET procedure for HD patients after the first 90-minute PET acquisition 
block, the subsequent 30-minute PET acquisition blocks are made optional per Investigator’s judgement.
The first dose of pridopidine will be high (90 mg) for subjects enrolled in the first dose cohort but may be changed 
to another dose based on PRIDE-HD study results. Subsequent doses (0.5 or 1 mg in healthy subjects; 2.5, 5, 10, 
22.5, 45, or 67.5 mg in healthy subjects and HD patients; and a high dose of 112.5 mg in HD patients) will be 
determined on the basis of the RO results following PET session 2 and the time-activity profiles of (S)-(-)-
[18F]fluspidine from previous cohort subjects. In addition, the timing of the PET sessions may also be revised. If any 
of the postdose PET investigations are compromised due to technical or logistic reasons, a repeat investigation may 
be considered, provided that the resulting cumulative radiation exposure by (S)-(-)-[18F]fluspidine for all PET 
sessions does not exceed the allowed overall study exposure (effective dose not exceeding 20 mSv), when using 


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tracer administered activity of 300±30 MBq per PET session, and further respecting a washout of 7 days of 
pridopidine and its metabolites. PET session 2 will start at 2 hours postdose of pridopidine.
Up to 15 subjects may be evaluated in Part B to characterize the D2R binding of pridopidine. The cohort structure 
will also comprise up to 4 subjects. Each of the 2 PET sessions will consist of 4 subsets of acquisition blocks that 
will be acquired in list mode: 0 to 90 minutes, 120 to 150 minutes, 180 to 210 minutes, and 360 to 390 minutes
post-injection of 200±20 MBq [18F]fallypride. Each PET acquisition block will be acquired in list mode in order to 
allow variable subdivision into multiple time frames, and will be according to the institutional standard as detailed 
further in the imaging manual. PET session 2 will start at approximately 2 hours postdose of pridopidine. The PET 
imaging protocol is essentially the same as for (S)-(-)-[18F]fluspidine. From the second block onwards, acquisition 
can commence within ±10 minutes of the nominal time, but the duration should still be 30 minutes for each of these 
blocks. In an effort to facilitate easier PET procedure for HD patients after the first 90-minute PET acquisition 
block, the subsequent 30-minute PET acquisition blocks are made optional per Investigator’s judgement.
Brain MRI scans will be performed at screening to ensure subjects are qualified for the study but will also provide 
data to aid the analysis of PET data. Additional functional MRI scans (MR-AC, T1 MPRAGE 3D, ASL, 2D MRS, 
and rs-fMRI) will be performed in parallel with the PET imaging sessions to evaluate the relationship between brain 
activity and S1R or D2 receptor occupancy by pridopidine.
The dose of pridopidine in Part B will be determined based on the results obtained using (S)-(-)-[18F]fluspidine in
Part A. The timing of the [18F]fallypride PET scan may also be revised. If any of the postdose PET investigations are 
compromised due to technical or logistic reasons, a repeat investigation may be considered, provided that the 
resulting cumulative [18F]fallypride dose for all PET sessions does not exceed the authorized overall study exposure 
(effective dose not exceeding 20 mSv), when using tracer administered activity of 200±20 MBq per PET session, 
and further respecting a washout of 7 days of pridopidine and its metabolites.
Blood samples for determination of pridopidine and TV-45065 plasma concentrations and exploratory biomarkers 
will be collected during the timing of the PET examinations in visit 3.
Safety and tolerability (the number [%]) of healthy subjects and HD patients who failed to complete the study due to 
adverse events) will be assessed throughout the study by monitoring adverse events and by conducting clinical 
safety laboratory tests, ECG, physical examination, and vital sign assessments.
Method of Randomization and Blinding: This is a non-randomized, open-label study and there is no blinding.
Study Drug Dose, Mode of Administration, and Administration Rate:
Investigational Product:
In this study, pridopidine can be administered as 0.5 or 1 mg in healthy subjects (Part A only); 2.5, 5, 10, 22.5, 45,
67.5, or 90 mg in healthy subjects and HD patients; and a higher dose of 112.5 mg may also be administered to HD 
patients. The applicable dose will be given selecting the lowest possible number of capsules. Pridopidine will be 
administered orally with 240 mL of water.
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.
If lower pridopidine doses will be required, it will be prepared on site as follows:

0.5 and 1 mg – size 2 capsules will be filled with the appropriate amount of blend taken from the drug 
product capsules and diluted with 


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
2.5 mg pridopidine – size 2 capsules will be filled with the appropriate amount of blend taken from the 
drug product capsules

5 and 10 mg pridopidine – size 2 capsules will be filled with the appropriate amount of the active 
ingredient (neat)
Tracers:
The radiolabeled PET tracer [18F]fluspidine for the neuroimaging of S1R receptors with PET will be administered as 
a single intravenous bolus for each PET scan, not exceeding 330 MBq and <50 μg mass.
The radiolabeled PET tracer [18F]fallypride will be administered as a single intravenous bolus for each PET scan, 
not exceeding 220 MBq and <2 μg mass.
Duration of Patient Participation: Total study duration for each subject is expected to not exceed 12 weeks, with 
recruitment and screening lasting up to 8 weeks and the study period for each subject lasting up to 4 weeks.
Inclusion Criteria: Subjects may be included in the study only if they meet all of the following criteria:
Healthy Subjects:
a.
Male subjects between 25 and 55 years (inclusive) of age, with a body mass index (BMI) ≥18.0 to 
≤30 kg/m2 and a body weight of at least 50 kg (inclusive).
b.
In general, good physical and mental health as determined by medical history and psychiatric history, 
suicidality assessment, physical examination, 12-lead ECG, vital signs, and clinical laboratory tests. A 
subject with a clinical abnormality in the laboratory profile or BP can be included only if the 
investigator or his designee considers that the abnormality does not introduce an additional risk factor 
for the subject's health, or interfere with the study objectives.
c.
Men who are potentially fertile (not surgically [eg, vasectomy] or congenitally sterile), whose female 
partners are of childbearing potential, must use contraception for the duration of the study and for 
90 days after discontinuation of study drug (because of the possible effects on spermatogenesis). 
Highly effective methods of contraception are those with a failure rate of less than 1% per year (eg, 
female partner’s use of hormonal contraceptive [oral, implanted, transdermal, injected], female 
partner’s use of an intrauterine device [IUD]), and barrier method with spermicide. In addition, male 
subjects may not donate sperm for the duration of the study and for 90 days after discontinuation of 
study drug.
d.
Are able to understand the requirements of the study; are willing to comply with the requirements of 
the study (eg, imaging procedures, all dietary, exercise, and alcohol restrictions) and provided their 
written informed consent to participate in the study.
e.
Willing to provide a blood sample for genetic analyses (including CYP2D6 status, S1R polymorphs, 
genetic long QT syndrome in subjects who had QT prolongation following study drug administration 
or any other genetic analyses related to pridopidine response) at the screening visit.
Patients with Huntington’s disease:
a.
Diagnosis of HD based on clinical features and the presence of ≥36 cytosine-adenosine-guanine (CAG) 
repeats in the huntingtin gene.
b.
Male age ≥25 years, with an onset of HD after 18 years of age.
c.
Men who are potentially fertile (not surgically [eg, vasectomy] or congenitally sterile), whose female 
partners are of childbearing potential, must use contraception for the duration of the study and for 
90 days after discontinuation of study drug (because of the possible effects on spermatogenesis). 
Highly effective methods of contraception are those with a failure rate of less than 1% per year (eg, 
female partner’s use of hormonal contraceptive [oral, implanted, transdermal, injected], female 


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partner’s use of an IUD), and barrier method with spermicide. In addition, male patients may not 
donate sperm for the duration of the study and for 90 days after discontinuation of study drug.
d.
Body weight ≥50 kg.
e.
A sum of ≥25 points on the UHDRS-TMS at the screening visit.
f.
Able and willing to provide written informed consent prior to any study related procedure being 
performed at the screening visit. Patients with a legal guardian should be consented according to local 
requirements.
g.
Willing to provide a blood sample for genetic analyses (including CAG analysis, CYP2D6 status, S1R 
polymorphs, genetic long QT syndrome in patients who had QT prolongation following study drug 
administration or any other genetic analyses related to pridopidine response or HD) at the screening 
visit.
h.
Willing and able to take oral medication and able to comply with the study specific procedures.
i.
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.
j.
Availability and willingness of a caregiver, informant or family member to accompany the patient to 
the clinic at study visits. The suitability of the caregiver should be judged by the investigator.
k.
For patients taking allowed antipsychotic, antidepressant or other psychotropic medication, the dosing 
of medication must have been kept constant for at least 6 weeks before baseline (visit 2, day -1) and 
must be kept constant during the study.
l.
Are able to understand the requirements of the study; are willing to comply with the requirements of 
the study (eg, imaging procedures, all restrictions) and provided their written informed consent to 
participate in the study.
Exclusion Criteria: Subjects will be excluded from participating in this study if they meet any of the following 
criteria:
Healthy Subjects:
a.
CYP2D6 poor metabolizers
b.
The subject has been previously exposed to ionizing radiation or radioactive substances as a result of 
clinical research or medical treatment in the past 10 years.
c.
The subject has large scale tattoos, in particular involving the head and neck area.
d.
The subject has a counterindication to having an MRI, including (but not limited to): 

The presence of metal implants (excluding metal dental crowns) that could affect MRI imaging 
OR

has worked with ferrous metals either as a vocation or hobby (for example sheet metal worker, 
welder or machinist) in such a way that might have led to unknown indwelling of metal fragments 
that could cause injury if moved in response to the magnetic fields during the MRI imaging.
e.
The subject suffers from claustrophobia or needle phobia.
f.
The subject has a finding on screening MRI that will, in the opinion of the principal investigator (PI)
impair the safety of the subject or the scientific integrity of the study.
g.
The subject has a known coagulation abnormality.
h.
Parts A and 0 only: Individuals who had evidence of only one patent arterial supply to the hand 
(modified Allen test).
i.
Any current or history of heart condition or increased pro-arrhythmic risk, including:

History of cardiovascular disease (eg, coronary artery disease, stroke, arrhythmias, congestive 
heart failure, uncontrolled hypertension, deep vein thrombosis, pulmonary embolism, family 
history of thrombophilia)

History of Long QT Syndrome or a first degree relative with this condition 


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
Family history of sudden death/Brugada syndrome

A prolonged Fridericia-corrected QT (QTcF) interval (defined as a QTcF interval of >450 msec) 
at the screening or admission (baseline) visit(s). If there is evidence of a prolonged QTcF interval 
from the initial (single) measurement, then the ECG can be repeated twice, and the mean of the 
3 screening measurements will be used to determine whether or not the subject is suitable for 
inclusion in the study.

Any repolarization deficits

Untreated hypokalemia and/or untreated hypomagnesaemia

Unclear syncopes

Any other clinically significant abnormal ECG as judged by the investigator.
j.
Creatinine clearance <90 mL/min at screening, calculated using the Cockcroft-Gault equation. It is 
permitted to repeat the test once, if clinically appropriate.
k.
Hemoglobin value below the lower limit of the reference range and evaluated by the investigator to be 
clinically significant.
l.
Positive serology for human immunodeficiency virus (HIV-1, HIV-2), hepatitis B surface antigen 
(HBsAg), and/or hepatitis C.
m. Presents or has a history of clinically significant diseases of the renal, hepatic, gastrointestinal, 
cardiovascular, musculoskeletal, immunological, endocrine (including diabetes even if controlled by 
diet), metabolic diseases, or other condition known to interfere with the absorption, distribution, 
metabolism or excretion of drugs, as judged by the investigator.
n.
History of alcohol, narcotic, or any other substance dependence in the past 2 years, as defined by the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American Psychiatric 
Association 2013).
o.
History of clinically significant psychiatric diseases, such as major depressive disorder or anxiety, as 
judged by the investigator.
p.
Subjects with adverse events of suicidal ideation or attempt at any time in the past or as measured by 
suicide ideation score of ≥3 on the Columbia-Suicide Severity Rating Scale (C-SSRS, screening 
version), or subjects 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 subjects who, in the opinion of the investigator, present a risk of 
suicide.
q.
Has had one of the following conditions:

major trauma or surgery in the 2 months before screening or at any time between screening and 
admission

acute/chronic infection within 2 weeks before screening or at any time between screening and 
admission

malignancy within the last 5 years

epilepsy, seizure, convulsions or syncope (including febrile seizures)

history of tuberculosis

BP outside the range of 90 to 139 mmHg (systolic) or 55 to 89 mmHg (diastolic); or pulse rate 
outside the range of 45 to 99 bpm; all measured after 5 minutes rest in seated or supine position. 
Vital signs may be retested twice at intervals of 5 minutes.
r.
Not willing or able to refrain from intensive physical exercise during the study.
s.
Current or history of clinically significant allergy or known hypersensitivity to any ingredients of the 
study medication 


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t.
Planned medical treatments (excluding dental care) during the study period, which may interfere with 
the study.
u.
Use of one of the following prohibited drugs, substances, or foods as follows:

an investigational drug (new chemical entity) within 6 weeks prior to the first day of study drug 
administration or within 5 half-lives (whichever is longer)

any monoamine oxidase inhibitors within 14 days before the first day of study drug administration

any other medications (including over-the-counter medications, vitamins, or herbal or nutritional 
supplements) within 7 days before the first day of study drug administration (except 
paracetamol/acetaminophen or ibuprofen used occasionally, up to 24 hours before the first day of 
study drug administration)

drugs known to significantly inhibit CYP2D6 enzyme drug metabolism within 21 days prior to the 
first day of study drug administration or within 5 half-lives (whichever is longer) before the first 
day of study drug administration, or drugs known to significantly induce CYP enzyme drug 
metabolism within 28 days before the first day of study drug administration

drugs known to cause significant QT-prolongation such as anti-arrhythmic drugs or 
antidepressants within 28 days before the first day of study drug administration

daily consumption of more than 6 units of caffeine and/or xanthine-containing products, within 
2 weeks before the first dose of study drug, or not able to refrain from consumption of more than 
2 units of caffeine-containing foods or drinks from 48 hours prior to admission visit and discharge. 
One caffeine unit is contained in the following items: 1 cup of coffee, 2 cans of cola, 1 cup of tea, 
½ cup of energy drink (eg, Red Bull) or 3 chocolate bars. Subject should be able to abstain from 
caffeine intake for 20 hours during any day.

cigarette smoking (defined as >5 cigarettes per week) or use of other nicotine-containing products 
(eg, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers). Ex-smokers should 
have ceased smoking at least 6 months before screening.

any food or drink/beverage containing alcohol, grapefruit or grapefruit juice, apple or orange juice, 
vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, 
brussel sprouts, mustard), and charbroiled meats within 7 days before the first day of study drug 
administration until after the last day of pharmacokinetic sampling.

a positive urine drug test or a positive alcohol breath analyzer test at admission visits, or not 
willing or able to refrain from illicit drugs during the study.
v.
Donation or reception of any blood products (eg, plasma, platelets, etc) in the 1 month before the first 
day of study drug administration, or has made more than 2 donations within the 12 months preceding 
the first day of study drug administration, or plans to donate during the study or during the 1 months 
after the last study visit.
w.
The subjects cannot participate or successfully complete the study, in the opinion of the investigator, 
for any of the following reasons:

The subject is mentally or legally incapacitated, or unable to give consent for any reason.

The subject is in custody due to an administrative or a legal decision, or under tutelage, or being 
admitted to a sanitarium or social institution.

The subject is unable to be contacted in case of emergency.

The subject is an employee of the site or a relative of an employee at the site.

Any other reason, at the discretion of the investigator.
Patients with Huntington’s disease:
a.
CYP2D6 poor metabolizers


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b.
The patient has been previously exposed to ionizing radiation or radioactive substances as a result of 
clinical research or medical treatment in the past 10 years.
c.
The patient has large scale tattoos, in particular involving the head and neck area.
d.
The patient has a counterindication to having an MRI, including (but not limited to): 

The presence of metal implants (excluding metal dental crowns) that could affect MRI imaging 
OR

has worked with ferrous metals either as a vocation or hobby (for example sheet metal worker, 
welder or machinist) in such a way that might have led to unknown indwelling of metal fragments 
that could cause injury if moved in response to the magnetic fields during the MRI imaging.
e.
The patient suffers from claustrophobia or needle phobia.
f.
The patient has a finding on screening MRI that will, in the opinion of the PI impair the safety of the 
subject or the scientific integrity of the study.
g.
The patient has a severe motor impairment that might cause artifacts.
h.
The patient has a known coagulation abnormality.
i.
Parts A and 0 only: Individuals who had evidence of only one patent arterial supply to the hand 
(modified Allen test).
j.
A prolonged QTcF interval (defined as a QTcF interval of >450 msec) at the screening visit. If there is 
evidence of a prolonged QTcF interval at screening from the initial (single) measurement, then the 
ECG will be repeated twice, and the mean of the 3 screening measurements will be used to determine 
whether or not the patient is suitable for inclusion in the study.
k.
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 first 
admission, 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,  (iv) history of deep vein thrombosis or pulmonary embolism, and/or (v) family history 
of thrombophilia.
l.
Patients with a known history of Long QT Syndrome or a first degree relative with this condition.
m. Patients with a history of epilepsy or of seizures within the last 5 years.
n.
Have other serious medical illnesses (including but not limited to uncontrolled hypertension, 
respiratory disease including severe form of asthma, hepatic disease, renal disease, AIDS, unstable 
psychiatric or other neurologic disorder, endocrine [including controlled diabetes], gastrointestinal, and 
metabolic diseases) which in the opinion of the investigator may put the patient at risk when 
participating in the study or may influence the results of the study or affect the patient's ability to take 
part in the study.
o.
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.
p.
Patients receiving medications (within the last 6 weeks prior to baseline [visit 2, day -1]) 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.


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q.
Patients receiving medications (within the last 6 weeks prior to baseline [visit 2, day -1]) that are 
metabolized by CYP2D6 and have the potential of reducing seizure threshold.
r.
Creatinine clearance <60 mL/min at screening, calculated using the Cockcroft-Gault equation: (140 -
age) × mass (kg) / 72 × serum creatinine (mg/dL).It is allowed to repeat the test once, if clinically 
appropriate. 
s.
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 enters the 
study.
t.
Alcohol and/or drug abuse within the 6 months prior to screening, as defined by the DSM-5 (American 
Psychiatric Association 2013).
u.
Patients with adverse events of suicidal ideation or attempt at any time in the past or as measured by 
suicide ideation score of ≥3 on the C-SSRS (screening version), 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.
v.
Patients with known intracranial neoplasms, vascular malformations, history of cerebrovascular 
accident, or intracranial hemorrhage.
w.
Current or history of clinically significant allergy or known hypersensitivity to any ingredients of the 
study medication 
x.
Treatment with tetrabenazine within 6 weeks of study baseline (visit 2, day -1).
y.
Treatment with any investigational product within 6 weeks prior to the first day of study drug 
administration or within 5 half-lives (whichever is longer) or patients planning to participate in another 
clinical study assessing any investigational product during the study.
z.
Use of one of the following prohibited substances, or foods as follows:

any food or drink/beverage containing alcohol, grapefruit or grapefruit juice, apple or orange juice, 
vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, 
brussel sprouts, mustard), and charbroiled meats within 7 days before the first day of study drug 
administration until after the last day of pharmacokinetic sampling.

a positive urine drug test or positive alcohol breath analyzer test at admission visits, or not willing 
or able to refrain from illicit drugs during the study.
aa. Positive serology for HIV-1, HIV 2, HBsAg, and/or hepatitis C.
Measures and Time Points:
Pharmacodynamic Measure and Time Point: 

PET acquisition up to 390 minutes after injection of the tracer.
Safety Measures and Time Points:

inquiries about adverse events at every visit

clinical laboratory (serum chemistry, hematology, and urinalysis) tests on day -1 at visits 2 and 3 and 
at the follow up (visit 4)

vital signs (BP, respiratory rate, body temperature, and pulse) measured at every visit

an ECG recorded at every visit

physical examinations on day -1 at visits 2 and 3 and at the follow up (visit 4)

inquiries about use of concomitant medication at every visit
Pharmacokinetic Measures and Time Points:

Collection of blood samples up to 24 hours postdose for calculation of pharmacokinetic parameters for 
pridopidine and its metabolite TV-45065 in plasma


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Exploratory Measures and Time Points:

Endogenous corticoid plasma levels, taken directly prior to tracer dosing

MR-AC, T1 MPRAGE 3D, ASL, MRS, and rs-fMRI scans in parallel with the PET imaging

Blood exploratory biomarkers including prolactin, BDNF, monoamines and histamine metabolites up 
to 24 hours after dosing

A pharmacogenetic blood sample will be collected at screening for genetic analyses of the CYP2D6 
metabolizer status and S1R polymorphs
Allowed and Prohibited Medications before and during the Study: For healthy subjects, other than study drug, 
no drug is allowed during the study, except for the occasional use of paracetamol/acetaminophen or ibuprofen. 
Prohibited medication restrictions will be applied to any HD patients that participate in the study.
Statistical Considerations:
Sample Size Rationale: This PET study is exploratory in nature; therefore, no formal hypothesis testing is planned. 
Thus, based on clinical and practical considerations, a sample size of up to approximately 38 subjects (up to 
4 subjects per dose level) is considered adequate for this type of study and to attain the study objectives. Up to 
45 subjects are planned to be enrolled in this study to ensure up to 38 evaluable subjects. Adaptive study design will 
allow increasing or reducing the study total sample size or each dose/time cohort as necessary. This sample size may 
include up to 4 patients with HD, which may be added to study engagement of pridopidine to the D2R and to 
explore the effects of neurodegeneration. It is anticipated that 3 dose levels will be sufficient to characterize the 
exposure-response profile. However, additional cohorts may be studied.
Pharmacodynamic Analysis: 
Appropriate analysis will be performed to estimate the S1R binding potential and RO. Available evidence suggests 
that there is no viable reference region in the brain for (S)-(-)-[18F]fluspidine that can be used for modeling purpose. 
Therefore, metabolite-corrected arterial plasma input function will be estimated and used in the calculation of 
regional PET volume of distribution (VT), regional binding potential (BPND) and RO defined as the 
treatment-induced relative change in the concentration in the available receptor density as:
%
100
)
(
)
(
1








baseline
BP
treatment
BP
RO
ND
ND
Where BPND(treatment) is the binding potential under the treatment condition and BPND(baseline) the binding 
potential at baseline. The BPND is a parameter proportional to the density of the available receptors and the affinity 
of the tracer to the receptor.
Due to the fact that a reference region most likely does not exist the following procedure is likely be used to derive 
the relevant PET parameters:

VT, representing the total radioligand in tissue (ie, free, non-displaceable and specifically bound) 
and a global non-displaceable volume of distribution (VND) will be calculated for each brain region 
and for each postdose scan using appropriate compartmental models.

VT and VND will allow the estimation of BPND, and the global occupancy. 
RO expressed as a percentage will be calculated for each subject and each postdose scan. Spatial normalization of 
the PET scan to a brain atlas template will be performed using a corresponding MRI scan. All PET parameters will 
be calculated globally, for the whole brain, and for specific predefined brain areas.
The occupancy data for the study will be combined with the plasma concentration of pridopidine and used to derive 
the in vivo affinity of pridopidine for the S1R and the time-course of the occupancy of S1R by pridopidine.


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Test-retest variability of (S)-(-)-[18F]fluspidine uptake will be estimated using 2 baseline (S)-(-)-[18F]fluspidine scans 
in up to 6 subjects. This will be used to calculate the uncertainty of the RO estimate.
The analysis using [18F]fallypride will be similar to that using (S)-(-)-[18F]fluspidine. 
For calculation of BPND and RO for [18F]fallypride a tissue reference model can be used using the cerebellum as 
reference region without specific binding. 
Pharmacokinetic Analysis: Pharmacokinetic parameters will be calculated for pridopidine and its metabolite 
TV-45065 in the plasma using non compartmental methods, when possible. No formal statistical analyses of the 
pharmacokinetic data will be performed. All data will be listed and summarized descriptively by cohort (dose) and 
status (healthy subject or HD patient) and presented in tabular and graphical form where appropriate.
Pharmacokinetic/Pharmacodynamic Analysis:
The relationship between the pridopidine plasma concentrations and the RO will be explored graphically. If 
possible, an exposure-response model will be developed to quantitatively define the relationship between RO and 
pridopidine exposure. It will be based on the following Emax model (equation) to fit the pharmacokinetic-
pharmacodynamic (PK/PD) data.
C
EC
C
E
E



50
max
Where E represents the receptor occupancy (%); C is the plasma concentration (ng/mL) corresponding to the 
receptor occupancy E; Emax is an asymptote representing the maximum receptor occupancy (%); EC50 is the plasma 
concentration (ng/mL) corresponding to 50% of Emax.
Two additional parameters derived to characterize various levels of receptor occupancy are: 
o
EC80 - the plasma concentration (ng/mL) corresponding to 80% of Emax. It is calculated directly from the 
equation by substituting E=80% of Emax and then solving for C. 
o
ECopt - plasma concentration (ng/mL) corresponding to optimal receptor occupancy. ECopt was defined as 
the lowest observed plasma concentration that achieved the model estimated Emax.
Safety Analyses:
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Each subject 
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 adverse events (overall and by severity), adverse events determined by the 
investigator to be related to study treatment (ie, reasonable possibility) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing withdrawal from the 
study. Summaries will be presented by treatment group and for all subjects. Subject listings of serious adverse 
events 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 predefined criteria to identify potentially clinically significant values or changes, 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 subject is treated with study drug.
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will 
be provided for actual values and changes from baseline to each time point. For categorical variables, subject counts 
and percentages will be provided. Descriptive summaries of serious adverse events, subject withdrawals due to 


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adverse events, and potentially clinically significant abnormal values (clinical laboratory or vital signs) based on 
predefined criteria will be provided as well.
If any subject dies during the study, a listing of deaths will be provided and all relevant information will be 
discussed in the subject narrative included in the clinical study report.
Tolerability Variables and Analysis:
Subject tolerability assessments (the number [%] of subjects who fail to complete the study, number [%] of subjects 
who fail to complete the study due to adverse events, and the number of subjects who experience 
treatment-emergent adverse events) will be summarized.
Pharmacogenetic and Biomarker Analysis:
Levels in exploratory biomarkers will be compared to baseline and summary tables may be generated. Exploratory
biomarker results will be generated at a future point and handled in a separate addendum report.


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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 ...............................................7
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................30
1.
BACKGROUND INFORMATION...........................................................................34
1.1.
Introduction.................................................................................................................34
1.1.1.
Huntington’s Disease..................................................................................................34
1.1.2.
Pridopidine..................................................................................................................34
1.2.
Name and Description of Investigational Product......................................................35
1.3.
Findings from Nonclinical and Clinical Studies.........................................................35
1.3.1.
Nonclinical Studies.....................................................................................................35
1.3.2.
Clinical Studies...........................................................................................................35
1.3.2.1.
Clinical Pharmacology Studies...................................................................................36
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................38
1.4.
Known and Potential Benefits and Risks to Subjects.................................................39
1.4.1.
Known and Potential Benefits and Risks of Pridopidine............................................39
1.4.1.1.
Benefits of Pridopidine...............................................................................................39
1.4.1.2.
Risks of Pridopidine ...................................................................................................39
1.4.2.
Known and Potential Benefits and Risks of [18F]fluspidine.......................................41
1.4.2.1.
Benefits of [18F]fluspidine..........................................................................................41
1.4.2.2.
Risks of [18F]fluspidine...............................................................................................41
1.4.3.
Known and Potential Benefits and Risks of [18F]fallypride .......................................41
1.4.3.1.
Benefits of [18F]fallypride...........................................................................................41
1.4.3.2.
Risks of [18F]fallypride...............................................................................................41
1.4.4.
Overall Benefit and Risk Assessment for This Study ................................................42
1.5.
Selection of Drugs and Doses.....................................................................................42
1.5.1.
Justification for Dose of Active Drug.........................................................................42
1.5.2.
Justification for Use of [18F]fluspidine.......................................................................43


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1.5.3.
Justification for Use of [18F]fallypride .......................................................................43
1.6.
Compliance Statement................................................................................................43
1.7.
Study Population and Justification .............................................................................43
1.8.
Location and Study Duration......................................................................................44
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................45
2.1.
Purpose of the Study...................................................................................................45
2.2.
Study Objectives.........................................................................................................45
2.2.1.
Primary Objective.......................................................................................................45
2.2.2.
Secondary Objectives .................................................................................................45
2.2.3.
Exploratory Objectives ...............................................................................................45
2.3.
Study Endpoints..........................................................................................................46
2.3.1.
Pharmacodynamic Endpoints .....................................................................................46
2.3.2.
Pharmacokinetic Endpoints ........................................................................................46
2.3.3.
Safety and Tolerability Endpoints ..............................................................................46
2.3.4.
Biomarker Endpoints..................................................................................................47
2.3.5.
Pharmacogenetic Endpoints........................................................................................47
3.
STUDY DESIGN .......................................................................................................48
3.1.
General Design and Study Schematic Diagram..........................................................48
3.2.
Justification for Study Design ....................................................................................53
3.3.
Pharmacodynamic Measures and Time Points...........................................................53
3.4.
Safety Measures and Time Points...............................................................................53
3.5.
Pharmacokinetic Measures and Time Points..............................................................53
3.6.
Exploratory Measures and Time Points......................................................................53
3.7.
Randomization and Blinding......................................................................................54
3.8.
Maintenance of Randomization and Blinding............................................................54
3.8.1.
Maintenance of Randomization..................................................................................54
3.8.2.
Blinding/Unblinding...................................................................................................54
3.8.3.
Data Monitoring Committee.......................................................................................54
3.9.
Drugs Used in the Study.............................................................................................54
3.9.1.
Investigational Product - Pridopidine.........................................................................54
3.9.2.
PET Tracers ................................................................................................................55
3.9.2.1.
[18F]fluspidine.............................................................................................................55
3.9.2.2.
[18F]fallypride .............................................................................................................55


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3.10.
Drug Supply and Accountability ................................................................................55
3.10.1.
Drug Storage and Security..........................................................................................55
3.10.2.
Drug Accountability ...................................................................................................56
3.11.
Duration of Subject Participation and Justification....................................................56
3.12.
Stopping Rules and Discontinuation Criteria .............................................................56
3.13.
Source Data Recorded on the Case Report Form .......................................................56
3.14.
Study Procedures and Assessments............................................................................57
3.14.1.
Procedures for Screening and Enrollment (Visit 1)....................................................61
3.14.2.
Visit 2 (PET Session 1)...............................................................................................62
3.14.2.1.
Visit 2, Day -1.............................................................................................................62
3.14.2.2.
Visit 2, Day 1..............................................................................................................62
3.14.3.
Visit 3 (PET Session 2)...............................................................................................63
3.14.3.1.
Visit 3, Day -1.............................................................................................................63
3.14.3.2.
Visit 3, Day 1..............................................................................................................63
3.14.3.3.
Visit 3, Day 2..............................................................................................................64
3.14.4.
Procedures After Study Drug Treatment (Visit 4)......................................................64
3.14.5.
Unscheduled Visits .....................................................................................................64
4.
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................66
4.1.
Subject Inclusion Criteria ...........................................................................................66
4.2.
Subject Exclusion Criteria..........................................................................................67
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................73
4.4.
Withdrawal Criteria and Procedures...........................................................................74
5.
TREATMENT OF SUBJECTS..................................................................................75
5.1.
Drugs Administered During the Study .......................................................................75
5.1.1.
Pridopidine..................................................................................................................75
5.1.2.
[18F]fluspidine.............................................................................................................75
5.1.3.
[18F]fallypride .............................................................................................................75
5.2.
Restrictions .................................................................................................................76
5.3.
Prior and Concomitant Medication or Treatment.......................................................77
5.3.1.
Prohibited Medication for HD Patients ......................................................................78
5.3.1.1.
Antipsychotic Medication...........................................................................................78
5.3.1.2.
Antidepressant Medication.........................................................................................78
5.3.1.3.
Antiarrhythmic Medication ........................................................................................78


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5.3.1.4.
Medications Lowering Seizure Thresholds ................................................................78
5.3.1.5.
Medications Interfering with Blood Coagulation.......................................................78
5.3.1.6.
Other Prohibited Medications.....................................................................................79
5.4.
Procedures for Monitoring Subject Compliance ........................................................79
5.5.
Total Blood Volume ...................................................................................................79
6.
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................81
6.1.
Pharmacokinetic Assessment......................................................................................81
6.1.1.
Specimen Sampling and Handling..............................................................................81
6.1.2.
Shipment and Analysis of Samples ............................................................................82
6.2.
Pharmacodynamic Assessment...................................................................................82
6.2.1.
Determination of [18F]fluspidine and [18F]Fallypride Functions................................82
6.2.1.1.
[18F]fluspidine (Part 0 and Part A)..............................................................................83
6.2.1.2.
[18F]fallypride (Part B) ...............................................................................................84
7.
ASSESSMENT OF SAFETY.....................................................................................85
7.1.
Adverse Events ...........................................................................................................85
7.1.1.
Definition of an Adverse Event..................................................................................85
7.1.2.
Recording and Reporting of Adverse Events .............................................................86
7.1.3.
Severity of an Adverse Event .....................................................................................86
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................87
7.1.5.
Serious Adverse Events..............................................................................................87
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................87
7.1.5.2.
Expectedness...............................................................................................................88
7.1.5.3.
Reporting a Serious Adverse Event............................................................................88
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................90
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................90
7.1.8.
Overdose of Study Drug .............................................................................................91
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................91
7.2.
Pregnancy ...................................................................................................................91
7.3.
Medication Error and Special Situations....................................................................91
7.4.
Clinical Laboratory Tests ...........................................................................................92
7.4.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................92
7.4.2.
Other Clinical Laboratory Tests .................................................................................93


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7.4.2.1.
Urine Drug Screen ......................................................................................................93
7.4.2.2.
Corticoid Plasma Levels.............................................................................................94
7.5.
Vital Signs ..................................................................................................................94
7.6.
Electrocardiography....................................................................................................94
7.7.
Physical Examinations................................................................................................94
7.8.
Concomitant Medication or Treatment.......................................................................95
7.9.
Assessment of Local Tolerability and Pain ................................................................95
7.10.
Modified Allen Test....................................................................................................95
7.11.
Columbia Suicide Severity Rating Scale....................................................................95
7.12.
Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-
TMS) (HD Patients Only)...........................................................................................96
7.13.
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data.............................................................................................................................96
8.
ASSESSMENT OF BIOMARKERS AND PHARMACOGENETICS.....................97
8.1.
Assessment of Exploratory Biomarkers .....................................................................97
8.1.1.
Biomarker Assessments..............................................................................................97
8.1.2.
Pharmacogenetic Assessment.....................................................................................97
8.1.3.
Specimen Sampling and Handling..............................................................................98
8.1.3.1.
Biomarker Samples.....................................................................................................98
8.1.3.2.
Pharmacogenetic Samples ..........................................................................................99
8.1.4.
Shipment and Analysis of Samples ............................................................................99
8.1.4.1.
Biomarker Samples.....................................................................................................99
8.1.4.2.
Pharmacogenetic Samples ..........................................................................................99
9.
STATISTICS ............................................................................................................100
9.1.
Sample Size and Power Considerations ...................................................................100
9.2.
Analysis Sets.............................................................................................................100
9.2.1.
Enrolled Analysis Set ...............................................................................................100
9.2.2.
Safety Analysis Set...................................................................................................100
9.2.3.
Pharmacokinetic Analysis Set ..................................................................................100
9.2.4.
Pharmacodynamic Analysis Set ...............................................................................100
9.3.
Data Handling Conventions......................................................................................101
9.3.1.
Handling Withdrawals and Missing Data.................................................................101
9.4.
Study Population.......................................................................................................101


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9.4.1.
Subject Disposition...................................................................................................101
9.4.2.
Demographic and Baseline Characteristics ..............................................................101
9.5.
Pharmacodynamic Analysis......................................................................................101
9.5.1.
Analysis with (S)-(-)-[18F]fluspidine........................................................................101
9.5.2.
Analysis Using [18F]fallypride..................................................................................101
9.6.
Pharmacokinetic Analysis ........................................................................................102
9.7.
Pharmacokinetic/Pharmacodynamic Analysis..........................................................102
9.8.
Planned Method of Analysis.....................................................................................102
9.9.
Multiple Comparisons and Multiplicity....................................................................102
9.10.
Safety Endpoints and Analysis .................................................................................103
9.10.1.
Safety Endpoints.......................................................................................................103
9.10.2.
Safety Analysis .........................................................................................................103
9.11.
Tolerability Variables and Analysis .........................................................................103
9.12.
Pharmacogenetic and Biomarker Analysis...............................................................103
9.13.
Relationship Between Unified Huntington’s Disease Rating Scale Total 
Motor Score (UHDRS-TMS) and Other Endpoints .................................................104
9.14.
Planned Interim Analysis..........................................................................................104
9.15.
Reporting Deviations from the Statistical Plan ........................................................104
10.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS.............................105
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................106
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................106
11.1.1.
Protocol Amendments ..............................................................................................106
11.1.2.
Protocol Violations...................................................................................................106
11.2.
Information to Study Personnel................................................................................106
11.3.
Study Monitoring......................................................................................................107
11.4.
Clinical Product Complaints.....................................................................................107
11.4.1.
Product Complaint Information Needed from the Investigational Center................108
11.4.2.
Handling of Study Drug at the Investigational Center .............................................108
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................109
11.4.4.
Documenting a Product Complaint ..........................................................................109
11.5.
Audit and Inspection.................................................................................................109
12.
ETHICS ....................................................................................................................110


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12.1.
Informed Consent .....................................................................................................110
12.2.
Competent Authorities and Independent Ethics Committees/Institutional 
Review Boards..........................................................................................................110
12.3.
Confidentiality Regarding Study Subjects................................................................110
12.4.
Declaration of the End of Clinical Study..................................................................111
12.5.
Registration of the Clinical Study.............................................................................111
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING .................................................................................................................112
13.1.
Data Collection.........................................................................................................112
13.2.
Data Quality Control.................................................................................................112
13.3.
Archiving of Case Report Forms and Source Documents........................................113
13.3.1.
Sponsor Responsibilities...........................................................................................113
13.3.2.
Investigator Responsibilities.....................................................................................113
14.
FINANCING AND INSURANCE...........................................................................115
15.
REPORTING AND PUBLICATION OF RESULTS..............................................116
16.
REFERENCES .........................................................................................................117
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................120
17.1.
Summary of changes Amendment 02 Dated 06 October 2017 ................................120
17.2.
Summary of changes Amendment 01.......................................................................129


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................58
Table 2:
Blood Volumes (Part 0 and Part A)............................................................................79
Table 3:
Blood Volumes (Part A [Dose Cohorts 0.5 and 1 mg Only]).....................................80
Table 4:
Blood Volumes (Part B) .............................................................................................80
Table 5:
Clinical Laboratory Tests ...........................................................................................93


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................51


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table of Abbreviations
Abbreviation
Term
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASL
arterial spin labeling
AST
aspartate aminotransferase
AUC
area under the drug concentration by time curve
AUC0–24
area under the concentration time curve from time 0 to 24 hours
AUC0–∞
area under the concentration time curve from time 0 to infinity
AUC0–t
area under the concentration time curve from time 0 to time of last measurable concentration
BCRP
breast cancer resistance protein
BDNF
brain-derived neurotrophic factor
bid
twice daily
BMI
body mass index 
BP
blood pressure
BPND
regional binding potential
BUN
blood urea nitrogen
CAG
cytosine-adenosine-guanine
Caverage
average plasma concentration
CDMS
clinical data management system 
CFR
Code of Federal Regulations (US)
Cmax
maximum observed concentration
CNS
central nervous system
CPK
creatine phosphokinase
CPP
clinical project physician
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450 
D2R
dopamine-2 receptor
DHEA
dehydroepiandrosterone
DNA
deoxyribonucleic acid


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Abbreviation
Term
DSM–5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSMB
Data and Safety Monitoring Board
EC50
plasma concentration corresponding to 50% of Emax
EC80
plasma concentration corresponding to 80% of Emax
ECG
electrocardiography, electrocardiogram
ECopt
plasma concentration corresponding to optimal receptor occupancy
EDTA
ethylenediaminetetraacetic acid
EM
extensive metabolizer
Emax
an asymptote representing the maximum receptor occupancy
ET
early termination
EU
European Union
FDA
Food and Drug Administration (US)
FU
Follow up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
GMP
good manufacturing practice
HART
Huntington’s disease ACR16 Randomized Trial
HBsAg
hepatitis B surface antigen
HD
Huntington’s disease
HDL
high density lipoprotein
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medical product
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
intrauterine device
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LLOQ
lower limits of quantification
LSO
local safety officer 
MAD
multiple ascending dose


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Abbreviation
Term
MATE1
multidrug and toxin extrusion protein 1
MATE2K
multidrug and toxin extrusion protein 2-K
MedDRA
Medical Dictionary for Regulatory Activities 
MermaiHD
Multinational European Multicentre ACR16 study in Huntington’s Disease
mMS
Modified Motor Score
MR-AC
MRI-based Attenuation Correction
MRI
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MTD
maximum tolerated dose
n
number
NDA
New Drug Application
NOAEL
no observed adverse effect level
OAT1
organic anion transporter 1
OAT3
organic anion transporter 3
OATP1B1
organic anion transporting polypeptide 1B1
OATP1B3
organic anion transporting polypeptide 1B3
OCT1
organic cation transporter 1
OCT2
organic cation transporter 2
OTC
over-the-counter
PET 
positron emission tomography
P-gp
P-glycoprotein
PI
principal investigator
pi
post-injection of tracer
PM
poor metabolizer
qd
once daily
QTcF
Fridericia-corrected QT interval
RBC
red blood cell
RNA
ribonucleic acid
RO
receptor binding/occupancy
rs-fMRI
resting state functional magnetic resonance imaging
RSI
reference safety information
S1R
sigma-1 receptor
SD
standard deviation
SOC
system organ class


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Abbreviation
Term
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t½
terminal elimination half-life 
T1 MPRAGE
T1-weighted rapid 3-dimensional gradient-echo technique
tmax
time to reach maximum (peak) concentration
TMS
Total Motor Score
TV-45065
main metabolite of pridopidine
UHDRS
Unified Huntington’s Disease Rating Scale
ULN
upper limit of normal
US(A)
United States (of America)
V
visit
Vd/F
apparent volume of distribution of the drug following extravascular administration
VND
global non-displaceable volume of distribution
VT
PET total volume of distribution
WBC
white blood cell
WHO
World Health Organization
WHO Drug
World Health Organization (WHO) drug dictionary


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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).
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
 
 
 
 
In vitro binding studies show low affinity of pridopidine for the dopamine D2 receptor (D2R) 
with half maximal inhibitory concentration (IC50) of about 10 µM
 
 
 
 In addition to pridopidine's 
activity on the dopamine D2 receptor, it was found to have high affinity towards the sigma-1 
receptor (S1R) (Sahlholm et al 2013), with IC50 of about 100 nM (100 fold higher compared to 
the D2R). The S1R is a transmembrane protein located endoplasmic reticulum/mitochondria 


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associated membrane (Ishikawa and Hashimoto 2010) and has been implicated as potential 
treatment in neurodegenerative and neuropsychiatric diseases (Hayashi and Su 2004; Luedtke et 
al 2012). The contribution of the S1R to the mechanism of action of pridopidine and the effect on 
HD progression is currently under evaluation. Further information on the mechanism of action of 
pridopidine is provided in the current Investigator’s Brochure (IB).
The expression levels and distribution of S1R is altered in neurodegenerative diseases (Mishina 
et al 2008; Ruscher and Wieloch 2014). Quantifying the receptor binding/occupancy (RO) by 
pridopidine will provide information regarding the potential to use pridopidine in the treatment 
of neurodegenerative diseases. 
The binding of [18F]fluspidine to the S1R has been demonstrated in vitro and in pigs and human 
study is ongoing at 
. 
(S)-(-)-[18F]fluspidine demonstrates a more favorable metabolic profile compared to its 
R-enantiomer, and its binding to the S1R is reversible, whereas binding of the R-enantiomer is 
irreversible (Fischer et al 2011).
Binding of pridopidine to the D2 receptor may also be explored using [18F]fallypride. 
Pridopidine binds to the D2 receptor with affinity of 10 µM. Recent data suggest a role of this 
receptor in neurodegenerative diseases (Robertson et al 2015).
1.2.
Name and Description of Investigational Product
The investigational product is pridopidine (TV-7820) capsules, and the active ingredient is 
4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride.
Pridopidine will be provided as hard gelatin capsules. A more detailed description of the product 
is given in Section 3.9.
1.3.
Findings from Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
Brief summaries of clinical studies are provided in the following sections. More detailed 
information, as well as nonclinical pharmacology, pharmacokinetics, and toxicology summaries,
are provided in the current IB.
1.3.2.
Clinical Studies
 
 
 
 
 
 
 
 
 


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(TV7820-CNS-20002, PRIDE-HD; completed as of July 2016).. The study TV7820-CNS-20016
(Open PRIDE-HD) is a multi-center, open-label extension of the PRIDE-HD study, evaluating 
the safety, tolerability and efficacy of pridopidine in patients with HD. As of 11 February 2016, 
89 patients were randomized in this study. 
 
 
1.3.2.1.
Clinical Pharmacology Studies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Further details may be found in the current IB. 
1.3.2.1.1. Pridopidine Maximal Tolerated Dose
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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) 
study (ACR16C008) investigated the efficacy and safety of 45 mg given qd and bid over 
26 weeks of treatment in 437 patients.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Further details may be found in the current IB.
1.4.
Known and Potential Benefits and Risks to Subjects
1.4.1.
Known and Potential Benefits and Risks of Pridopidine
1.4.1.1.
Benefits of Pridopidine
This study involves healthy subjects (with optional HD patients), and so pridopidine is not 
expected to provide any benefits to participants in the study.
1.4.1.2.
Risks of Pridopidine
The following are general risks considered to be associated with pridopidine administration:

 
 
 
 
 
 


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Additional information regarding benefits and risks to subjects may be found in the current IB.
1.4.1.2.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies have been performed with pridopidine.
The genotoxicity of pridopidine has been evaluated in vitro and in vivo.
 
 
 
 
 
1.4.1.2.2. 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.
1.4.1.2.3. Suicidal Ideation and Suicidal Attempts
 
 
 
 
 


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1.4.2.
Known and Potential Benefits and Risks of [18F]fluspidine
1.4.2.1.
Benefits of [18F]fluspidine
[18F]fluspidine has demonstrated potential for the neuroimaging of S1R with positron emission 
tomography (PET). Data from preclinical studies and preliminary data from an ongoing initial 
clinical trial in healthy subjects (Sigma-PET; see
) 
have demonstrated that [18F]fluspidine binds to the S1R in the brain with a high specific uptake 
(Fischer et al 2011; Maisonial et al 2012), making it a suitable PET tracer for use in this study. 
There are no direct benefits to the study subject from exposure to [18F]fluspidine in this trial.
1.4.2.2.
Risks of [18F]fluspidine
The mass dose of [18F]fluspidine proposed for use in this study is not sufficient to elicit a 
pharmacologic response to the agent. To date, no untoward effects have been attributed to 
[18F]fluspidine in the ongoing clinical trial; however, it is possible that there are unknown risks 
with the use of this tracer as it has not been fully characterized at this time. 
When using a tracer administered activity of 300±30 MBq per PET session, the radiation 
exposure due to the cumulative [18F]fluspidine dose for all PET sessions will not exceed 20 mSv
which is the maximum specified by the German Radiation Protection Ordinance 
(Strahlenschutzverordnung §24) for radiation exposure of healthy subjects in medical research. 
The conversion factor for the effective dose to humans is 22.1 µSv/MBq (Sattler et al 2016;
Kranz et al 2016) resulting in an effective dose of 7.3 mSv if the maximum considered activity of 
330 MBq (300+10%) would be administered.
A washout period of 7 days will occur between any necessary repeat PET sessions, if applicable.
1.4.3.
Known and Potential Benefits and Risks of [18F]fallypride
1.4.3.1.
Benefits of [18F]fallypride
[18F]fallypride is a well-characterized high-affinity ligand frequently used in PET studies for the 
quantification of D2 receptors in the brain; it binds to the D2 receptor with a high specific uptake 
(Mukherjee et al 1996; Siessmeier et al 2005), making it a suitable PET tracer for use in this 
study.
There are no direct benefits to the study subject from exposure to [18F]fallypride in this trial.
1.4.3.2.
Risks of [18F]fallypride
The mass dose of [18F]fallypride proposed for use in this study is not sufficient to elicit a 
pharmacologic response to the agent. To date, no untoward effects have been attributed to 
[18F]fallypride during use as a radiolabeled tracer in PET. Therefore, the risk to subjects exposed 
to this agent is expected to be minimal.
When using a tracer administered activity of 200±20 MBq per PET session, the radiation 
exposure due to the cumulative [18F]fallypride dose for all PET sessions will not exceed 20 mSv 
which is the maximum specified by the German Radiation Protection Ordinance 
(Strahlenschutzverordnung §24) for radiation exposure of healthy subjects in medical research. 


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The conversion factor for the effective dose to humans is 21.6 µSv/MBq (Kessler et al 2000) 
resulting in an effective dose of 4.8 mSv if the maximum considered activity of 220 MBq 
(200+10%) would be administered.
A washout period of 7 days will occur between any necessary repeat PET sessions, if applicable.
1.4.4.
Overall Benefit and Risk Assessment for This Study
This study is intended to demonstrate target engagement, RO of pridopidine to S1R in the brain 
of healthy subjects and (optional) HD patients. 
Single doses of pridopidine will be given to the subjects participating in this study. The starting 
dose of 90 mg/day was selected for this study because it is the highest single dose that has been 
given to healthy subjects and is also inclusive of the dose in the ongoing Phase 2 
TV7820-CNS-20002 (PRIDE-HD) study in patients with HD. Also, the administration of the 
tracers and the exposure to them is expected to be minimal. 
The results of this study will provide further information and support to pridopidine's proposed 
mechanism of action in interacting with the D2 and S1R receptors. 
The radiation risk by the use [18F]fluspidine and [18F]fallypride is in the order of that by other 
well established and approved 18F-labeled radioligands for brain PET imaging 
(Zanotti-Fregonara 2013) and, thus, is justifiable for the intended research purpose.
Based on experience to date with single doses, the highest dose levels selected for this study 
(90 mg for subjects and 112.5 mg for HD patients) are considered to be safe and well tolerated. 
It is therefore the sponsor's belief that the overall benefit and risk assessment for this study is 
favorable.
1.5.
Selection of Drugs and Doses
A detailed description of study drug administration is presented in Section 5.1.
1.5.1.
Justification for Dose of Active Drug
 
 
 
 
 
 
 
 
 


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1.5.2.
Justification for Use of [18F]fluspidine
[18F]fluspidine has demonstrated a high potential for the neuroimaging of S1R brain receptors 
with PET. Data from preclinical studies and preliminary data from an ongoing initial clinical trial 
in healthy subjects have demonstrated that [18F]fluspidine binds to the brain receptor with a high 
specific uptake (Fischer et al 2011; Maisonial et al 2012), making it a suitable PET tracer for use 
in this study.
1.5.3.
Justification for Use of [18F]fallypride
[18F]fallypride is a well-characterized high-affinity ligand frequently used in PET studies for the 
quantification of D2 receptors in the brain; it binds to the receptor with a high specific uptake 
(Mukherjee et al 1996; Seissmeier et al 2005), making it a suitable PET tracer for use in this 
study.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Council for Harmonisation 
(ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6 and any applicable 
national and local laws and regulations (eg, Title 21 Code of Federal Regulations [21CFR] 
Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament and of the 
Council on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice 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 clinical 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 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the subjects 
during and after the clinical study; and must ensure that trained personnel are immediately 
available in the event of a medical emergency. The investigator and the involved clinical study 
personnel must be familiar with the background 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 (PI) at the investigational center has the overall responsibility for the 
conduct and administration of the clinical study and for contacts with study management, with 
the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with competent 
authorities.
1.7.
Study Population and Justification
This study will recruit healthy non-smoking men between 25 and 55 years of age (inclusive) and 
(optional) men aged ≥25 years with HD. Healthy subjects and HD patients who are poor 
CYP2D6 metabolizers will be excluded from participation in this study.
Healthy subjects are included so that a relatively homogenous population without significant 
medical issues can be studied.


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HD patients, with neuronal degeneration in the brain, may be included to examine if the results 
observed in healthy subjects are replicated in patients.
Only men will be enrolled due to safety concerns with women of childbearing potential being 
exposed to radioactivity and potential effects of corticoid hormones on S1R binding.
1.8.
Location and Study Duration
This study is planned to be conducted in Germany at 1 investigational center.
The study is expected to start in Q1 2017 (first subject admission) and be completed in Q1 2018
(last subject last visit). 


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The purpose of this study is to demonstrate engagement of pridopidine with S1R and D2R 
(optional) in the living human brain and to characterize the exposure-response curve after a 
single dose administration of pridopidine. No formal statistical analysis will be conducted.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objectives of the study are:

To demonstrate target engagement, receptor binding/occupancy (RO) of pridopidine 
to sigma-1 receptors (S1R) in the brain (whole brain, cortical and subcortical regions) 
of healthy subjects and (optional) Huntington’s disease (HD) patients after single oral 
dose administration; 

To establish the relationship between the plasma pridopidine concentrations and the 
S1R occupancy in the brain of healthy subjects and (optional) HD patients following 
a single oral dose of pridopidine. 
2.2.2.
Secondary Objectives
The secondary objectives of this study are:

To establish test-retest variability of (S)-(-)-[18F]fluspidine positron emission 
tomography (PET) imaging of S1R in healthy subjects;

To evaluate the pharmacokinetics of pridopidine following single oral administration 
in healthy subjects and (optional) HD patients;

To assess safety of pridopidine in healthy subjects and (optional) HD patients. 
2.2.3.
Exploratory Objectives
Exploratory objectives are:

To explore a potential impact of endogenous corticoid levels on RO of pridopidine to 
S1R;

To explore target engagement, RO of pridopidine to the dopamine-2 receptors (D2R) 
in the brain of healthy subjects and (optional) HD patients;

To explore the relationship between the plasma pridopidine concentrations and D2R 
occupancy in the brain of healthy subjects and (optional) HD patients following a 
single oral dose of pridopidine;

To establish the relationship between the plasma metabolite TV-45065 concentrations 
and the S1R occupancy in the brain following a single oral dose of pridopidine to 
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
 
 
 
 
 
 
 
 
 
 
 
2.3.
Study Endpoints
2.3.1.
Pharmacodynamic Endpoints
The PET acquisition, as well as advanced magnetic resonance imaging (MRI) protocols 
(MR-AC, T1 MPRAGE 3D, ASL, 2D MRS, and rs-fMRI) will be detailed in dedicated imaging 
manuals. These will also contain an analysis plan for the image data. Imaging manuals will be 
provided prior to initiating the study.
2.3.2.
Pharmacokinetic Endpoints
Blood samples for analysis of pridopidine and the metabolite TV-45065 will be obtained up to 
24 hours after dosing. Pharmacokinetic parameters to be calculated are detailed in Section 6.1.
2.3.3.
Safety and Tolerability Endpoints
The safety and tolerability endpoints are:

occurrence of adverse events during the study

clinical laboratory (serum chemistry, hematology, and urinalysis) test results

vital signs (blood pressure [BP], respiratory rate, body temperature, and pulse) 
measurements at each visit

ECG findings

physical examination findings, including body weight measurements 

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
number (%) of subjects who did not complete the study (end of study)

number (%) of subjects who did not complete the study due to adverse events
2.3.4.
Biomarker Endpoints
Blood samples for biomarker analysis in serum, plasma, and ribonucleic acid (RNA) will be 
collected up to 24 hours after dosing in visit 3. 
2.3.5.
Pharmacogenetic Endpoints
A pharmacogenetic blood sample will be collected at screening for genetic analyses of the 
CYP2D6 metabolizer status and S1R polymorphs.


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3.
STUDY DESIGN
3.1.
General Design and Study Schematic Diagram
This is a Phase 1, single-dose, open-label, adaptive design (S)-(-)-[18F]fluspidine PET study in 
healthy subjects and (optional) in patients with HD designed to demonstrate target engagement 
and to assess the occupancy of the S1R by pridopidine. PET with the tracer 
(S)-(-)-[18F]fluspidine will be used to quantify changes in S1R availability following the 
administration of pridopidine (Part A). Binding of pridopidine to D2R may be assessed using 
PET imaging with [18F]fallypride (Part B, optional). Note that this protocol will refer to all study 
participants (including the HD patients) as ‘subjects’ except for when specifically referring to the 
HD patients.
Since endogenous corticoid hormones have been described to competitively bind to S1R 
(Maurice et al 2006), the test-retest variability of (S)-(-)-[18F]fluspidine PET will be determined 
in up to 6 healthy subjects in parallel (Part 0). To minimize variability associated with the 
potential impact of circadian corticoid plasma level changes, individual scan and re-scan sessions 
will be performed at comparable times of the day for all subjects. 
In addition, plasma corticoid levels (to include dehydroepiandrosterone [DHEA], progesterone, 
testosterone, cortisol, and, where feasible, androstanolone, allopregnanolone, pregnenolone) will 
be assessed immediately before each (S)-(-)-[18F]fluspidine or [18F]fallypride injection in all 
subjects.
Pharmacogenetic samples will be collected at screening for CYP2D6 and exploratory 
genotyping. Biomarker pharmacodynamic samples will be collected at visit 3, prior to dosing
and 4, 8, and 24 hours post pridopidine dose (a 10-minute window will be allowed).
Up to 45 subjects are planned to be enrolled in this study to ensure up to 38 evaluable subjects. 
The study will consist of a screening period of up to 8 weeks prior to first dosing, including a T1 
MPRAGE 3D MRI scan (visit 1), a study period of up to 4 weeks (including visits 2 and 3), and 
a follow-up visit (visit 4). During the study period, the subjects will undergo a baseline PET 
investigation (PET session 1) at visit 2, and subsequently a post-treatment PET investigation 
(PET session 2) following a single oral dose of pridopidine at visit 3. Each dose cohort will 
comprise up to 4 subjects. It is expected that each dose cohort within Part A or Part B will 
receive a different dose of pridopidine; however, subjects within each cohort will be 
administered the same dose (deviation will also be allowed). It is possible that subjects in 
different cohorts within Part A or Part B may receive the same dose of pridopidine if timing of 
the PET imaging is changed or unchanged (eg, cohort with HD patients).
Subjects in Part A and B may receive the same dose of pridopidine for different tracers or 
different populations (healthy volunteers or patients with HD). The maximal dose of pridopidine 
administered will not exceed 90 mg in healthy subjects or 112.5 mg in HD patients (the highest 
dose investigated in the PRIDE-HD study).
Up to 20 subjects may be evaluated in Part A, although it is expected that study objectives may 
be achieved with fewer subjects (more subjects will also be allowed). At the day of each PET 
session, prior to PET imaging, a cubital or forearm vein will be cannulated to inject 


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(S)-(-)-[18F]fluspidine and (at visit 3 only) to obtain venous blood samples for quantification of 
pridopidine and its metabolite TV-45065, and also for other exploratory biomarker analysis. The 
subject’s radial artery on the other arm (or the same arm if this cannot be achieved) will be 
cannulated to obtain arterial blood samples during PET imaging for the quantification of plasma 
radioactivity associated with (S)-(-)-[18F]fluspidine, in order to estimate a metabolite-corrected 
arterial plasma input function for PET data analysis.
The PET imaging will consist of subsets of PET scans that will be acquired in list mode: 4 blocks 
with breaks in between. The first PET acquisition block of 90 minutes duration (0 to 90 minutes) 
will be started together with the intravenous injection of 300±30 MBq (S)-(-)-[18F]fluspidine; the
following acquisition blocks of 30 minutes duration each will be started at 2, 3, and 6 hours 
post-injection of the PET tracer. Each PET acquisition block will be acquired in list mode in 
order to allow variable subdivision into multiple time frames as detailed in the imaging manual.
In an effort to facilitate easier PET procedure for HD patients after the first 90-minute PET 
acquisition block, the subsequent 30-minute PET acquisition blocks are made optional per 
Investigator’s judgement (refer to study Imagine Manual for details).
The first dose of pridopidine will be high (90 mg) for subjects enrolled in the first dose cohort
but may be changed to another dose based on PRIDE-HD study results. Subsequent doses (0.5 or
1 mg in healthy subjects (Part A only); 2.5, 5, 10, 22.5, 45, or 67.5 mg in healthy subjects and 
HD patients; and a high dose of 112.5 mg in HD patients) will be determined on the basis of the 
RO results following PET session 2 and the time-activity profiles of (S)-(-)-[18F]fluspidine from 
previous cohort subjects. In addition, the timing of the PET sessions may also be revised. If any 
of the postdose PET investigations are compromised due to technical or logistic reasons, a repeat 
investigation may be considered, provided that the resulting cumulative radiation exposure by 
(S)-(-)-[18F]fluspidine for all PET sessions does not exceed the allowed overall study exposure 
(effective dose not exceeding 20 mSv), when using tracer administered activity of 300±30 MBq 
per PET session, and further respecting a washout of 7 days of pridopidine and its metabolites. 
PET session 2 will start at 2 hours postdose of pridopidine.
Up to 15 subjects may be evaluated in Part B to characterize the D2R binding of pridopidine. 
The cohort structure will also comprise up to 4 subjects. Each of the 2 PET sessions will consist 
of 4 subsets of acquisition blocks that will be acquired in list mode: 0 to 90 minutes, 120 to 
150 minutes, 180 to 210 minutes, and 360 to 390 minutes post-injection of 200±20 MBq 
[18F]fallypride. Each PET acquisition block will be acquired in list mode in order to allow 
variable subdivision into multiple time frames, and will be according to the institutional standard 
as detailed further in the imaging manual. PET session 2 will start at approximately 2 hours 
postdose of pridopidine. The PET imaging protocol is essentially the same as for 
(S)-(-)-[18F]fluspidine. From the second block onwards, acquisition can commence within 
±10 minutes of the nominal time, but the duration should still be 30 minutes for each of these 
blocks. In an effort to facilitate easier PET procedure for HD patients after the first 90-minute 
PET acquisition block, the subsequent 30-minute PET acquisition blocks are made optional per 
Investigator’s judgement.
Brain MRI scans will be performed at screening to ensure subjects are qualified for the study but 
will also provide data to aid the analysis of PET data. Additional functional MRI scans (MR-AC, 
T1 MPRAGE 3D, ASL, 2D MRS, and rs-fMRI) will be performed in parallel with the PET 


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imaging sessions to evaluate the relationship between brain activity and S1R or D2R occupancy 
by pridopidine. These scans will be further detailed in the imaging manual.
The dose of pridopidine in Part B will be determined based on the results obtained using 
(S)-(-)-[18F]fluspidine in Part A. The timing of the [18F]fallypride PET scan may also be revised. 
If any of the postdose PET investigations are compromised due to technical or logistic reasons, a 
repeat investigation may be considered, provided that the resulting cumulative [18F]fallypride 
dose for all PET sessions does not exceed the authorized overall study exposure (effective dose 
not exceeding 20 mSv), when using tracer administered activity of 200±20 MBq per PET 
session, and further respecting a washout of 7 days of pridopidine and its metabolites.
For the test-retest cohort (Part 0), fluspidine will be administered twice. The 2 tracer doses will 
be administered separately within a certain time frame, without pridopidine. The PET session 2 
will take place at approximately a similar time of day (±1 hour) as the baseline PET session 1, on
another day (at least 24 hours ~10 half-lives 18F apart)
Blood samples for determination of pridopidine and TV-45065 plasma concentrations and 
exploratory biomarkers will be collected during the timing of the PET examinations in visit 3. 
Safety and tolerability (the number [%]) of healthy subjects and HD patients who failed to 
complete the study due to adverse events) will be assessed throughout the study by monitoring 
adverse events and by conducting clinical safety laboratory tests, ECG, physical examination, 
and vital sign assessments.
The assessments and procedures performed during each study visit are detailed in Table 1 and 
Section 3.14.
The study schematic diagram is presented in Figure 1.


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Figure 1:
Overall Study Schematic Diagram 


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Abbreviations: ASL=Arterial Spin Labeling; 2D MRS=2-dimensional multi-voxel magnetic resonance spectroscopy; D2R=dopamine 2 receptor; ET=Early 
Termination; FU=follow up; hrs=hours; min=minutes; MR-AC=MRI-based attenuation correction; PET=positron emission tomography; p.i.=post-injection of 
tracer; rs-fMRI=resting state functional magnetic resonance imaging; S1R=sigma-1 receptor; T1 MPRAGE 3D=T1-weighted rapid 3-dimensional gradient-echo 
technique; TBD=to be determined;


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3.2.
Justification for Study Design
The number of subjects studied per dose group is expected to be sufficient to meet the study 
objectives, which are not based on formal statistical hypothesis. Each dose-group will comprise 
up to 4 subjects (deviations will be allowed). An additional subject will be added if the results 
from 1 out of 3 subjects are discordant. It is anticipated that 3 dose levels will be sufficient to 
characterize the exposure-response profile (deviations will be allowed). However, additional 
cohorts may be studied. A cohort of HD patients may be added to study engagement of 
pridopidine to S1R and 2D receptors and to explore the effects of neurodegeneration in patients 
with HD.
3.3.
Pharmacodynamic Measures and Time Points

PET acquisition up to 390 minutes after injection of the tracer.
3.4.
Safety Measures and Time Points
The following safety and tolerability measures will be implemented during the study:

inquiries about adverse events at every visit

clinical laboratory (serum chemistry, hematology, and urinalysis) tests on day -1 at 
visits 2 and 3 and at the follow-up (visit 4)

vital signs (BP, respiratory rate, body temperature, and pulse) measured at every visit

an ECG recorded at every visit

physical examinations on day -1 at visits 2 and 3 and at the follow-up (visit 4)

inquiries about use of concomitant medication at every visit
A description of the safety measures is provided in Section 7.
3.5.
Pharmacokinetic Measures and Time Points
Blood samples for analysis of pridopidine and the metabolite TV-45065 will be obtained prior to 
pridopidine dosing (<1 hour), at 5 (±1 minute), 15, 30, 45 and 60 minutes after dosing 
(±2 minutes), and at 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours after dosing. A 10-minute window 
will be allowed for all postdose sampling intervals from 1.5 hours up to and including 24 hours 
after dosing.
A description of the pharmacokinetic parameters is provided in Section 6.1.
3.6.
Exploratory Measures and Time Points
The exploratory/other efficacy measures and time points are:

Endogenous corticoid plasma levels, taken directly prior to tracer dosing

MR-AC, T1 MPRAGE 3D, ASL, MRS, and rs-fMRI scans in parallel with the PET 
imaging


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
Blood exploratory biomarkers including prolactin, BDNF, monoamines and histamine 
metabolites up to 24 hours after dosing

A pharmacogenetic blood sample will be collected at screening for genetic analyses 
of the CYP2D6 metabolizer status and S1R polymorphs
3.7.
Randomization and Blinding
This is a non-randomized, open-label study and there is no blinding.
3.8.
Maintenance of Randomization and Blinding
3.8.1.
Maintenance of Randomization
Not applicable.
3.8.2.
Blinding/Unblinding
This is an open-label study with no blinding.
3.8.3.
Data Monitoring Committee
This study will not be overseen by a Data Monitoring Committee.
3.9.
Drugs Used in the Study
3.9.1.
Investigational Product - Pridopidine
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.
If lower pridopidine doses will be required, it will be prepared on site as follows:

0.5 and 1 mg - size 2 capsules will be filled with the appropriate amount of blend 
taken from the drug product capsules and diluted with 
 

2.5 mg pridopidine – size 2 capsules will be filled with the appropriate amount of 
blend taken from the drug product capsules

5 and 10 mg pridopidine – size 2 capsules will be filled with the appropriate amount 
of the active ingredient (neat)
A more detailed description of the preparation of lower doses can be found in the pharmacy 
manual.
A more detailed description of administration procedures is given in Section 5.1.
This is an uncontrolled study with no other study drug.
Additional details may be found also in the current IB for pridopidine.


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3.9.2.
PET Tracers
3.9.2.1.
[18F]fluspidine
The radiolabeled PET tracer [18F]fluspidine for the neuroimaging of S1R receptors with PET will 
be administered as a single intravenous bolus for each PET scan in Part A of the study, not 
exceeding 330 MBq and <50 μg mass. (S)-(-)-[18F]fluspidine will be manufactured according to 
good manufacturing practice (GMP) daily, on an as-needed basis for use in the study, and 
provided as a clear, colorless, particle free solution consisting of 50 to 4000 MBq/mL 
(S)-(-)-[18F]fluspidine, 7.5 mL sterile water for injection, 1.5 mL PEG400, 1 mL ethanol, and 
0.1 mL of a concentrated sodium phosphate solution. The product will be packaged in TC-Elu-5 
multidose containers 
) consisting of a colorless type 1 (Ph. Eur.) glass 
vessel which is sealed with a gray latex sulfur-free chlorbutyl rubber stopper covered with a blue 
aluminum and plastic flip-off seal.
The tracer will be labeled containing information regarding the composition of the product.
A more detailed description of administration procedures is given in Section 5.1.
3.9.2.2.
[18F]fallypride
The radiolabeled PET tracer [18F]fallypride will be administered as a single intravenous bolus for 
each PET scan in Part B of the study, not exceeding 220 MBq and <2 μg mass. 
(S)-(-)-[18F]fallypride will be manufactured according to GMP daily, on an as needed basis, for 
use in the study and provided as a clear, colorless, particle free solution consisting of 50 to 
1000 MBq/mL [18F]fallypride, 9 mL sterile isotonic saline solution for injection, 1 mL ethanol, 
and 0.1 mL of a concentrated sodium phosphate solution. The product will be packaged in 
TC-Elu-5 multi-dose containers 
 consisting of a colorless type 1 
(Ph. Eur.) glass vessel which is sealed with a gray latex sulfur-free chlorbutyl rubber stopper 
covered with a blue aluminum and plastic flip-off seal.
The tracer will be labeled containing information regarding the composition of the product.
A more detailed description of administration procedures is given in Section 5.1.
3.10.
Drug Supply and Accountability
3.10.1.
Drug Storage and Security
The study drug (pridopidine) must be stored according to the manufacturer’s drug product 
stipulation, in a dry place, and in a securely locked, substantially constructed cabinet or 
enclosure.
All study drug supplies must be stored at room temperature (15°C to 25°C/59°F to 77°F). 
Medication must not be refrigerated.
The tracers should be stored shielded, at room temperature (15°C to 25°C/59°F to 77°F).
Only authorized personnel will have access to the study drug. The study site personnel at the site 
will be responsible for correct storage and handling of the study drug.


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3.10.2.
Drug Accountability
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 national and local regulations, and used in accordance 
with this protocol.
A record of study drug accountability (ie, study drug and other materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the PI or designee, with an account given 
for any discrepancies. Empty, partially used, and unused bottles of study drug will be disposed of
by the study center according to local procedures.
3.11.
Duration of Subject Participation and Justification
Total study duration for each subject is expected to not exceed 12 weeks, with recruitment and 
screening lasting up to 8 weeks and the study period for each subject lasting up to 4 weeks. 
Subjects are expected to participate in this study for its entire duration. See Section 12.4 for the 
definition of the end of study.
3.12.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of:

new toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment

discontinuation of the development of the study drug
A subject may discontinue participation in the study at any time for any reason (eg, withdrawal 
of consent, adverse event); every effort should be undertaken to find out the reason for 
discontinuation. The investigator or sponsor can withdraw a subject 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).
3.13.
Source Data Recorded on the Case Report Form
All subject data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or means (eg, clinical laboratory, central image 
center, or electronic diary data) the results will be sent to the investigational center, where they 
will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. These 
data may also be sent electronically to the sponsor (or organization performing data 


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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.
3.14.
Study Procedures and Assessments
Study procedures and assessments with their time points are summarized in Table 1. Detailed 
by-visit information is provided starting with Section 3.14.1. Detailed descriptions of each 
assessment are provided in Section 6 (pharmacokinetic and pharmacodynamic assessments),
Section 7 (safety assessments), and Section 8 (biomarker and pharmacogenetic assessments).


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Table 1:
Study Procedures and Assessments
Time period
Up to 8 weeks to 
2 weeks before 
Visit 2
Up to 4 weeks
Visit number
Visit 1
Visit 2
Visit 3
Visit 4
Procedures and assessments
Screening
a
Day -1
(first admission)
Day 1
Day -1
(second 
admission)
Day 1
Day 2
Follow-up
b
Informed consent
X
Medical history
c
X
X
Prior medication history
d
X
X
Inclusion and exclusion criteria
X
X
Clinical laboratory tests (hematology, serum chemistry, 
urinalysis)
X
X
X
X
Coagulation test
X
Corticoid plasma levels
e
X
X
Virology
f
X
Urine drug screen
X
X
X
Physical examination
g
X
X
X
X
Modified Allen test
h
X
UHDRS-TMS (HD patients only)
X
X
X
X
X
12-lead standard ECG
i
X
X
X
X
X
X
X
Vital signs measurement
j
X
X
X
X
X
X
X
C-SSRS (screening version)
X
Pridopidine administration
k
X
(S)-(-)-[18F]fluspidine or [18F]fallypride administration
l
X
X
Screening T1 MPRAGE 3D MRI
m
X
PET scan for test-retest cohort
n
X
X
PET session 1
o
X
PET session 2
p
X


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Time period
Up to 8 weeks to 
2 weeks before 
Visit 2
Up to 4 weeks
Visit number
Visit 1
Visit 2
Visit 3
Visit 4
Procedures and assessments
Screening
a
Day -1
(first admission)
Day 1
Day -1
(second 
admission)
Day 1
Day 2
Follow-up
b
MR-AC, T1 MPRAGE 3D MRI, ASL, 2DMRS, rs-
fMRI
X
q
Xp
Blood samples for radioactivity levels
r
X
X
Blood samples for PK analyses
s
X
X
Blood samples for PD biomarker analysis
t
X
X
X
Genotyping for CYP2D6 and exploratory
u
X
Monitoring of adverse events
v
X
X
X
X
X
X
X
Concomitant medication
w
X
X
X
X
X
X
X
Check of study compliance
X
X
a The screening procedures can be performed over several days as long as they are completed within the defined visit window. During screening, subjects will be 
informed of study restrictions and compliance requirements.
b The follow-up visit will take place 6 days after the visit 3 dose (±1 day).
c Events that occurred prior to the signing of the informed consent form will be recorded in the medical history.
d Medications administered prior to any study drug administration will be recorded as prior medications.
e Corticoid plasma levels, to be taken directly prior to tracer dosing (DHEA, progesterone, testosterone, cortisol, where feasible also androstanolone, 
allopregnanolone, pregnenolone).
f Virology testing will include: human immunodeficiency virus (HIV-1, HIV 2), HBsAg, and/or hepatitis C.
g Height, weight, and body mass index will be measured only at screening. Complete physical examination on screening and follow up/early termination visits 
only. On other occasions, abbreviated/symptom- oriented physical examination will be conducted.
h Part 0 and Part A subjects only.
i The 12-lead ECG is to be performed before pridopidine administration; immediately before administration of the tracer (approximately 90 minutes after 
pridopidine administration), and at the end of the first PET scan (approximately 3.5 hours after pridopidine administration). When ECG collection coincides 
with a pharmacokinetic sample, ECG will be collected before the pharmacokinetic sample.
j Vital signs (pulse, respiratory rate, body temperature, and systolic and diastolic BP) will be measured with the subject seated or supine immediately prior to 
administration of pridopidine, and prior to and immediately after each PET scan. BP will be measured in the same arm throughout the study, whenever 
possible. When vital signs collection coincides with PK sample, vital signs will be collected before the PK sample.
k Except for test-retest cohort (Part 0).
l [18F]fluspidine for Parts A and 0, [18F]fallypride administration for Part B.


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m This should be performed as the final procedure of the screening visit, after all other eligibility criteria have been fulfilled.
n For the test-retest cohort, fluspidine will be administered twice. The 2 tracer doses will be administered separately within a certain time frame, without 
pridopidine. The PET session 2 will take place at approximately a similar time of day (±1 hour) as the baseline PET session 1, on another day (at least 24 hours 
~10 half-lives 18F apart).
o In an effort to facilitate easier PET procedure for HD patients, after the first 90-minute PET acquisition block, the subsequent 30-minute PET acquisition blocks 
are made optional per Investigator’s judgement (refer to study Imaging Manual for details).
p The PET session 2 will take place at approximately a similar time of day (±1 hour) as the baseline PET session 1, on another day (per PET slots scheduling 
availability). It will begin approximately 2 hours after pridopidine administration. The complete scan duration is 3 hours for both fluspidine and fallypride with 
breaks. Note: In an effort to facilitate easier PET procedure for HD patients, after the first 90-minute PET acquisition block, the subsequent 30-minute PET 
acquisition blocks are made optional per Investigator’s judgement (refer to study Imaging Manual for details).
q These should be done simultaneously to the dynamic list-mode PET scans.
r Arterial blood samples for radioactivity levels will be obtained after administration of (S)-(-)-[18F]fluspidine; a total of 51 samples (43 × 2 mL and 8 × 10 mL) 
will be collected at 39 time points during 210 minutes after injection of the tracer. Note: samples will not be collected for Part B.
s Blood samples for analysis of pridopidine and the metabolite TV-45065 will be obtained prior to pridopidine dosing (<1 hour) at 5 (±1 minute), 15, 30, 45 and 
60 minutes after dosing (±2 minutes), and at 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours after dosing. A 10-minute window will be allowed for all postdose 
sampling intervals from 1.5 hours up to and including 24 hours after dosing. Note: samples will not be collected for Part 0
t At visit 3, blood will be collected for exploratory biomarker analysis on day -1 and on days 1 and 2 (prior to treatment, and at 4, 8, and 24 hours postdose; a 
10-minute window will be allowed). For Part 0 where no treatment is given the time points corresponds to 2 hours prior to and 2, 6, and 22 hours post tracer 
injection.
u Blood sampling for pharmacogenetics can be performed at a separate visit within the screening period after informed consent is obtained. Remnant sample will 
be retained for future exploratory analysis.
v Adverse events inquiry and concomitant medication review will occur throughout the study. The period for adverse event reporting is defined as the time 
period from signing of the informed consent form through the end of the follow-up period. Conditions that worsen or events that occur after signing of 
informed consent will be recorded as an adverse event. 
w Medications administered following the first dose and throughout the study will be recorded as concomitant medication.
Abbreviations: ASL=arterial spin labeling; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP2D6=cytochrome P450 2D6; 
DHEA=dehydroepiandrosterone; 2DMRS=two dimensional multi-voxel magnetic resonance spectroscopy; ECG=electrocardiography; HBsAg=hepatitis B 
surface antigen; HD=Huntington’s disease; HIV=human immunodeficiency virus; MR-AC=MRI-based attenuation correction; MRI=magnetic resonance 
imaging; PD=pharmacodynamic; PET=positron emission tomography; PK=pharmacokinetics; rs-fMRI=resting state functional magnetic resonance imaging; T1 
MPRAGE 3D=T1-weighted rapid 3-dimensional gradient-echo technique; UHDRS-TMS=Unified Huntington's Disease Rating Scale – Total Motor Score


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3.14.1.
Procedures for Screening and Enrollment (Visit 1)
A signed and dated informed consent form will be obtained before any screening procedures 
commence (see Section 12.1). Assessments conducted as part of routine medical care for HD 
patients and performed during the screening period may be used in place of the protocol-specific 
assessments. In addition, HD-specific assessments performed within a specified time frame 
before informed consent may be used for the study. Subjects will acknowledge and agree to the 
possible use of this information for the study by giving informed consent.
After informed consent is obtained, subjects who are screened will be assigned an 8-digit 
permanent identification number such that all subjects from each investigational center are given 
consecutive identification numbers in successive order of inclusion. The first 2 digits of the 
screening number will be the number assigned to the country where the investigational center is 
located, the next 3 digits will be the assigned number of the investigational center, and the last 
3 digits will be assigned at the investigational center (eg, if the number assigned to the country is 
01, the 3rd subject screened at 5th investigational center would be given the number of 
01005003).
A subject who is screened but not enrolled, eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time, may be considered for screening again 
if, eg, there is a change in the subject’s medical background or a modification of study inclusion 
and exclusion criteria.
The screening visit (visit 1) will take place between 8 and 2 weeks before visit 2. The following 
procedures will be performed at visit 1:

obtain written informed consent before any study-related procedures are performed

review medical history

review prior medication history

review inclusion and exclusion criteria

clinical laboratory tests (hematology, serum chemistry, urinalysis, and coagulation)

virology testing for human immunodeficiency virus (HIV-1, HIV-2), hepatitis B 
surface antigen (HBsAg) and/or hepatitis C

urine drug screen

full physical examination (including height and weight)

modified Allen test for both hands (except for Part B subjects)

UHDRS-TMS (HD patients only)

12-lead standard ECG

vital signs measurements

Columbia-Suicide Severity Rating Scale (C-SSRS, screening version)

genotyping for CYP2D6 metabolism status and storage of deoxyribonucleic acid 
(DNA) remnant for S1R and exploratory genotyping


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
genotyping for cytosine-adenosine-guanine (CAG) (HD patients only)

concomitant medication review

monitoring for adverse events (post informed consent form signature)

inform subjects of study restrictions and compliance requirements

T1 MPRAGE 3D MRI (this should be performed as the final procedure of the 
screening visit, after all other eligibility criteria have been fulfilled)
3.14.2.
Visit 2 (PET Session 1)
Subjects who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2.
Subjects who continue to meet the inclusion and exclusion criteria will be assigned a permanent 
unique treatment number. This assigned number will be entered in the CRF.
3.14.2.1.
Visit 2, Day -1
The following procedures will be performed at visit 2, day -1:

review of medical history

review of prior medication history

review inclusion and exclusion criteria

clinical laboratory testing (hematology, serum chemistry, and urinalysis)

urine drug screen

abbreviated/symptom-oriented physical examination

UHDRS-TMS (HD patients only)

12-lead standard ECG

vital signs measurements

inquire about adverse events

review of concomitant medication

review study compliance
3.14.2.2.
Visit 2, Day 1
The following procedures will be performed at visit 2, day 1:

corticoid plasma level measurements

UHDRS-TMS (HD patients only)

12-lead standard ECG

vital signs measurements

[18F]fluspidine (Parts A and 0) or [18F]fallypride (Part B) administration – refer to 
study Imaging Manual for details


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
PET scan (session 1) - refer to study Imaging Manual for details

MR-AC, T1 MPRAGE 3D, ASL, 2DMRS, and rs-fMRI – refer to study Imaging 
Manual for details

collect blood samples for measurement of radioactivity levels (excluding Part B 
subjects) – refer to study Imaging Manual for details

inquire about adverse events

review of concomitant medication
3.14.3.
Visit 3 (PET Session 2)
3.14.3.1.
Visit 3, Day -1
The following procedures will be performed at visit 3, day -1:

clinical laboratory testing (hematology, serum chemistry, and urinalysis)

urine drug screen

abbreviated/symptom-oriented physical examination

UHDRS-TMS (HD patients only)

12-lead standard ECG

vital signs measurements

inquire about adverse events

review of concomitant medication

review study compliance

collection of blood for exploratory pharmacodynamic biomarker analysis
3.14.3.2.
Visit 3, Day 1 
The following procedures/assessments will be performed at visit 3, day 1:

corticoid plasma level measurements

UHDRS-TMS (HD patients only)

12-lead standard ECG

vital sign measurements

pridopidine administration

[18F]fluspidine (Parts A and 0) or [18F]fallypride (Part B) administration – refer to 
study Imaging Manual for details

PET scan (session 2) – refer to study Imaging Manual for details

MR-AC, T1 MPRAGE 3D, ASL, 2DMRS, and rs-fMRI – refer to study Imaging 
Manual for details


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
collect blood samples for measurement of radioactivity levels (excluding Part B 
subjects) – refer to study Imaging Manual for details

collect blood samples for pharmacokinetic analyses (predose and up to 12 hours after 
dosing)

collect blood samples for exploratory pharmacodynamic biomarker analysis (predose 
and 4 and 8 hours postdose)

monitoring of adverse events

review of concomitant medication
3.14.3.3.
Visit 3, Day 2
The following procedures/assessments will be performed at visit 3, day 2:

12-lead standard ECG

vital signs measurements

collect blood samples for pharmacokinetic analyses (24 hours postdose)

collect blood samples for exploratory pharmacodynamic biomarker analysis (24 hours 
postdose)

monitoring of adverse events

review of concomitant medications
3.14.4.
Procedures After Study Drug Treatment (Visit 4) 
For subjects who complete the study or withdraw prematurely, final evaluations will be 
performed at visit 4, which will take place 6 days after the visit 3 dose (±1 day). The following 
procedures are to be performed at visit 4:

clinical laboratory testing (hematology, serum chemistry, and urinalysis)

full physical examination

12-lead standard ECG

vital signs measurements

monitoring of adverse events 

review of concomitant medications
Procedures for subjects who withdraw prematurely from the study are described in Section 4.4
Subjects with ongoing adverse events will be monitored as described in Section 7.1.2. Otherwise, 
the follow-up visit will be the last study visit.
3.14.5.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the subject’s request and 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 


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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 inquiry

vital signs measurements

adverse event inquiry
Other procedures may be performed at the discretion of the investigator.


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4.
SELECTION AND WITHDRAWAL OF SUBJECTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow subjects to 
be enrolled are not granted by Teva (see Section 11.1.2).
4.1.
Subject Inclusion Criteria
Subjects may be enrolled in this study only if they meet all of the following criteria:
Healthy Subjects:
a.
Male subjects between 25 and 55 years (inclusive) of age, with a body mass index 
(BMI) ≥18.0 to ≤30 kg/m2 and a body weight of at least 50 kg (inclusive).
b. In general, good physical and mental health as determined by medical history and 
psychiatric history, suicidality assessment, physical examination, 12-lead ECG, vital 
signs, and clinical laboratory tests. A subject with a clinical abnormality in the 
laboratory profile or BP can be included only if the investigator or his designee 
considers that the abnormality does not introduce an additional risk factor for the 
subject's health, or interfere with the study objectives.
c.
Men who are potentially fertile (not surgically [eg, vasectomy] or congenitally 
sterile), whose female partners are of childbearing potential, must use contraception 
for the duration of the study and for 90 days after discontinuation of study drug 
(because of the possible effects on spermatogenesis). Highly effective methods of 
contraception are those with a failure rate of less than 1% per year (eg, female 
partner’s use of hormonal contraceptive [oral, implanted, transdermal, injected], 
female partner’s use of an intrauterine device [IUD]), and barrier method with 
spermicide. In addition, male subjects may not donate sperm for the duration of the 
study and for 90 days after discontinuation of study drug.
d. Are able to understand the requirements of the study; are willing to comply with the 
requirements of the study (eg, imaging procedures, all dietary, exercise, and alcohol 
restrictions) and provided their written informed consent to participate in the study.
e.
Willing to provide a blood sample for genetic analyses (including CYP2D6 status, 
S1R polymorphs, genetic long QT syndrome in patients who had QT prolongation 
following study drug administration or any other genetic analyses related to 
pridopidine response) at the screening visit.
Patients with Huntington’s disease:
a.
Diagnosis of HD based on clinical features and the presence of ≥36 CAG repeats in 
the huntingtin gene.
b. Male age ≥25 years, with an onset of HD after 18 years of age.
c.
Men who are potentially fertile (not surgically [eg, vasectomy] or congenitally 
sterile), whose female partners are of childbearing potential, must use contraception 
for the duration of the study and for 90 days after discontinuation of study drug 
(because of the possible effects on spermatogenesis). Highly effective methods of 


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contraception are those with a failure rate of less than 1% per year (eg, female 
partner’s use of hormonal contraceptive [oral, implanted, transdermal, injected], 
female partner’s use of an IUD), and barrier method with spermicide. In addition, 
male patients may not donate sperm for the duration of the study and for 90 days after 
discontinuation of study drug.
d. Body weight ≥50 kg.
e.
A sum of ≥25 points on the UHDRS-TMS at the screening visit.
f.
Able and willing to provide written informed consent prior to any study related 
procedure being performed at the screening visit. Patients with a legal guardian 
should be consented according to local requirements.
g. Willing to provide a blood sample for genetic analyses (including CAG analysis, 
CYP2D6 status, S1R polymorphs, genetic long QT syndrome in patients who had QT 
prolongation following study drug administration or any other genetic analyses 
related to pridopidine response or HD) at the screening visit.
h. Willing and able to take oral medication and able to comply with the study specific 
procedures.
i.
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.
j.
Availability and willingness of a caregiver, informant or family member to 
accompany the patient to the clinic at study visits. The suitability of the caregiver 
should be judged by the investigator.
k. For patients taking allowed antipsychotic, antidepressant or other psychotropic 
medication, the dosing of medication must have been kept constant for at least 
6 weeks before baseline (visit 2, day -1) and must be kept constant during the study.
l.
Are able to understand the requirements of the study; are willing to comply with the 
requirements of the study (eg, imaging procedures, all restrictions) and provided their 
written informed consent to participate in the study.
4.2.
Subject Exclusion Criteria
Subjects will not be enrolled in this study if they meet any of the following criteria:
Healthy Subjects:
a.
CYP2D6 poor metabolizers
b. The subject has been previously exposed to ionizing radiation or radioactive 
substances as a result of clinical research or medical treatment in the past 10 years.
c.
The subject has large scale tattoos, in particular involving the head and neck area.
d. The subject has a counterindication to having an MRI, including (but not limited to): 

The presence of metal implants (excluding metal dental crowns) that could affect 
MRI imaging OR


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
has worked with ferrous metals either as a vocation or hobby (for example sheet 
metal worker, welder or machinist) in such a way that might have led to unknown 
indwelling of metal fragments that could cause injury if moved in response to the 
magnetic fields during the MRI imaging.
e.
The subject suffers from claustrophobia or needle phobia.
f.
The subject has a finding on screening MRI that will, in the opinion of the PI impair 
the safety of the subject or the scientific integrity of the study.
g. The subject has a known coagulation abnormality.
h. Parts A and 0 only: Individuals who had evidence of only one patent arterial supply to 
the hand (modified Allen test).
i.
Any current or history of heart condition or increased pro-arrhythmic risk, including:

History of cardiovascular disease (eg, coronary artery disease, stroke, 
arrhythmias, congestive heart failure, uncontrolled hypertension, deep vein 
thrombosis, pulmonary embolism, family history of thrombophilia)

History of Long QT Syndrome or a first degree relative with this condition 

Family history of sudden death/Brugada syndrome

A prolonged Fridericia-corrected QT (QTcF) interval (defined as a QTcF interval 
of >450 msec) at the screening or admission (baseline) visit(s). If there is 
evidence of a prolonged QTcF interval from the initial (single) measurement, then 
the ECG can be repeated twice, and the mean of the 3 screening measurements 
will be used to determine whether or not the subject is suitable for inclusion in the 
study.

Any repolarization deficits

Untreated hypokalemia and/or untreated hypomagnesaemia

Unclear syncopes

Any other clinically significant abnormal ECG as judged by the investigator.
j.
Creatinine clearance <90 mL/min at screening, calculated using the Cockcroft-Gault 
equation. It is permitted to repeat the test once, if clinically appropriate.
k. Hemoglobin value below the lower limit of the reference range and evaluated by the 
investigator to be clinically significant.
l.
Positive serology for HIV-1, HIV-2, HBsAg, and/or hepatitis C.
m. Presents or has a history of clinically significant diseases of the renal, hepatic, 
gastrointestinal, cardiovascular, musculoskeletal, immunological, endocrine 
(including diabetes even if controlled by diet), metabolic diseases, or other condition 
known to interfere with the absorption, distribution, metabolism or excretion of drugs, 
as judged by the investigator.


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n. History of alcohol, narcotic, or any other substance dependence in the past 2 years, as 
defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5, American Psychiatric Association 2013).
o. History of clinically significant psychiatric diseases, such as major depressive 
disorder or anxiety, as judged by the investigator.
p. Subjects with adverse events of suicidal ideation or attempt at any time in the past or 
as measured by suicide ideation score of ≥3 on the C-SSRS (screening version), or 
subjects 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 subjects who, in the opinion 
of the investigator, present a risk of suicide.
q.
Has had one of the following conditions:

major trauma or surgery in the 2 months before screening or at any time between 
screening and admission

acute/chronic infection within 2 weeks before screening or at any time between 
screening and admission

malignancy within the last 5 years

epilepsy, seizure, convulsions or syncope (including febrile seizures)

history of tuberculosis

BP outside the range of 90 to 139 mmHg (systolic) or 55 to 89 mmHg (diastolic); 
or pulse rate outside the range of 45 to 99 bpm; all measured after 5 minutes rest 
in seated or supine position. Vital signs may be retested twice at intervals of 
5 minutes.
r.
Not willing or able to refrain from intensive physical exercise during the study.
s.
Current or history of clinically significant allergy or known hypersensitivity to any 
ingredients of the study medication 
 
t.
Planned medical treatments (excluding dental care) during the study period, which 
may interfere with the study.
u. Use of one of the following prohibited drugs, substances, or foods as follows:

an investigational drug (new chemical entity) within 6 weeks prior to the first day 
of study drug administration or within 5 half-lives (whichever is longer)

any monoamine oxidase inhibitors within 14 days before the first day of study 
drug administration

any other medications (including over-the-counter [OTC] medications, vitamins, 
or herbal or nutritional supplements) within 7 days before the first day of study 
drug administration (except paracetamol/acetaminophen or ibuprofen used 
occasionally, up to 24 hours before the first day of study drug administration)


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
drugs known to significantly inhibit CYP2D6 enzyme drug metabolism within 
21 days prior to the first day of study drug administration or within 5 half-lives 
(whichever is longer) before the first day of study drug administration, or drugs 
known to significantly induce CYP enzyme drug metabolism within 28 days 
before the first day of study drug administration

drugs known to cause significant QT-prolongation such as anti-arrhythmic drugs 
or antidepressants within 28 days before the first day of study drug administration

daily consumption of more than 6 units of caffeine and/or xanthine-containing 
products, within 2 weeks before the first dose of study drug, or not able to refrain 
from consumption of more than 2 units of caffeine-containing foods or drinks 
from 48 hours prior to admission visit and discharge. One caffeine unit is 
contained in the following items: 1 cup of coffee, 2 cans of cola, 1 cup of tea, ½ 
cup of energy drink (eg, Red Bull) or 3 chocolate bars. Subject should be able to 
abstain from caffeine intake for 20 hours during any day.

cigarette smoking (defined as >5 cigarettes per week) or use of other 
nicotine-containing products (eg, snuff, nicotine patch, nicotine chewing gum, 
mock cigarettes, or inhalers). Ex-smokers should have ceased smoking at least 
6 months before screening.

any food or drink/beverage containing alcohol, grapefruit or grapefruit juice, 
apple or orange juice, vegetables from the mustard green family (eg, kale, 
broccoli, watercress, collard greens, kohlrabi, brussel sprouts, mustard), and 
charbroiled meats within 7 days before the first day of study drug administration 
until after the last day of pharmacokinetic sampling.

a positive urine drug test or a positive alcohol breath analyzer test at admission 
visits, or not willing or able to refrain from illicit drugs during the study.
v. Donation or reception of any blood products (eg, plasma, platelets, etc) in the 
1 month before the first day of study drug administration, or has made more than 
2 donations within the 12 months preceding the first day of study drug administration, 
or plans to donate during the study or during the 1 months after the last study visit.
w. The subjects cannot participate or successfully complete the study, in the opinion of 
the investigator, for any of the following reasons:

The subject is mentally or legally incapacitated, or unable to give consent for any 
reason.

The subject is in custody due to an administrative or a legal decision, or under 
tutelage, or being admitted to a sanitarium or social institution.

The subject is unable to be contacted in case of emergency.

The subject is an employee of the site or a relative of an employee at the site.

Any other reason, at the discretion of the investigator.


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Patients with Huntington’s disease:
a.
CYP2D6 poor metabolizers
b. The patient has been previously exposed to ionizing radiation or radioactive 
substances as a result of clinical research or medical treatment in the past 10 years.
c.
The patient has large scale tattoos, in particular involving the head and neck area.
d. The patient has a counterindication to having an MRI, including (but not limited to): 

The presence of metal implants (excluding metal dental crowns) that could affect 
MRI imaging OR

has worked with ferrous metals either as a vocation or hobby (for example sheet 
metal worker, welder or machinist) in such a way that might have led to unknown 
indwelling of metal fragments that could cause injury if moved in response to the 
magnetic fields during the MRI imaging.
e.
The patient suffers from claustrophobia or needle phobia.
f.
The patient has a finding on screening MRI that will, in the opinion of the PI impair 
the safety of the subject or the scientific integrity of the study.
g. The patient has a severe motor impairment that might cause artifacts.
h. The patient has an known coagulation abnormality.
i.
Parts A and 0 only: Individuals who had evidence of only one patent arterial supply to 
the hand (modified Allen test).
j.
A prolonged QTcF interval (defined as a QTcF interval of >450 msec) at the 
screening visit. If there is evidence of a prolonged QTcF interval at screening from 
the initial (single) measurement, then the ECG will be repeated twice, and the mean 
of the 3 screening measurements will be used to determine whether or not the patient 
is suitable for inclusion in the study.
k. 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 first admission, 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, (iv) history of deep 
vein thrombosis or pulmonary embolism, and/or (v) family history of thrombophilia.
l.
Patients with a known history of Long QT Syndrome or a first degree relative with 
this condition.
m. Patients with a history of epilepsy or of seizures within the last 5 years.


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n. Have other serious medical illnesses (including but not limited to uncontrolled 
hypertension, respiratory disease including severe form of asthma, hepatic disease, 
renal disease, AIDS, unstable psychiatric or other neurologic disorder, endocrine 
[including controlled diabetes], gastrointestinal, and metabolic diseases) which in the 
opinion of the investigator may put the patient at risk when participating in the study 
or may influence the results of the study or affect the patient's ability to take part in 
the study.
o. 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.
p. Patients receiving medications (within the last 6 weeks prior to baseline [visit 2, 
day -1]) 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.
q. Patients receiving medications (within the last 6 weeks prior to baseline [visit 2, 
day -1]) that are metabolized by CYP2D6 and have the potential of reducing seizure 
threshold.
r.
Creatinine clearance <60 mL/min at screening, calculated using the Cockcroft-Gault 
equation: (140 - age) × mass (kg) / 72 × serum creatinine (mg/dL). It is allowed to 
repeat the test once, if clinically appropriate.
s.
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 enters the study.
t.
Alcohol and/or drug abuse within the 6 months prior to screening, as defined by 
DSM-5 (American Psychiatric Association 2013).
u. Patients with adverse events of suicidal ideation or attempt at any time in the past or 
as measured by suicide ideation score of ≥3 on the C-SSRS (screening version), 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.
v. Patients with known intracranial neoplasms, vascular malformations, history of 
cerebrovascular accident, or intracranial hemorrhage.
w. Current or history of clinically significant allergy or known hypersensitivity to any 
ingredients of the study medication 
 
x. Treatment with tetrabenazine within 6 weeks of study baseline (visit 2, day -1).
y. Treatment with any investigational product within 6 weeks of screening prior to the 
first day of study drug administration or within 5 half-lives (whichever is longer) or 


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patients planning to participate in another clinical study assessing any investigational 
product during the study.
z. Use of one of the following prohibited substances, or foods as follows:

any food or drink/beverage containing alcohol, grapefruit or grapefruit juice, 
apple or orange juice, vegetables from the mustard green family (eg, kale, 
broccoli, watercress, collard greens, kohlrabi, brussel sprouts, mustard), and 
charbroiled meats within 7 days before the first day of study drug administration 
until after the last day of pharmacokinetic sampling.

a positive urine drug test or positive alcohol breath analyzer test at admission 
visits, or not willing or able to refrain from illicit drugs during the study.
aa. Positive serology for HIV-1, HIV-2, HBsAg, and/or hepatitis C.
4.3.
Justification for Key Inclusion and Exclusion Criteria
The majority of participants enrolled in this study will be healthy subjects; therefore, the 
inclusion/exclusion criteria established for this trial are those typically utilized to define this 
population. Due to unknown potential effects of the 18F-tracers on a developing fetus, women 
have been excluded from participation in the trial, and male subjects must agree to use 
contraception for the duration of the trial and for 90 days after discontinuation of the study drug. 
 
, subjects with current or history of a heart 
condition or increased pro-arrhythmic risk, epilepsy or seizures within the last 5 years, and 
clinically significant psychiatric diseases such as major depressive disorder or anxiety are to be 
excluded from participation in this study.
All subjects participating in this study will receive multiple scans (MRI and PET); therefore,
individuals with a history of claustrophobia will be excluded from participation in this study. 
Additionally, subjects may not have counterindications to MRI such as the presence of metal 
implants, exposure to ferrous metals either as a vocation or hobby in such a way that unknown 
embedded metal fragments may cause injury to the subject during exposure to the magnetic field 
generated during imaging.
Since all subjects will be receiving 2 applications of the radioactive tracer resulting in more than 
10 mSv effective dose as part of this study, all subjects must not have been exposed to ionizing 
radiation as a result of research or radiation treatment procedures during the previous 10 years 
(§88(2) German Radiation Protection Act), excluding diagnostic procedures (eg, computed 
tomography).
and to ensure a reasonable minimum 
clearance in all subjects through the renal pathway, subjects with a creatinine clearance 
(calculated by the Cockcroft-Gault formula) <90 mL/min and HD patients with creatinine 
clearance <60 mL/min will be excluded from the study.
Exposure has been shown to correlate with body weight; therefore, subjects with body weight 
below 50 kg will be excluded from the study.


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4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of intercurrent illness, adverse 
events, or other reasons concerning the health or well-being of the subject, or in the event of lack 
of cooperation. In addition, a subject may be withdrawn from the study drug treatment as 
described in Sections 3.12, 3.14.4, and 7.1.7.
Should a subject decide to withdraw after administration of study drug(s), or should the 
investigator decide to withdraw the subject, 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 
subject’s withdrawal should be made and an explanation given as to why the subject is 
withdrawing or being withdrawn from the study.
The reason for and date of withdrawal from study drug treatment and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed to the 
CRF. If a subject withdraws consent, every attempt will be made to determine the reason. If the 
reason for withdrawal is an adverse event or a 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 subject 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 to the 
CRF.


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5.
TREATMENT OF SUBJECTS
5.1.
Drugs Administered During the Study
5.1.1.
Pridopidine
In this study, pridopidine can be administered as 0.5 or 1 mg in healthy subjects (Part A only);
2.5, 5, 10, 22.5, 45, 67.5, or 90 mg in healthy subjects and HD patients; and a higher dose of 
112.5 mg may also be administered to HD patients. The applicable dose will be given selecting 
the lowest possible number of capsules. Pridopidine will be administered orally with 240 mL of 
water.
Study drug will be packaged in bottles and will be provided to the site for administration to
subjects (see Section 3.9).
Lower dose study drugs will be packed in bottles on site (1 bottle per patient), prior to 
administration to the subjects.
5.1.2.
[18F]fluspidine
The radiolabeled PET tracer [18F]fluspidine will be provided as a sterile, clear, colorless particle 
free solution to be administered intravenously for the neuroimaging of S1R brain receptors. The 
label on the tracer delivered for use in the PET scans will contain information regarding the 
composition of the product.
During the study period, the subjects will undergo a baseline PET investigation (PET session 1) 
and a post-treatment PET investigation during the study period (PET session 2) following a 
single oral dose of the study drug, pridopidine. On the day of each PET session, prior to PET 
imaging, a cubital or forearm vein will be cannulated to inject (S)-(-)-[18F]fluspidine 
(300±30 MBq) and, at visit 3, to obtain venous blood samples for quantification of pridopidine 
and its metabolite TV-45065 and other exploratory biomarker analysis. The subject’s radial 
artery on the other arm (or the same arm if this cannot be achieved) will be cannulated to obtain 
arterial blood samples during PET imaging for the quantification of plasma radioactivity 
associated with (S)-(-)-[18F]fluspidine, in order to estimate a metabolite-corrected arterial plasma 
input function for PET data analysis. A total of 51 samples (43 × 2 mL and 8 × 10 mL) will be 
collected at 39 time points during 210 minutes after injection of the tracer. The arterial sampling 
intervals will be according to the institutional standards, as detailed in the study imaging manual.
If any of the postdose PET investigations are compromised due to technical or logistic reasons, a 
repeat investigation may be considered, provided that the resulting cumulative 
(S)-(-)-[18F]fluspidine dose for all PET sessions does not exceed the authorized overall study 
exposure (effective dose not exceeding 20 mSv), when using tracer administered activity of 
300±30 MBq per PET session, and further respecting a washout of 7 days of pridopidine and its 
metabolites.
5.1.3.
[18F]fallypride
The radiolabeled PET tracer [18F]fallypride will be provided as a sterile clear colorless particle 
free solution to be administered intravenously for the neuroimaging of D2 receptors in the brain. 


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The label on the tracer delivered for use in the PET scans will contain information regarding the 
composition of the product.
During the study period, the subjects will undergo a baseline PET investigation (PET session 1) 
and a post-treatment PET investigation during the study period (PET session 2) following a 
single oral dose of the study drug, pridopidine. On the day of each PET session, prior to PET 
imaging, a cubital or forearm vein will be cannulated to inject [18F]fallypride (200±20 MBq) and, 
at visit 3, to obtain venous blood samples for quantification of pridopidine and its metabolite 
TV-45065 and other exploratory biomarker analysis. 
If any of the postdose PET investigations are compromised due to technical or logistic reasons, a 
repeat investigation may be considered, provided that the resulting cumulative [18F]fallypride 
dose for all PET sessions does not exceed the authorized overall study exposure (effective dose 
not exceeding 20 mSv), when using tracer administered activity of 200±20 MBq per PET 
session, and further respecting a washout of 7 days of pridopidine and its metabolites.
5.2.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.3. Restrictions 
in regard to birth control and required laboratory values are provided in the inclusion and 
exclusion criteria. 
Healthy subjects will be required to comply with the following additional restrictions:

Activity

Subjects must remain seated or supine for safety reasons during the pridopidine 
administration and for 1 hour after each pridopidine administration. Subjects will 
be allowed to use the restroom (escorted by investigational center staff) during 
this time, as needed.

Subjects will be asked to maintain normal physical activity from at least 5 days 
before the start of the study.

Subjects are not to engage in strenuous exercise during the inpatient periods of 
this study.

Fasting

Subjects will fast from waking; a light breakfast (without caffeine) is allowed, to 
be completed at least 2 hours before drug administration.

Specific food, beverages, etc

Subjects may not consume any food or drink/beverage containing alcohol, 
grapefruit or grapefruit juice, apple or orange juice, vegetables from the mustard 
green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, brussel 
sprouts, mustard), and charbroiled meats within 7 days before the first day of 
study drug administration until after the last day of pharmacokinetic sampling.

Daily consumption of more than 6 units of caffeine and/or xanthine-containing 
products will be prohibited for a minimum of 2 weeks before the first dose of 
study drug. One caffeine unit is contained in the following items: 1 cup of coffee, 


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2 cans of cola, 1 cup of tea, ½ cup of energy drink (eg, Red Bull), or 3 chocolate 
bars. Consumption of such products will be restricted to no more than 2 units of 
caffeine-containing foods or drinks from 48 hours prior to admission visit and 
discharge. Subject should be able to abstain from caffeine intake for 20 hours 
during any day. Caffeine must not be consumed after 1800 hours on day -1 at 
visits 2 and 3, and should not be provided with breakfast on day 1 of 
visits 2 and 3.

Subjects must not donate any blood products (eg, plasma, platelets, etc) during the 
study or during the 1 month after the last study visit.

Smoking >5 cigarettes per week is not permitted during the study.
Patients will be required to comply with the following additional restrictions to the best of their 
ability:

Activity

Patients must remain seated or supine for safety reasons during the pridopidine 
administration and for 1 hour after each pridopidine administration. Patients will 
be allowed to use the restroom (escorted by investigational center staff) during 
this time, as needed.

Fasting

Patients will fast from waking; a light breakfast (without caffeine) is allowed, to 
be completed at least 2 hours before drug administration.

Specific food, beverages, etc

Patients may not consume any food or drink/beverage containing alcohol, 
grapefruit or grapefruit juice, apple or orange juice, vegetables from the mustard 
green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, brussel 
sprouts, mustard), and charbroiled meats within 7 days before the first day of 
study drug administration until after the last day of pharmacokinetic sampling.

Caffeine must not be consumed after 1800 hours on day -1 at visits 2 and 3, and 
should not be provided with breakfast on day 1 of visits 2 and 3.

Patients must not donate any blood products (eg, plasma, platelets, etc) during the 
study or during the 1 month after the last study visit.
5.3.
Prior and Concomitant Medication or Treatment
Medications administered prior to any study drug administration will be recorded as prior 
medications and medications administered following the first dose and throughout the study will 
be recorded as concomitant medication. Any prior or concomitant therapy, medication, or 
procedure a subject has had within 28 days before study drug administration and up to the end of 
the study period, including follow-up, will be recorded on the CRF. Generic or trade name, 
indication, dosage, and dosing start and stop times will be recorded. The sponsor will encode all 
therapy and medication according to the World Health Organization drug dictionary 
(WHO Drug).


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For healthy subjects, other than study drug, no drug is allowed during the study, except for the 
occasional use of paracetamol/acetaminophen or ibuprofen. Prohibited medication for HD 
patients is detailed in Section 5.3.1.
At each clinic visit after the screening visit, the investigator will ask subjects whether they have 
taken any medications (other than study drug), including 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.
Prohibited Medication for HD Patients
5.3.1.1.
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 2, day -1) and during the study.
5.3.1.2.
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 2, day -1) and during the study.
5.3.1.3.
Antiarrhythmic Medication
Disopyramide, procainamide, quinidine, flecainide, propafenone, amiodarone, dofetilide, 
ibutilide, and sotalol are not allowed within 6 weeks of baseline (visit 2, day -1) and during the 
study.
5.3.1.4.
Medications Lowering Seizure Thresholds
Maprotiline, dipipanone, dihydrocodeine, methadone, oxycodone, papaveretum, pentazocine, 
and tramadol are not allowed within 6 weeks of baseline (visit 2, day -1) and during the study
5.3.1.5.
Medications Interfering with Blood Coagulation
The following medications are not allowed within 6 weeks of baseline (visit 2, day -1) and 
during the study (except if required to treat adverse events):

Drugs which inhibit platelet function (antithrombic drugs) – aspirin, dipyridamole, 
sulfinpyrazone, dextran 

Drugs which decrease fibrin formation (anticoagulants) - heparin, oral anticoagulants: 
coumarin (warfarin, bishydroxycoumarin) and indanedione (phenindione) derivatives.

thrombolytic drugs: streptokinase, urokinase, tissue plasminogen activator

Miscellaneous drugs which are used to affect hemostasis: aminocaproic acid; 
tranexamic acid; desmopressin; dihydroergotamine mesylate; pentoxifyllin.


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5.3.1.6.
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 2, day -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 Subject Compliance
Study drug will be administered under the supervision of the site personnel.
5.5.
Total Blood Volume
The total blood volume to be collected for each subject in this study is approximately 436.9 mL 
for Part 0 (Table 2, see table footnote), 467.8 mL for Part A (Table 2), 499.6 mL for Part A (0.5 
and 1 mg only [Table 3]), and approximately 135.8 mL for Part B (Table 4), where arterial 
sampling will not be performed.
Table 2:
Blood Volumes (Part 0 and Part A)
Type of samples
Volume per sample (mL)
Total number of samples
Total volume (mL)
Serum chemistry
4.7
4
18.8
Hematology
2.7
4
10.8
Coagulation
2.7
1
2.7
Virology
4.7
1
4.7
Corticoid
4.7
2
9.4
Arterial (1)
2
86
172
Arterial (2)
10
16
160
Pharmacokinetic
a
2
16
32
Pharmacogenetic
4.9
1
4.9
Biomarkers
10.5
5
52.5
Total
467.8
a Not applicable for Part 0, where total blood volume will be approximately 436.9 mL.


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Table 3:
Blood Volumes (Part A [Dose Cohorts 0.5 and 1 mg Only])
Type of samples
Volume per sample (mL)
Total number of samples
Total volume (mL)
Serum chemistry
4.7
4
18.8
Hematology
2.7
4
10.8
Coagulation
2.7
1
2.7
Virology
4.7
1
4.7
Corticoid
4.7
2
9.4
Arterial (1)
2
86
172
Arterial (2)
10
16
160
Pharmacokinetic
6
16
96
Pharmacogenetic
2.7
1
2.7
Biomarkers
4.5
5
22.5
Total
499.6
Table 4:
Blood Volumes (Part B)
Type of samples
Volume per sample (mL)
Total number of samples
Total volume (mL)
Serum chemistry
4.7
4
18.8
Hematology
2.7
4
10.8
Coagulation
2.7
1
2.7
Virology
4.7
1
4.7
Corticoid
4.7
2
9.4
Pharmacokinetic
2
16
32
Pharmacogenetic
4.9
1
4.9
Biomarkers
10.5
5
52.5
Total
135.8


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6.
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS
6.1.
Pharmacokinetic Assessment
The following pharmacokinetic parameters will be calculated for pridopidine and its metabolite 
TV-45065 in plasma using non-compartmental methods, when possible:
Cmax
:
maximum observed concentration
tmax
:
time to reach maximum (peak) concentration 
AUC0-24
:
area under the concentration time curve from time 0 to 24 hours
AUC0-t
:
area under the concentration time curve from time 0 to time of 
last measurable concentration
AUC0-∞
:
area under the concentration time curve from time 0 to infinity
t½
: 
terminal elimination half-life
Vd/F
:
apparent volume of distribution of the drug following extravascular 
administration
Actual sampling times will be used in the analysis.
Additional pharmacokinetic parameters, including partial AUCs and respective average plasma 
concentration (Caverage) to be inclusive of the PET scan duration, may be calculated as well, as 
deemed necessary.
6.1.1.
Specimen Sampling and Handling
Blood samples (either 6 mL for doses 0.5 and 1 mg [Part A only] or 2 mL for doses ≥2.5 mg) 
will be collected for analysis of pridopidine and the metabolite TV-45065 up to 1 hour prior to 
pridopidine dosing, at 5 (±1 minute), 15, 30, 45 and 60 minutes after dosing (±2 minutes), and at 
1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours after dosing. A 10-minute window will be allowed for 
all postdose sampling intervals from 1.5 hours up to and including 24 hours after dosing. 
Every effort must be made to obtain the pharmacokinetic samples at the scheduled times or 
within the allowed limits for sampling times, as defined in Table 1. The date and time of each 
pharmacokinetic sample and the date and time of the last drug administration prior to any 
collected pharmacokinetic sample will be recorded as source documentation and transcribed onto 
the CRF. Deviations from the scheduled blood sampling time points will be commented on the 
respective page of the CRF.
In case of a serious adverse event, the aim will be to collect an additional pharmacokinetic 
sample at the closest time possible to the serious adverse event.
Samples will be collected in tripotassium ethylenediaminetetraacetic acid (K3EDTA)-containing 
tubes. Immediately following collection, samples will be cooled and centrifuged within 


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45 minutes at approximately 4°C at 1500 × g for 15 minutes. The plasma will then be transferred 
into 2 polypropylene tubes (Nunc cryovials 1.8 mL) (first aliquot [Set A] and back-up [Set B]) 
and stored below -20°C until bioanalysis.
Sample labels should include the study number, pridopidine dose tracer, permanent unique 
treatment number, nominal collection time, set (A or B), and indication that they are pridopidine 
plasma pharmacokinetic samples.
6.1.2.
Shipment and Analysis of Samples
Plasma pridopidine and TV-45065 pharmacokinetic samples for all subjects will be shipped from 
the investigational center to the sponsor or its designee for analysis. Samples will be stored in an 
upright position at –20ºC or below until assayed. The laboratory will be notified before the 
shipment of the samples and will be sent the shipping information when the samples are shipped.
Shipments will be made following each cohort, with all samples from individual subject shipped 
together
Set A samples will be transported, frozen with sufficient dry ice for 4 days, by next-day courier 
to the laboratory identified in the front matter of this protocol. 
Set B samples will be sent to the same laboratory as that for Set A on a subsequent day by 
next-day courier. Set B samples will be sent shortly after arrival of Set A samples.
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
Samples of cohorts ≥ 2.5 mg of pridopidine will be analyzed using an appropriate validated 
method for pridopidine and its main metabolite TV-45065 (IRD-MA-119). The lower limits of 
quantification (LLOQ) for pridopidine and TV-45065 in plasma are approximately 2 ng/mL and 
1 ng/mL, respectively. Incurred sample reanalysis may be performed. For cohorts 0.5 and 1 mg 
pridopidine (Part A only), a lower bioanalytical range will be validated for both pridopidine and 
TV-45065, with a LLOQ of 40 pg/mL (method IRD-MA-155). Incurred sample reanalysis will 
be performed.
6.2.
Pharmacodynamic Assessment
The imaging procedures will be performed as detailed in the study imaging manual.
6.2.1.
Determination of [18F]fluspidine and [18F]Fallypride Functions 
During the study period, the subjects will undergo a baseline PET investigation (PET session 1) 
and a post-dosing PET investigation (PET session 2) following a single oral dose of pridopidine. 
The PET sessions will be started approximately 2 hours postdose of pridopidine in order to 
acquire PET images centered around the mean plasma concentration which would be expected 
on average for repeated dosing every 12 hours. Subjects will have fasted at least 2 hours prior to 
dosing. Starting with a high dose of 90 mg in dose cohort 1, the subsequent doses for following 
dose cohort will be determined based on the receptor occupancy determined for previous dose 
cohorts.
At the day of each PET session, prior to PET imaging, a cubital or forearm vein will be 
cannulated to inject the PET tracer and, at visit 3, to obtain venous blood samples for 


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quantification of pridopidine and its metabolite TV-45065 and other exploratory biomarker 
analysis. 
6.2.1.1.
[18F]fluspidine (Part 0 and Part A)
The subject’s radial artery on the other arm (or the same arm if this cannot be achieved) will be 
cannulated to obtain arterial blood samples during PET imaging for the quantification of plasma 
radioactivity associated with the PET tracer in order to estimate a metabolite-corrected arterial 
plasma input function for PET data analysis. [18F]fluspidine binds to S1R. The PET imaging will 
consist of 4 blocks with breaks in between: the first PET acquisition block of 90 minutes
duration (0 to 90 minutes) will be started together with the intravenous injection of 300±30 MBq 
[18F]fluspidine as a single bolus, the second acquisition block of 30 minutes duration will be 
started approximately 2 hours post-injection of the PET tracer (120 to 150 minutes), the third 
block of 30 minutes duration will be started 3 hours post-injection (180 to 210 minutes), and the 
fourth block of 30 minutes duration will be started 6 hours (360 to 390 minutes) post-injection. 
From the second block onwards, acquisition can commence within ±10 minutes of the nominal 
time, but the duration should still be 30 minutes for each of these blocks. Each PET acquisition 
block will be acquired in list mode in order to allow variable subdivision into multiple time 
frames. The PET session 2 will start 2 hours postdose of pridopidine. Prior to any blocking with 
pridopidine, a test-retest will be performed for up to 6 subjects under similar conditions. In an 
effort to facilitate easier PET procedure for HD patients, after the first 90-minute PET 
acquisition block, the subsequent 30-minute PET acquisition blocks are made optional per 
Investigator’s judgement.
Test-retest variability of [18F]fluspidine uptake will be estimated using 2 baseline [18F]fluspidine 
scans in up to 6 subjects. This will be used to calculate the uncertainty of the RO estimate.
Appropriate analysis will be performed to estimate the S1R binding potential and RO. Available 
evidence suggests that there is no viable reference region in the brain for [18F]fluspidine that can 
be used for modeling purpose. Therefore, metabolite-corrected arterial plasma input function will 
be estimated and used in the calculation of regional PET volume of distribution (VT), regional 
binding potential (BPND) and RO defined as the treatment-induced relative change in the 
concentration in the available receptor density as:
%
100
)
(
)
(
1








baseline
BP
treatment
BP
RO
ND
ND
Where BPND(treatment) is the binding potential under the treatment condition and 
BPND(baseline) the binding potential at baseline. The BPND is a parameter proportional to the 
density of the available receptors and the affinity of the tracer to the receptor.
Due to the fact that a reference region most likely does not exist the following procedure is likely 
be used to derive the relevant PET parameters:

VT, representing the total radioligand in tissue (ie, free, non-displaceable and 
specifically bound) and a global non-displaceable volume of distribution (VND) will 
be calculated for each brain region and for each postdose scan using appropriate
compartmental models.

VT and VND will allow the estimation of BPND, and the global occupancy.


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RO expressed as a percentage will be calculated for each subject and each postdose scan. 
Spatial normalization of the PET scan to a brain atlas template will be performed using a 
corresponding MRI scan. All PET parameters will be calculated globally, for the whole brain, 
and for specific predefined brain areas.
6.2.1.2.
[18F]fallypride (Part B)
[18F]fallypride binds to D2R in striatal and to a lesser extent in extra-striatal regions. The PET 
imaging will consist of 4 blocks with breaks in between: the first PET acquisition block of 
90 minutes duration (0 to 90 minutes) will be started together with the intravenous injection of 
200±20 MBq [18F]fallypride as a single bolus, the second acquisition block of 30 minutes
duration will be started approximately 2 hours post-injection of the PET tracer (120 to 
150 minutes), the third block of 30 minutes duration will be started 3 hours post-injection (180 to 
210 minutes), and the fourth block of 30 minutes duration will be started 6 hours (360 to 
390 minutes) post-injection. From the second block onwards, acquisition can commence within 
±10 minutes of the nominal time, but the duration should still be 30 minutes for each of these 
blocks. Each PET acquisition block will be acquired in list mode in order to allow variable 
subdivision into multiple time frames. The PET session 2 will start approximately 2 hours 
postdose of pridopidine. In an effort to facilitate easier PET procedure for HD patients, after the 
first 90-minute PET acquisition block, the subsequent 30-minute PET acquisition blocks are 
made optional per Investigator’s judgement.
The cerebellum can be used as a reference region for [18F]fallypride since it has been shown to 
have a minimal presence or a lack of D2 receptors, and therefore the simplified reference tissue 
model can be applied.
Reference region: cerebellum (excluding vermis) using Automated Anatomical Labeling atlas. 
Specific binding regions of interest: caudate, putamen, medial inferior temporal gyri, thalamus, 
amygdala, hippocampus, arbitofrontal cortex, anterior cingulate gyrus using Tzioritzi atlas plus 
striatum with subdivisions in 
 using 
anterior/posterior commissure transaxial plane.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight and height measurements), and use of concomitant 
medication.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a subject 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 subject 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.
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

drug interactions

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 subject
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, 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 subject from entering the study or receiving study 
treatment are not considered adverse events.)


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7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse event, the study period is defined for each subject as that time period 
from signature of the informed consent form to the end of the follow-up period. The follow-up 
period is defined as 7 days after the last dose of study drug.
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed to the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the serious adverse event form must be 
completed and the serious adverse event must be reported immediately (see Section 7.1.5.3.1).
The investigator does not need to actively monitor subjects for adverse events once the study has 
ended. Serious adverse events occurring in a subject after the treatment of that subject 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 subject, the investigator or designee must question the subject 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 serious adverse event, on the 
serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved,
stabilized, or returned to baseline; or until the subject is referred for continued care to a 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 and times, duration, action taken regarding study drug, treatment 
administered, and outcome for each adverse event must be recorded on the source documentation 
and transcribed to the CRF.
The relationship of each adverse event to study drug 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


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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 subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject.

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 subject’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the subject.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
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 serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

death

a life-threatening adverse event (ie, the subject 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 or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event


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Hospitalizations scheduled before the subject signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
preexisting condition during the subject’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 subject 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.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of 
>3× the upper limit of normal (ULN)

total bilirubin elevation of >2× ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)
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 serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the pridopidine IB.
The sponsor’s Global Patient Safety and Pharmacovigilance will determine the expectedness for 
all serious adverse events.
For the purpose of suspected unexpected serious adverse reaction (SUSAR) reporting, the 
version of the IB at the time of occurrence of the SUSAR applies.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (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 


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the investigator learns about it. Completing the serious adverse event 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 subjects for adverse events once this study has ended.
Serious adverse events occurring to a subject after the treatment of that subject has ended should 
be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the sponsor’s LSO in Germany (contact
information is in the Clinical Study Personnel Contact Information section).
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

subject 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 subject

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 medication (including doses, routes of administration, 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)
The investigator must ensure that the IEC/IRB is also informed of the event, in accordance with 
national and local regulations.


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Each report of a serious adverse event 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 serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator 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 and Pharmacovigilance will distribute the 
Council for International Organizations of Medical Sciences (CIOMS) form/Extensible Markup 
Language (XML) file to the LSO/CRO for submission to the competent authorities, IEC/IRBs, 
and investigators, according to regulations. The investigator is responsible for ensuring that the 
IEC/IRB is also informed of the event, in accordance with national and local regulations.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, 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 competent authorities (and 
IEC/IRB, as appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other measures may be required, including:

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 all 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 subject should be discontinued from the study and
referred to a psychiatrist for evaluation and monitoring.
7.1.7.
Withdrawal Due to an Adverse Event
Any subject 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 subject is withdrawn wholly or in 


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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 obtained for the measurement of study drug concentrations.
The subject will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the subject 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 clinical project physician (CPP)/clinical leader (CL) as soon as 
possible of each subject who is being considered for withdrawal due to adverse events. 
Additional reports must be provided when requested.
If a subject is withdrawn from the study drug 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 prohibited medication, thereby requiring discontinuation of the subject. In such a case, 
the reason for discontinuation would be need to take a prohibited medication, not the adverse 
event.
7.1.8.
Overdose of Study Drug
Any dose of study drug (whether the investigational product or tracers), 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 subject experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure subject safety, after the event has stabilized 
or treatment has been administered (or both), the investigator or other physician in attendance 
must contact the physician 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 subject should continue to participate in the study.
7.2.
Pregnancy
Only male healthy subjects and (optional) HD patients will be enrolled in this study.
All pregnancies of female partners of men participating in the study that occur within 3 months 
of completion of the study, are to be reported immediately to the physician 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 serious adverse event but using the pregnancy form (see 
Section 7.1.5.3).
7.3.
Medication Error and Special Situations
Any administration of medication that is not in accordance with the study protocol should be 
reported on the CRF either as a violation, if it meets the violation criteria specified in the 
protocol (Section 11.1.2), or as a deviation, in the subjects source documents, regardless of 


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whether an adverse event occurs as a result. All instances of incorrect medication administration 
should be categorized on the CRF as “Non-Compliance to investigational medicinal product 
(IMP)”.
Types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
subject, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied.
3. Misuse: Situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects.
5. Off-label use: Situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information.
6. Occupational exposure: Exposure to a medicinal product, as a result of one’s professional 
or non-professional occupation.
7.4.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation, transcribed to the CRF as an adverse event, and monitored as 
described in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in the withdrawal of the subject 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 may be predefined by the sponsor for 
selected laboratory test variables (see Section 9.10.2) and, if so, will be documented in the 
statistical analysis plan or other relevant documents (eg, medical monitoring plan or laboratory 
analysis plan).
7.4.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. Clinical laboratory tests will be performed using 
a central laboratory. Specific laboratory tests to be performed are provided in Table 5.


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Table 5:
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
calcium
phosphorus
sodium
potassium
magnesium
chloride
glucose
blood urea nitrogen (BUN)
creatinine (including calculation of 
creatinine clearance using the 
Cockcroft-Gault formula)
cholesterol (low density lipoprotein 
(LDL)/high density lipoprotein (HDL)
/total)
uric acid
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
lactate dehydrogenase (LDH)
gamma-glutamyl transpeptidase (GGT)
alkaline phosphatase
creatine phosphokinase (CPK) - in case 
of elevated CPK, the MB fraction should 
be measured
total protein
albumin
total bilirubin
direct bilirubin
indirect bilirubin
prolactin
hemoglobin
hematocrit
red blood cell (RBC) count
RBC indices
platelet count
white blood cell (WBC) count, and 
differential count and percentage
absolute neutrophil count (ANC)
polymorphonuclear leukocytes 
(neutrophils)
lymphocytes
eosinophils
monocytes
basophils
atypical lymphocytes
Prothrombin International Normalized 
Ratio (INR)
Activated partial Thromboplastin Time 
(aPTT)
protein
glucose
ketones
blood (hemoglobin)
pH
specific gravity
microscopic
bacteria
RBCs
WBCs
casts
crystals
7.4.2.
Other Clinical Laboratory Tests
At screening, subjects will be tested for HIV-1, HIV-2, HBsAg, and hepatitis C antibody.
7.4.2.1.
Urine Drug Screen
A urine drug screen will be performed at screening and on day -1. The drug screen will detect the 
presence of amphetamines, cocaine, opiates, cannabis, barbiturates, and benzodiazepine. A 
positive result for any of these drugs or their metabolites, without medical explanation, will 
preclude the subject from enrollment or continued participation in the study.


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7.4.2.2.
Corticoid Plasma Levels
Endogenous corticoid plasma levels will be measured on day 1 of visits 2 and 3 (immediately 
before the tracer injection). The analysis will include measurement of DHEA, progesterone, 
testosterone, cortisol, and, where feasible, androstanolone, allopregnanolone, pregnenolone.
7.5.
Vital Signs
Vital signs (pulse, BP, body temperature, and respiratory rate) will be measured at the time 
points detailed in Table 1. All vital signs results outside of the reference ranges will be judged by 
the investigator as belonging to one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Before pulse and BP are measured, the subject must be in a seated or supine 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 subject.) 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.
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected vital signs (see Section 9.10.2) and, if so, will be documented in the statistical analysis 
plan or other relevant documents (eg, medical monitoring plan).
When vital signs collection coincides with a pharmacokinetic sample, vital signs will be 
collected before the pharmacokinetic sample.
7.6.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 1. A qualified physician will 
be responsible for interpreting the ECG. Any ECG finding that is judged by the investigator as 
clinically significant will be considered an adverse event, recorded on the source documentation,
transcribed to the CRF, and monitored as described in Section 7.1.2.
The 12-lead ECG is to be performed before pridopidine administration; immediately before 
administration of the tracer (approximately 90 minutes after pridopidine administration), and at 
the end of the first PET scan (approximately 3.5 hours after pridopidine administration).
When ECG collection coincides with a pharmacokinetic sample, ECG will be collected before 
the pharmacokinetic sample.
7.7.
Physical Examinations
Physical examinations, including height and weight (to be obtained at the screening visit only),
will be performed at the time points detailed in Table 1. Any new physical examination finding 
that is judged by the investigator as clinically significant will be considered an adverse event,
recorded on the CRF, and monitored as described in Section 7.1.2.


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A complete physical examination will be performed at screening and at the follow-up/ET visits 
only. On other occasions, an abbreviated/symptom-oriented physical examination will be 
performed.
7.8.
Concomitant Medication or Treatment
Use of concomitant medication or treatment will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.
7.9.
Assessment of Local Tolerability and Pain
Local tolerability at the injection site of the tracer (eg, pain, erythema, ecchymosis, induration) 
will be evaluated as part of the standard medical supervision during administration.
7.10.
Modified Allen Test
The Modified Allen Test will be performed at screening for Part 0 and Part A subjects only.
A modified Allen test measures arterial competency, and should be performed for both hands. 
The procedure for performing the test is as follows (derived from 
1. The subject is instructed to clench his fist; if the subject is unable to do this, the subject’s 
hand is to be tightly closed by the assessor.
2. Using fingers, occlusive pressure is applied to both the ulnar and radial arteries, to 
obstruct blood flow to the hand.
3. While applying occlusive pressure to both arteries, the subject should relax his hand, and 
a check is performed as to whether the palm and fingers have blanched, to ensure that the 
arteries are completely occluded.
4. The occlusive pressure on the ulnar artery is released to determine whether the modified 
Allen test is positive or negative:

Positive modified Allen test – If the hand flushes within 5 to 15 seconds it indicates 
that the ulnar artery has good blood flow; this normal flushing of the hand is 
considered to be a positive test.

Negative modified Allen test – If the hand does not flush within 5 to 15 seconds, it 
indicates that ulnar circulation is inadequate or nonexistent.
7.11.
Columbia Suicide Severity Rating Scale
The C-SSRS (screening version) will be used at screening to rate the subject’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). Subjects with a history of suicidality based upon clinical 
history or C-SSRS scoring will not be eligible for the study. The person administering the 
C-SSRS should have performed the rater training and have obtained a training certificate within 
the previous 2 years.


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In any event of suspected active suicidality (eg, active suicidal ideation or intent, significant 
suicidal behavior) or clinical findings suggesting that the subject is dangerous to himself or 
herself, the subject should be referred for immediate psychiatric evaluation.
The version of C-SSRS used will be translated into German and linguistically validated. 
7.12.
Unified Huntington’s Disease Rating Scale Total Motor Score 
(UHDRS-TMS) (HD Patients Only)
For HD patients only, UHDRS-TMS is performed at the time points detailed in Table 1.
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, 
with each assessment rated on a 5-point scale from 0 (normal) to 4 (maximally abnormal).
7.13.
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data
All adverse events will be reviewed on a periodic basis by the CPP/medical monitor according to 
the safety monitoring plan (eg, scheduled safety reviews for pridopidine) as interim/preliminary 
safety databases become available. In addition, safety data will be evaluated periodically and ad 
hoc (if necessary) in the Product Safety Group.
Methods and time points of assessing safety data are discussed in Section 3.14. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.10.2.


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8.
ASSESSMENT OF BIOMARKERS AND PHARMACOGENETICS
8.1.
Assessment of Exploratory Biomarkers
8.1.1.
Biomarker Assessments
Biomarkers are defined as biological substances that monitor physiological effects, assessing 
drug activity, predicting clinical outcome, safety, and treatment response.
Biomarker assessment potentially includes the following:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The final list of biomarkers that will be investigated will be selected at a later stage before the 
analysis so as to allow updating with new scientific information.
8.1.2.
Pharmacogenetic Assessment
and it is known that subjects with functional 
mutations resulting in inactive enzyme will show higher exposures and are at greater risk of 
known emergent adverse events. As a result, DNA will be collected, and subjects identified as 
poor CYP2D6 metabolizers will be excluded from the study. Remnant DNA will also be 
genotyped to identify extensive, intermediate and ultra CYP2D6 metabolizers. Genotyping may 
also be conducted for QTc in the event of any emergent safety findings. In addition, functional 
genetic polymorphisms have been described in the S1R receptor that results in decreased 
receptor expression (Miyatake et al 2004). Examination of the known S1R polymorphisms did 
not impact fluvoxamine displacement with SA4503 (Ishikawa et al 2007). However, the impact 
of these polymorphisms on fluspidine displacement is not known.
 
 


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Genetic long QT syndrome genotyping may also be conducted retrospectively and assessed only 
in subjects experiencing QT prolongation following study drug administration leading to study 
discontinuation. Blood sampling for pharmacogenetics can be performed at a separate visit 
within the screening period after informed consent is obtained.
8.1.3.
Specimen Sampling and Handling
8.1.3.1.
Biomarker Samples
For all dose cohorts ≥2.5 mg, biomarker blood samples of 4 mL to provide 2 mL serum, 4 mL to 
provide 2 mL plasma, with an additional 2.5 mL collected in a PAXgene tube will be collected. 
For the 0.5 and 1 mg dose cohort in Part A, biomarker blood samples of 2 mL for plasma, 
2.5 mL of PAXgene tube, and no serum samples will be collected.
The date and time of each biomarker sample and the dates and times of the last drug 
administration prior to any collected biomarker sample will be recorded on the source 
documentation and transcribed onto the CRF. Only major deviations (>5%) from the scheduled 
blood sampling time points will be commented on the respective page of the CRF.
When the biomarker blood sample collection coincides with pharmacokinetic measures, the 
biomarker samples should be collected after pharmacokinetic sampling.
For plasma, samples will be collected in lavender-top (K3EDTA) Vacutainer venous blood 
collection tubes following site standard phlebotomy practices and procedures. Immediately 
following collection, the tube should be gently inverted 4 to 8 times, and cooled on wet ice. 
Within 45 minutes of collection, the tube should be centrifuged at approximately 4°C at 1500 × g 
for 15 minutes. The plasma should then be immediately transferred into 2 polypropylene tubes 
(first aliquot [Set A] and back-up [Set B]) and stored below -70°C (or -20°C in a non-defrosting 
freezer if -70°C is not available) until shipment to the sponsor specified biorepository
), where they will be retained for at least 15 years.
For serum, samples will be collected into red-top Vacutainer tubes (serum separators should not 
be used) following site standard phlebotomy practices and procedures. Tubes should be gently 
inverted 4 to 6 times and stored upright at room temperature for 30 to 45 minutes. Within 
45 minutes of collection, tubes should be centrifuged at approximately 4°C at 1500 × g for 
15 minutes. The serum should then be immediately transferred into 2 polypropylene tubes (first 
aliquot [Set A] and back-up [Set B]) and stored below -70°C (or -20°C in a non-defrosting 
freezer if -70°C is not available) until shipment to the sponsor specified biorepository
), where they will be retained for at least 15 years.
For RNA, samples will be collected into a PAXgene blood RNA tube at room temperature 
following site standard phlebotomy practices and procedures. The PAXgene tube should be 
collected after the serum and plasma collections and held in an upright vertical position below 
the donor’s arm during blood collection. For a complete blood draw, at least 10 seconds should 
be allowed and it should be ensured that blood has stopped flowing into the tube before 


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removing from the holder. The PAXgene blood RNA tube should be gently inverted (not shaken)
8 to 10 times and stored upright at room temperature. The tube should be incubated at room 
temperature for 2 hours to ensure complete lysis before freezing. Samples should be frozen for at 
least 24 hours at -20°C and then transferred to -70°C until shipment to the sponsor specified 
biorepository
), where they will be retained for at 
least 15 years.
8.1.3.2.
Pharmacogenetic Samples
Pharmacogenetic blood samples will be collected at screening only. For all dose cohorts ≥2.5 
mg, the pharmacogenetic blood should be collected into a 4.9-mL (K3EDTA) Sarstedt 
Monovette® venous blood collection tube labeled with the subject coded number and following 
site standard phlebotomy practices and procedures. For the 0.5 and 1 mg dose cohort in Part A, 
the pharmacogenetic blood should be collected into a 2.7-mL (K3EDTA) Sarstedt Monovette®
venous blood collection tube labeled with the subject coded number and following site standard 
phlebotomy practices and procedures.
Immediately following collection, the tube should be gently inverted (not shaken) 4 to 8 times. 
The tubes must not be centrifuged. Samples are to be stored and shipped at 4°C if they are to 
arrive to the genotyping laboratory within 48 hours for CYP2D6 genotyping; if not, samples 
should be stored at -20°C in a non-defrosting freezer at the study site until shipment
 
 
8.1.4.
Shipment and Analysis of Samples
8.1.4.1.
Biomarker Samples
Biomarker sample aliquots should be shipped on dry ice by overnight courier to 
 
and stored at -70°C. Vendor contact details will be provided by 
the sponsor.
8.1.4.2.
Pharmacogenetic Samples
Pharmacogenetic samples should be shipped by overnight courier to a specified vendor 
 
 during screening (either ambient if to be received by the genotyping 
laboratory within 48 hours or on dry ice if stored at -20°C). Remnant DNA should be retained 
and stored at the vendor until the end of study and then shipped to the biorepository
 
 The remnant samples will be labeled with a new code so 
genetic data will not be recorded with a subject number.


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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 
(CSR).
9.1.
Sample Size and Power Considerations
This PET study is exploratory in nature; therefore, no formal hypothesis testing is planned. Thus, 
based on clinical and practical considerations, a sample size of up to approximately 38 subjects 
(up to 4 subjects per dose level) is considered adequate for this type of study and to attain the 
study objectives. Up to 45 subjects are planned to be enrolled in this study to ensure up to 
38 evaluable subjects. Adaptive study design will allow increasing or reducing the study total 
sample size or each dose/time cohort as necessary. This sample size may include up to 4 patients 
with HD, which may be added to study engagement of pridopidine to the D2R and to explore the 
effects of neurodegeneration.
It is anticipated that 3 dose levels will be sufficient to characterize the exposure-response profile. 
However, additional cohorts may be studied. 
9.2.
Analysis Sets
9.2.1.
Enrolled Analysis Set
The enrolled analysis set will include all enrolled subjects, regardless of whether or not a subject
took any study drug. A subject is considered enrolled according to the status reported in the 
database.
9.2.2.
Safety Analysis Set
The safety analysis set will include all subjects who receive at least 1 dose of study drug. In this 
analysis set, treatment will be assigned based on the treatment subjects actually received.
9.2.3.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will include those subjects in the safety analysis set who have 
sufficient data to calculate at least 1 evaluable pharmacokinetic parameter for pridopidine or its 
metabolites.
9.2.4.
Pharmacodynamic Analysis Set
The pharmacodynamic analysis set will include those subjects in the safety analysis set who have 
evaluable imaging data before and after pridopidine administration.


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9.3.
Data Handling Conventions
For all variables, only the observed data from the subjects will be used in the statistical analyses, 
ie, there is no plan to estimate missing data, unless otherwise specified. Detailed data imputation 
rules will be described in statistical analysis plan.
9.3.1.
Handling Withdrawals and Missing Data
Missing data will not be imputed, unless otherwise specified.
9.4.
Study Population
The enrolled analysis set (see Section 9.2) will be used for all study population summaries unless 
otherwise specified. 
9.4.1.
Subject Disposition
Data from subjects screened, subjects screened but not enrolled (and reason not enrolled), 
subjects who are enrolled, subjects enrolled but not treated (and reason), subjects in the safety 
and pharmacokinetic analysis sets, subjects who complete the study, and subjects who withdraw 
from the study will be summarized using descriptive statistics. Data from subjects who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics.
9.4.2.
Demographic and Baseline Characteristics
Subject 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, subject counts and percentages will be 
provided. Categories for missing data will be presented if necessary.
9.5.
Pharmacodynamic Analysis
9.5.1.
Analysis with (S)-(-)-[18F]fluspidine 
Details of the analysis to be performed are presented in Section 6.2.1.1.
The occupancy data for the study will be combined with the plasma concentration of pridopidine 
and used to derive the in vivo affinity of pridopidine for the S1R and the time-course of the 
occupancy of S1R by pridopidine.
Test-retest variability of (S)-(-)-[18F]fluspidine uptake will be estimated using 2 baseline 
(S)-(-)-[18F]fluspidine scans in up to 6 subjects. This will be used to calculate the uncertainty of 
the RO estimate.
9.5.2.
Analysis Using [18F]fallypride 
The analysis using [18F]fallypride will be similar to that using (S)-(-)-[18F]fluspidine. 
For calculation of BPND and RO for [18F]fallypride, a tissue reference model can be used using 
the cerebellum as reference region without specific binding. 


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9.6.
Pharmacokinetic Analysis
The pharmacokinetic parameters to be calculated for pridopidine and its metabolite TV-45065 in 
the plasma using non-compartmental methods, when possible, are detailed in Section 6.1. 
Additional pharmacokinetic parameters, including partial AUCs and corresponding Caverage to be 
inclusive of the PET scan duration, may be calculated as well, as deemed necessary.
No formal statistical analyses of the pharmacokinetic data will be performed. All data will be 
listed and summarized descriptively by cohort (dose) and status (healthy subject or HD patient) 
and presented in tabular and graphical form where appropriate. The pharmacokinetic analysis set 
(see Section 9.2.3) will be used for all pharmacokinetic analyses.
9.7.
Pharmacokinetic/Pharmacodynamic Analysis
The relationship between the pridopidine plasma concentrations and the RO will be explored 
graphically. If possible, an exposure-response model will be developed to quantitatively define 
the relationship between RO and pridopidine exposure. It will be based on the following Emax
model (equation) to fit the pharmacokinetic-pharmacodynamic (PK/PD) data (Grachev et al 
2014):
C
EC
C
E
E



50
max
Where E represents the receptor occupancy (%); C is the plasma concentration (ng/mL) 
corresponding to the receptor occupancy E; Emax is an asymptote representing the maximum 
receptor occupancy (%); EC50 is the plasma concentration (ng/mL) corresponding to 50% of 
Emax.
Two additional parameters derived to characterize various levels of receptor occupancy are: 

EC80 - the plasma concentration (ng/mL) corresponding to 80% of Emax. It is 
calculated directly from the equation by substituting E=80% of Emax and then solving 
for C. 

ECopt - plasma concentration (ng/mL) corresponding to optimal receptor occupancy. 
ECopt was defined as the lowest observed plasma concentration that achieved the 
model estimated Emax.
Details of the analysis will be provided in a separate analysis plan.
9.8.
Planned Method of Analysis
The enrolled analysis set (see Section 9.2.1) will be used for all pharmacodynamic analyses. 
Summaries will be presented by treatment group.
9.9.
Multiple Comparisons and Multiplicity
No adjustments will be made for the preplanned multiple comparisons/endpoints.


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9.10.
Safety Endpoints and Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.2).
9.10.1.
Safety Endpoints
Safety measures and time points are provided in Table 1.
9.10.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each subject 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 (ie, 
reasonable possibility; see Section 7.1.4) (defined as related or with missing relationship) 
(overall and by severity), serious adverse events, and adverse events causing withdrawal from 
the study. Summaries will be presented by treatment group and for all subjects. Subject listings 
of serious adverse events 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 predefined criteria to identify potentially clinically significant 
values or changes, 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 subject 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, subject counts and percentages will be provided. Descriptive summaries of serious 
adverse events, subject withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will be provided
as well.
If any subject dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the subject narrative included in the CSR.
9.11.
Tolerability Variables and Analysis
Subject tolerability assessments (the number [%] of subjects who fail to complete the study, 
number [%] of subjects who fail to complete the study due to adverse events, and the number of 
subjects who experience treatment-emergent adverse events) will be summarized.
9.12.
Pharmacogenetic and Biomarker Analysis
Levels in exploratory biomarkers will be compared to baseline and summary tables may be 
generated. Exploratory biomarker results will be generated at a future point and handled in a 
separate addendum report.


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9.13.
Relationship Between Unified Huntington’s Disease Rating Scale 
Total Motor Score (UHDRS-TMS) and Other Endpoints
Relationships between UHDRS-TMS (absolute score and change from baseline) and other 
endpoints will be evaluated in HD patients. Details of this analysis will be presented in the 
statistical analysis plan.
9.14.
Planned Interim Analysis
There will be no formal interim analysis.
9.15.
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 CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations.


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10.
DIRECT ACCESS TO SOURCE DATAAND DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that subject confidentiality is maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each subject’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 3.13).
The investigator will maintain a confidential subject identification list that allows the 
unambiguous identification of each subject. All study-related documents must be kept until 
notification by the sponsor.


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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 national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the subjects or when the change involves only nonsubstantial logistics or 
administration. The PI at the investigational center, the coordinating investigator (if applicable),
and the sponsor will sign the protocol amendment.
11.1.2.
Protocol Violations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include non-adherence on the part of the 
subject, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to study drug 
administration; use of prohibited medications. Protocol violations will be identified and recorded 
by investigational center personnel in 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 
subject from the study or permit the subject to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the subject and 
preserving the integrity of the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a subject who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol violation. If such subject has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of subject management, both before starting the study 
and during the course of the study (eg, when new personnel become involved). The investigator 
must ensure that all study personnel are qualified by education, experience, and training to 
perform their specific task. These study personnel members must be listed on the investigational 
center authorization form, which includes a clear description of each personnel 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 personnel, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 


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made available during the study when new personnel members 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 subjects have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (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 subjects 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 document [see Section 3.13]) 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 personnel 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 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 or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center 
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


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
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 subject’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 PI name

name, phone number, and address of the source of the complaint

clinical protocol number

subject identifier (subject study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

subject 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 serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling of 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 
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 study drug, the sponsor will 
provide the information needed to handle the return.


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11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively).
11.4.4.
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint,
and any actions taken to resolve the complaint and to preserve the safety of the subject. 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, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Clinical Development, is responsible for 
determining the need for (and timing of) an investigational center audit.
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines.


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12.
ETHICS
Details of compliance with regulatory requirements 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 
subject of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and oral information about the study will be provided in a language as 
nontechnical as practical to be understood by the subject. The subject 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 documents.
Written informed consent will be obtained from each subject 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 subject’s 
willingness to participate in the study will be documented in the informed consent form, which 
will be signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. The investigator will keep the original informed consent forms, and copies 
will be given to the subjects. It will also be explained to the subjects that the subject is free to 
refuse participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment.
Adult subjects with a legally acceptable representative should provide informed consent
according to national and local requirements.
12.2.
Competent Authorities and Independent Ethics 
Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national and local competent 
authority and to the IEC/IRB for review. As required, the study will not start before the IEC/IRB 
and competent authority (where applicable) for the investigational center give written approval 
or a favorable opinion.
12.3.
Confidentiality Regarding Study Subjects
The investigator must ensure that the privacy of the subjects, 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, subjects will be identified not by their names, but by an 
identification number.
Personal medical information may be reviewed for the purpose of subject safety or for verifying 
data in the source and transcribed to the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, Global Quality Assurance, or 
competent authorities. Personal medical information will always be treated as confidential.


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12.4.
Declaration of the End of Clinical Study
For 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/EC, Article 10(c); for other 
countries, national and local regulations will be followed.
12.5.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study may be registered on clinical trials registry websites.


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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 subject who provided informed consent. 
Subject identity should not be discernible from the data provided on the CRF. Data will be 
verified by the study monitor using the data source, 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, electronic subject-reported outcome [ePRO] Tablet), the 
results will be sent to the investigational center, where they will be retained but not entered in 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 in the clinical database. 
Laboratory test results will not be entered in the CRF unless otherwise specified in the protocol. 
All data from other sources will be available to the investigators.
For subjects who enter a study but do not meet entry criteria, at a minimum, data for screening
failure reason, demography, and adverse events from the time of informed consent will be 
entered in 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.
CRFs 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.


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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. Investigational 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 national and local laws, including, but not limited to:

full case histories

signed informed consent forms

subject identification lists

CRFs for each subject on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the study drug

copies of all correspondence with sponsor, the IEC/IRB, and any competent authority
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational 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 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 


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for appropriate archival or 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.


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14.
FINANCING AND INSURANCE
 
 
 
 
 
 


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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 national, local, and regional requirements and regulations for 
registration and posting of results.
The sponsor is responsible for the preparation of a CSR, in cooperation with the PI. The final 
report is signed by the sponsor and, if applicable, by the PI.
When the sponsor generates reports from the data collected in this study for presentation to 
competent authorities, drafts may be circulated to the PI for comments and suggestions. An 
endorsement of the final report will be sought from the PI.
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 
“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 investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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16.
REFERENCES
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th
edition). Arlington, VA: American Psychiatric Publishing, 2013.
Fischer S, Wiese C, Maestrup EG, Hiller A, Deuther-Conrad W, Scheunemann M, et al. 
Molecular imaging of σ receptors: synthesis and evaluation of the potent σ1 selective radioligand 
[18F]fluspidine. Eur J Nucl Med Mol Imaging 2011;38(3):540-51. 
Grachev ID, Doder M, Brooks DJ, Hinz R. An in vivo Positron Emission Tomography Study of 
Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects. J 
Diagn Imaging Ther 2014;1(1):20-48.
Hayashi T, Su TP. Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric 
disorders. CNS Drugs 2004;18(5):269-84.
Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC. Suicidality in 
Huntington's disease. J Affect Disord 2012;136(3):550-7.
Hubers AAM, van Duijn E, Roos RAC, Craufurd D, Rickards H, Landwehrmeyer GB, et al. 
Suicidal ideation in a European Huntington's disease population. J Affect Disord 2013;151:248–
58.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11(2):136-42.
Ishikawa M, Hashimoto K. The role of sigma-1 receptors in the pathophysiology of 
neuropsychiatric diseases. J Recept Ligand Channel Res 2010;3:25–36.
Ishikawa M, Ishiwata K, Ishii K, Kimura Y, Sakata M, Naganawa M, et al. High occupancy of 
sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron 
emission tomography study using [11C]SA4503. Biol Psychiatry. 2007;62(8):878-83.
Kessler RM, Mason NS, Jones C, Ansari MS, Manning RG, Price RR. [18F]N-allyl-5-
fluoroproplepidepride (Fallypride): Radiation dosimetry, quantification of striatal and 
extrastriatal dopamine receptors in man. Neuroimage 2000;11:S32.
Kranz M, Sattler B, Wüst N, Deuther-Conrad W, Patt M, Meyer PM, et al. Evaluation of the 
Enantiomer Specific Biokinetics and Radiation Doses of [18F]Fluspidine-A New Tracer in 
Clinical Translation for Imaging of σ₁ Receptors. Molecules. 2016;21(9).
Luedtke RR, Perez E, Yang SH, Liu R, Vangveravong S, Tu Z, et al. Neuroprotective effects of 
high affinity Σ1 receptor selective compounds. Brain Res 2012;1441:17-26.
Mahant N, McCusker EA, Byth K,Graham S, Huntington Study Group. Huntington’s disease. 
Clinical correlates of disability and progression. Neurology 2003;61:1085–92.
Maisonial A, Grosse Maestrup E, Wiese C, Hiller A, Schepmann D, Fischer S, et al. Synthesis, 
radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for 
central σ1 receptors and comparison with fluoroalkyl homologs. Bioorg Med Chem 
2012;20(1):257-69.


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Maurice T, Grégoire C, Espallergues J. Neuro(active)steroids actions at the neuromodulatory 
sigma1 (σ1) receptor: biochemical and physiological evidences, consequences in 
neuroprotection. Pharmacol Biochem Behav 2006;84(4):581-97.
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.
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.
Mishina M, Ohyama M, Ishii K, Kitamura S, Kimura Y, Oda K et al. Low density of sigma1 
receptors in early Alzheimer's disease. Ann Nucl Med 2008;22(3):151-6.
Miyatake R, Furukawa A, Matsushita S, Higuchi S, Suwaki H. Functional polymorphisms in the 
sigma1 receptor gene associated with alcoholism. Biol Psychiatry 2004;55(1):85-90.
Mukherjee J, Yang ZY, Brown T, Roemer J, Cooper M. 18F-desmethoxyfallypride: a 
fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for PET imaging 
studies of dopamine D2 receptors. Life Sci 1996;59(8):669-78.
Ponten H, Kullingsjö J, Lagerkvist S,Martin P, Pettersson F, Sonesson C, et al.In vivo 
pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 2010;644:88–95.
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.
Robertson CL, Ishibashi K, Mandelkern MA, Brown AK, Ghahremani DG, Sabb F, et al. Striatal 
D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects. 
J Neurosci 2015;35(15):5990-7.
Rung JP, Rung E, Johansson AM, Svensson K, Carlsson A, Carlsson ML. Effects of the 
dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and 
monoamine-depleted rats. Naunyn Schmiedebergs Arch Pharmacol 2011;384(1):39-45.
Ruscher K, Wieloch T. The involvement of the sigma-1 receptor in neurodegeneration and 
neurorestoration. J Pharmacol Sci 2015;127(1):30-5. 
Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and 
(-)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013;18(1):12-4.
Sattler B, Kranz M, Wuest N, Patt M, Meyer PM, Deuther-Conrad W, et al. First-in-man 
incorporation dosimetry of (S)-(-)-[18F]fluspidine. J Nucl Med 2016;57:1022.
Siessmeier T, Zhou Y, Buchholz H-G, Landvogt C, Vernaleken I, Piel M, et al. Parametric 
mapping of binding in human brain of D2 receptor ligands of different affinities. J Nucl Med 
2005;46(6):964-72.
Wetzel HH, Gehl CR, Dellefave-Castillo L, Schiffman JF, Shannon KM, Paulsen JS et al. 
Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res 
2011;188(3):372-6.


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Zanotti-Fregonara P, Lammertsma AA, Innis RB. Suggested pathway to assess radiation safety 
of 18F-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging. 
2013;40(11):1781-3.

SAP_001.pdf: 
Official Title: A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine 
and [18F]fallypride Positron Emission Tomography Study to Evaluate Sigma-1 and 
Dopamine-2 Receptor Occupancy by Pridopidine in the Human Brain of Healthy 
Volunteers and in Patients with Huntington’s Disease 
NCT Number: NCT03019289 
Document Date: 1 Feb 2018 


 
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TITL 
TITLE PAGE 
Statistical Analysis Plan 
Study TV7820-IMG-10082 
 
A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine and [18F]fallypride 
Positron Emission Tomography Study to Evaluate Sigma-1 and Dopamine-2 Receptor 
Occupancy by Pridopidine in the Human Brain of Healthy Volunteers and in Patients with 
Huntington’s Disease 
Phase 1 
 
 
 
IND number: 77,419; NDA number: N/A; EudraCT number: 2016-001757-41 
 
 
Approval Date: 01 February 2018 
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
 
 
 
 
 
 
 
Prepared by: 
 
Senior Biostatistician, PRA Health Sciences – Early Development Services 
 






 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
INTRODUCTION ...........................................................................................................................9 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
1.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................10 
1.1.1. 
Primary and Secondary Study Objectives ..................................................................10 
1.1.2. 
Endpoints ....................................................................................................................10 
1.1.2.1. 
Pharmacodynamic Endpoints .....................................................................................10 
1.1.2.2. 
Pharmacokinetic Endpoints ........................................................................................10 
1.1.2.3. 
Safety and Tolerability Endpoints ..............................................................................10 
1.1.2.4. 
Biomarker Endpoints ..................................................................................................11 
1.1.2.5. 
Pharmacogenetic Endpoints........................................................................................11 
1.2. 
Exploratory Objectives and Endpoints .......................................................................11 
1.2.1. 
Exploratory Objectives ...............................................................................................11 
1.2.2. 
Exploratory Endpoints ................................................................................................12 
2. 
STUDY DESIGN .......................................................................................................13 
2.1. 
General Design ...........................................................................................................13 
2.2. 
Randomization and Blinding ......................................................................................15 
2.3. 
Data Monitoring Committee .......................................................................................15 
2.4. 
Sample Size and Power Considerations .....................................................................15 
2.5. 
Sequence of Planned Analyses ...................................................................................15 
2.5.1. 
Planned Interim Analyses ...........................................................................................15 
2.5.2. 
Final Analyses and Reporting .....................................................................................16 
3. 
ANALYSIS SETS ......................................................................................................17 
3.1. 
Enrolled Analysis Set .................................................................................................17 
3.2. 
Safety Analysis Set .....................................................................................................17 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................17 
3.4. 
Pharmacodynamic Analysis Set .................................................................................17 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................18 
4.1. 
General ........................................................................................................................18 


 
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4.2. 
Specification of Baseline Values ................................................................................18 
4.3. 
Handling Withdrawals and Missing Data ...................................................................18 
4.4. 
Study Days and Visits .................................................................................................18 
5. 
STUDY POPULATION .............................................................................................20 
5.1. 
General ........................................................................................................................20 
5.2. 
Subject Disposition .....................................................................................................20 
5.3. 
Demographics and Baseline Characteristics ...............................................................20 
5.4. 
Medical History ..........................................................................................................20 
5.5. 
Prior Therapy and Medication ....................................................................................20 
5.6. 
Study Protocol Violations ...........................................................................................20 
6. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................21 
7. 
SAFETY ANALYSIS ................................................................................................22 
7.1. 
General ........................................................................................................................22 
7.2. 
Adverse Events ...........................................................................................................22 
7.3. 
Deaths .........................................................................................................................22 
7.4. 
Clinical Laboratory Tests ...........................................................................................22 
7.4.1. 
Laboratory Values Meeting Hy’s Law Criteria ..........................................................24 
7.4.2. 
Other Clinical Laboratory Tests .................................................................................24 
7.4.2.1. 
Urine Drug Screen ......................................................................................................24 
7.4.2.2. 
Alcohol Screen ............................................................................................................24 
7.4.2.3. 
Corticoid Plasma Levels .............................................................................................24 
7.5. 
Physical Examinations ................................................................................................24 
7.6. 
Vital Signs ..................................................................................................................24 
7.7. 
Electrocardiography ....................................................................................................25 
7.8. 
Concomitant Medications or Therapies ......................................................................26 
8. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................27 
9. 
PHARMACOKINETIC ANALYSIS .........................................................................28 
9.1. 
General ........................................................................................................................28 
9.2. 
Pharmacokinetic Parameters .......................................................................................28 
9.3. 
Plasma Pharmacokinetic Analysis ..............................................................................29 
9.3.1. 
Plasma Pharmacokinetic Concentrations ....................................................................29 
9.3.2. 
Plasma Pharmacokinetic Parameters ..........................................................................29 
10. 
PHARMACODYNAMIC ANALYSIS ......................................................................31 


 
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11. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ..............................32 
12. 
PHARMACOGENETIC AND BIOMARKER ANALYSIS .....................................33 
13. 
STATISTICAL SOFTWARE ....................................................................................34 
14. 
REFERENCES ...........................................................................................................35 
 


 
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LIST OF TABLES 
Table 1: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................23 
Table 2: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................25 
Table 3: 
Pharmacokinetic Parameters .......................................................................................28 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
ASL 
arterial spin labeling 
BP 
blood pressure 
BQL 
below the quantification limit   
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
CYP2D6 
cytochrome P450 2D6 
D2R 
dopamine-2 receptor 
DHEA 
dehydroepiandrosterone 
ECG 
electrocardiogram 
HD 
Huntington’s disease 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR-AC 
MRI-based Attenuation Correction 
MRI 
magnetic resonance imaging 
MRS 
magnetic resonance spectroscopy 
PET 
positron emission tomography 
R&D 
Research and Development 
RO 
receptor binding/occupancy 
Rs-fMRI 
resting state functional magnetic resonance imaging 
S1R 
sigma-1 receptor 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
standard international 
SOC 
system organ class 
SOP 
standard operating procedure 
T1 MPRAGE 3D 
T1-weighted rapid 3-dimensional gradient-echo technique 
ULN 
upper limit of normal 


 
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Abbreviation 
Term 
WHODD 
World Health Organization drug dictionary 
WNL 
WinNonlin® 
A detailed description of the pharmacokinetic parameters can be found in Section 9.2. 


 
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INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study TV7820-IMG-10082 (A Phase I, 
Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine and [18F]fallypride Positron Emission 
Tomography Study to Evaluate Sigma-1 and Dopamine-2 Receptor Occupancy by Pridopidine in 
the Human Brain of Healthy Volunteers and in Patients with Huntington’s Disease). 
The following documents are used or referred to for the SAP generation: 
• Clinical study protocol with Amendment 01, Approval date 11 November 2016 
• Case report forms (CRFs) for Study TV7820-IMG-10082 
• International Council for Harmonisation (ICH) E9 Guidance on Statistical Principles for 
Clinical Trials 
• ICH E3 Structure and Content of clinical study reports 
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 subject 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 
(CSR). 
 
 


 
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1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Primary and Secondary Study Objectives and Endpoints 
1.1.1. 
Primary and Secondary Study Objectives 
The primary objective of this study are: 
• To demonstrate target engagement, receptor binding/occupancy (RO) of pridopidine to 
sigma-1 receptors (S1R) in the brain (whole brain, cortical and subcortical regions) of 
healthy subjects and (optional) Huntington’s disease (HD) patients after single oral dose 
administration; 
• To establish the relationship between the plasma pridopidine concentrations and the S1R 
occupancy in the brain of healthy subjects and (optional) HD patients following a single 
oral dose of pridopidine. 
The secondary objectives of this study are: 
• To establish test-retest variability of (S)-(-)-[18F]fluspidine positron emission tomography 
(PET) imaging of S1R in healthy subjects; 
• To evaluate the pharmacokinetics of pridopidine following single oral administration in 
healthy subjects and (optional) HD patients; 
• To assess safety of pridopidine in healthy subjects and (optional) HD patients. 
1.1.2. 
Endpoints 
1.1.2.1. 
Pharmacodynamic Endpoints 
The PET acquisition, as well as advanced magnetic resonance imaging (MRI) protocols 
(MRI-based Attenuation Correction [MR-AC], T1-weighted rapid 3-dimensional gradient-echo 
technique [T1 MPRAGE 3D], arterial spin labeling [ASL], 2D multi-voxel magnetic resonance 
spectroscopy [MRS], and resting state functional magnetic resonance imaging [rs-fMRI]) will be 
detailed in dedicated imaging manuals. These will also contain an analysis plan explaining how 
the imaging data is calculated. Imaging manuals will be provided prior to initiating the study. 
1.1.2.2. 
Pharmacokinetic Endpoints 
Blood samples for analysis of pridopidine and the metabolite TV-45065 will be obtained up to 
24 hours after dosing. Pharmacokinetic parameters to be calculated are detailed in Section 9.2. 
1.1.2.3. 
Safety and Tolerability Endpoints 
The safety and tolerability endpoints are: 
• occurrence of adverse events during the study 
• clinical laboratory (serum chemistry, hematology, and urinalysis) test results 


 
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• vital signs (blood pressure [BP], respiratory rate, body temperature, and pulse) 
measurements at each visit 
• electrocardiogram (ECG) findings 
• physical examination findings, including body weight measurements 
• use of concomitant medication during the study 
• number (%) of subjects who did not complete the study (end of study) 
• number (%) of subjects who did not complete the study due to adverse events 
1.1.2.4. 
Biomarker Endpoints 
 
1.1.2.5. 
Pharmacogenetic Endpoints 
 
1.2. 
Exploratory Objectives and Endpoints 
1.2.1. 
Exploratory Objectives 
Exploratory objectives are: 
• To explore a potential impact of endogenous corticoid levels on RO of pridopidine to 
S1R; 
• To explore target engagement, RO of pridopidine to the dopamine-2 receptors (D2R) in 
the brain of healthy subjects and (optional) HD patients; 
• To explore the relationship between the plasma pridopidine concentrations and D2R 
occupancy in the brain of healthy subjects and (optional) HD patients following a single 
oral dose of pridopidine; 
• To establish the relationship between the plasma metabolite TV-45065 concentrations 
and the S1R occupancy in the brain following a single oral dose of pridopidine to healthy 
subjects and (optional) HD patients; 
• To evaluate the relationship between plasma pridopidine concentration and brain activity 
using functional magnetic resonance imaging (MRI-based Attenuation Correction [MR-
AC], T1-weighted rapid 3-dimensional gradient-echo technique [T1 MPRAGE 3D], 
Arterial Spin Labeling [ASL], 2D multi-voxel Magnetic Resonance Spectroscopy [MRS], 
and resting state functional Magnetic Resonance Imaging [rs-fMRI]); 
• To evaluate the relationship between S1R and D2 receptor occupancy in vivo by 
pridopidine and brain activity using functional magnetic resonance imaging (MR-AC, T1 
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• To explore any effects of pridopidine on brain activity, and link it to the occupancy of 
S1R and D2R; 
• 
 
 
 
 
 
 
 
 
1.2.2. 
Exploratory Endpoints 
Exploratory endpoints will be defined in the imaging analysis plan. 


 
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2. 
STUDY DESIGN 
2.1. 
General Design 
This is a Phase 1, single-dose, open-label, adaptive design (S)-(-)-[18F]fluspidine PET study in 
healthy subjects and (optional) in patients with HD designed to demonstrate target engagement 
and to assess the occupancy of the S1R by pridopidine. PET with the tracer (S)-(-)-
[18F]fluspidine will be used to quantify changes in S1R availability following the administration 
of pridopidine (Part A). Binding of pridopidine to D2R may be assessed using PET imaging with 
[18F]fallypride (Part B, optional).  
Since endogenous corticoid hormones have been described to competitively bind to S1R, the 
test-retest variability of (S)-(-)-[18F]fluspidine PET will be determined in 3 healthy subjects 
up-front or in parallel (Part 0). To minimize variability associated with the potential impact of 
circadian corticoid plasma level changes, individual scan and re-scan sessions will be performed 
at comparable times of the day for all subjects. 
In addition, plasma corticoid levels (to include dehydroepiandrosterone [DHEA], progesterone, 
testosterone, cortisol, and, where feasible, androstanolone, allopregnanolone, pregnenolone) will 
be assessed immediately before each (S)-(-)-[18F]fluspidine or [18F]fallypride injection in all 
subjects. 
Pharmacogenetic samples will be collected at screening for cytochrome P450 2D6 (CYP2D6) 
and exploratory genotyping. Biomarker pharmacodynamic samples will be collected at visit 3, 
prior to dosing and 4, 8, and 24 hours post pridopidine dose (a 10-minute window will be 
allowed). 
Up to 45 subjects are planned to be enrolled in this study to ensure up to 38 evaluable subjects. 
The study will consist of a screening period of up to 8 weeks prior to first dosing, including a T1 
MPRAGE 3D MRI scan (visit 1), a study period of up to 4 weeks (including visits 2 and 3), and 
a follow-up visit (visit 4). During the study period, the subjects will undergo a baseline PET 
investigation (PET session 1) at visit 2, and subsequently a post-treatment PET investigation 
(PET session 2) following a single oral dose of pridopidine at visit 3. Each dose cohort will 
comprise up to 4 subjects. It is expected that each dose cohort within Part A or Part B will 
receive a different dose of pridopidine; however, subjects within each cohort will be 
administered the same dose (deviation will also be allowed). It is possible that subjects in 
different cohorts within Part A or Part B may receive the same dose of pridopidine if timing of 
the PET imaging is changed or unchanged (eg, cohort with HD patients). 
Subjects in Part A and B may receive the same dose of pridopidine for different tracers or 
different populations (healthy volunteers or patients with HD). The maximal dose of pridopidine 
administered will not exceed 90 mg in healthy subjects or 112.5 mg in HD patients (the highest 
dose investigated in the PRIDE-HD study). 
Up to 20 subjects may be evaluated in Part A, although it is expected that study objectives may 
be achieved with fewer subjects (more subjects will also be allowed). At the day of each PET 
session, prior to PET imaging, a cubital or forearm vein will be cannulated at visits 2 and 3 to 
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quantification of pridopidine and its metabolite TV-45065, and also for other exploratory 
biomarker analysis. The subject’s radial artery on the other arm (or the same arm if this cannot 
be achieved) will be cannulated to obtain arterial blood samples during PET imaging for the 
quantification of plasma radioactivity associated with (S)-(-)-[18F]fluspidine, in order to estimate 
a metabolite-corrected arterial plasma input function for PET data analysis. 
The PET imaging will consist of subsets of PET scans that will be acquired in list mode: 4 blocks 
with breaks in between. The first PET acquisition block of 90 minutes duration (0 to 90 minutes) 
will be started together with the intravenous injection of 300±30 MBq (S)-(-)-[18F]fluspidine; the 
following acquisition blocks of 30 minutes duration each will be started at 2, 3, and 6 hours 
post-injection of the PET tracer. Each PET acquisition block will be acquired in list mode in 
order to allow variable subdivision into multiple time frames as detailed in the imaging manual. 
The first dose of pridopidine will be high (90 mg) for subjects enrolled in the first dose cohort 
but may be changed to another dose based on PRIDE-HD study results. Subsequent doses (2.5, 
5, 10, 22.5, 45, or 67.5 mg) will be determined on the basis of the RO results following PET 
session 2 and the time-activity profiles of (S)-(-)-[18F]fluspidine from previous cohort subjects. 
In addition, the timing of the PET sessions may also be revised. If any of the postdose PET 
investigations are compromised due to technical or logistic reasons, a repeat investigation may 
be considered, provided that the resulting cumulative radiation exposure by (S)-(-)-
[18F]fluspidine for all PET sessions does not exceed the allowed overall study exposure 
(effective dose not exceeding 20 mSv), when using tracer administered activity of 300±30 MBq 
per PET session, and further respecting a washout of 7 days of pridopidine and its metabolites. 
PET session 2 will start at 2 hours postdose of pridopidine. 
Up to 15 subjects may be evaluated in Part B to characterize the D2R binding of pridopidine. 
The cohort structure will also comprise up to 4 subjects. Each of the 2 PET sessions will consist 
of 4 subsets of acquisition blocks that will be acquired in list mode: 0 to 90 minutes, 120 to 
150 minutes, 180 to 210 minutes, and 360 to 390 minutes post-injection of 200±20 MBq 
[18F]fallypride. Each PET acquisition block will be acquired in list mode in order to allow 
variable subdivision into multiple time frames, and will be according to the institutional standard 
as detailed further in the imaging manual. PET session 2 will start at approximately 2 hours 
postdose of pridopidine. The PET imaging protocol is essentially the same as for (S)-(-)-
[18F]fluspidine. From the second block onwards, acquisition can commence within ±10 minutes 
of the nominal time, but the duration should still be 30 minutes for each of these blocks. 
Brain MRI scans will be performed at screening to ensure subjects are qualified for the study but 
will also provide data to aid the analysis of PET data. Additional functional MRI scans (MR-AC, 
T1 MPRAGE 3D, ASL, 2D MRS, and rs-fMRI) will be performed in parallel with the PET 
imaging sessions to evaluate the relationship between brain activity and S1R or D2R occupancy 
by pridopidine. These scans will be further detailed in the imaging manual. 
The dose of pridopidine in Part B will be determined based on the results obtained 
using (S)-(-)-[18F]fluspidine in Part A. The timing of the [18F]fallypride PET scan may 
also be revised. If any of the postdose PET investigations are compromised due to 
technical or logistic reasons, a repeat investigation may be considered, provided that the 
resulting cumulative [18F]fallypride dose for all PET sessions does not exceed the 
authorized overall study exposure (effective dose not exceeding 20 mSv), when using 


 
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tracer administered activity of 200±20 MBq per PET session, and further respecting a 
washout of 7 days of pridopidine and its metabolites. 
For the test-retest cohort (Part 0), fluspidine will be administered twice. The 2 tracer doses will 
be administered separately within a certain time frame, without pridopidine. The PET session 2 
will take place at approximately a similar time of day (±1 hour) as the baseline PET session 1, 
on another day (at least 24 hours ~10 half-lives 18F apart) 
Blood samples for determination of pridopidine and TV-45065 plasma concentrations and 
exploratory biomarkers will be collected during the timing of the PET examinations in 
visit 3. 
Safety and tolerability (the number [%]) of healthy subjects and HD patients who failed to 
complete the study due to adverse events) will be assessed throughout the study by 
monitoring adverse events and by conducting clinical safety laboratory tests, ECG, physical 
examination, and vital sign assessments. 
Study procedures and assessments with their time points are summarized in Table 1 of the study 
protocol. 
2.2. 
Randomization and Blinding 
This is a non-randomized, open-label study and there is no blinding. 
2.3. 
Data Monitoring Committee 
This study will not be overseen by a Data Monitoring Committee.  
2.4. 
Sample Size and Power Considerations 
This PET study is exploratory in nature; therefore, no formal hypothesis testing is planned. Thus, 
based on clinical and practical considerations, a sample size of up to approximately 38 subjects 
(up to 4 subjects per dose level) is considered adequate for this type of study and to attain the 
study objectives. Up to 45 subjects are planned to be enrolled in this study to ensure up to 
38 evaluable subjects. Adaptive study design will allow increasing or reducing the study total 
sample size or each dose/time cohort as necessary. This sample size may include up to 4 patients 
with HD, which may be added to study engagement of pridopidine to the D2R and to explore the 
effects of neurodegeneration. 
It is anticipated that 3 dose levels will be sufficient to characterize the exposure-response profile. 
However, additional cohorts may be studied.  
2.5. 
Sequence of Planned Analyses 
2.5.1. 
Planned Interim Analyses 
There will be no formal interim analysis for this study. PET data will be analyzed after each 
cohort for selection of the next cohort dose. 


 
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2.5.2. 
Final Analyses and Reporting 
All final, planned analyses for pharmacokinetic and safety measures 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 with SOP 
GBP_RD_702 (SAP). 
All analyses for pharmacodynamics (imaging data) will be detailed in the imaging manual 
prepared by 
 
 
 
 
 


 
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3. 
ANALYSIS SETS 
3.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all enrolled subjects, regardless of whether or not a subject 
took any study drug. A subject is considered enrolled according to the status reported in the 
database. 
3.2. 
Safety Analysis Set 
The safety analysis set will include all subjects who receive at least 1 dose of study drug 
(pridopidine or PET Tracer). In this analysis set, treatment will be assigned based on the 
treatment subjects actually received. 
3.3. 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include those subjects in the safety analysis set who have 
sufficient data to calculate at least 1 evaluable pharmacokinetic parameter for pridopidine or its 
metabolites. 
3.4. 
Pharmacodynamic Analysis Set 
The pharmacodynamic analysis set will include those subjects in the safety analysis set who have 
evaluable imaging data before and after pridopidine administration. The decision about inclusion 
and exclusion of subjects in this analysis set will be done after Teva will receive final PD data. 


 
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4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. For continuous pharmacokinetic parameters 
(except tmax), the geometric mean will also be calculated. Descriptive statistics for categorical 
variables include subject counts and percentages, missing category will be displayed as 
appropriate. 
For presentation the mean and median will be presented to 1 decimal greater than the original 
data, SD will be 2 greater than the original data and the minimum and maximum will have the 
same number of decimal places as the original data. The derived pharmacokinetic parameters 
will be summarized with a precision of 3 significant digits, while tmax will be presented with 
2 decimals. The percentage coefficient of variation (CV) and frequency percentages will be 
presented with 1 decimal. 
Tables will be presented by part and cohort, unless otherwise specified. Throughout the 
document cohort will mean the combination of dose level and population (healthy volunteers or 
patients with HD).  
In case different dose levels are used within a cohort the cohort will be split by dose level. In 
case similar dose levels are used in different cohorts within the same population, these data may 
be pooled. 
4.2. 
Specification of Baseline Values 
Baseline for postdose evaluations is defined as the last observation recorded before the first study 
drug administration.   The last observation can be an unscheduled / repeated measurement. 
4.3. 
Handling Withdrawals and Missing Data 
No imputation of missing data is planned, except for pharmacokinetic plasma concentration 
below the quantification limit (BQL) (see Section 9.3.1 and Section 9.3.2) and missing dates and 
times for AEs (see section 7.2). 
4.4. 
Study Days and Visits 
For by-visit (or by-time-point) summaries, if there are multiple assessments at a post baseline 
visit (or time point) then the scheduled assessment at that visit (or time point) will be used for the 
summary. For baseline and pre-baseline visits the last non-missing assessment at that visit (or 
time point) will be used for the summary (this includes scheduled and unscheduled assessments). 
For subjects who withdraw from the study, data at the early termination visit will be excluded 
from the by-visit summaries but will be included in the endpoint summaries.  
An early termination visit is defined as the follow-up visit for a subject that did not complete the 
study. 
Unscheduled measurements will be listed in the individual data listings.  


 
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Study days will be numbered relative to the first day of study drug administration in each visit 
(ie, visit 2 and visit 3). The start of treatment (day 1) is defined as the date on which a subject 
takes the first dose of study drug, as recorded on the CRF. 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). 


 
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5. 
STUDY POPULATION 
5.1. 
General 
The enrolled analysis set will be used for all study population summaries unless otherwise 
specified. Summaries will be presented by part and cohort, unless otherwise specified. 
5.2. 
Subject Disposition 
Data from subjects screened, subjects screened but not enrolled (and reason not enrolled), 
subjects who are enrolled, subjects enrolled but not treated (and reason), subjects in the safety 
and pharmacokinetic analysis sets, subjects who complete the study, and subjects who withdraw 
from the study will be summarized using descriptive statistics. Data from subjects who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics. The 
data will also be presented in a listing. 
5.3. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics, including medical history, and prior 
medications will be summarized using descriptive statistics by part and cohort. The results of the 
C-SSRS at screening will be listed. 
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. Subjects are counted only 
once in each preferred term and SOC category.  
5.5. 
Prior Therapy and Medication 
Medications administered prior to any study drug administration will be recorded as prior 
medications and medications administered following the first dose and throughout the study will 
be recorded as concomitant medication. Any prior therapy, medication, or procedure a subject 
has had within 28 days before study drug administration will be recorded on the CRF. Trade 
name or INN, indication, dosage, and dosing start and stop times will be recorded. The sponsor 
will encode all therapy and medication according to the World Health Organization drug 
dictionary (WHODD). 
5.6. 
Study Protocol Violations 
Data from subjects with any protocol violations (as recorded in the protocol violation CRF) 
during the study will be summarized overall and for each category using subject counts and 
percentages. 
 


 
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6. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustments will be made for the preplanned multiple comparisons/endpoints. 
 
 
 
 


 
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7. 
SAFETY ANALYSIS 
7.1. 
General 
The safety analysis set will be used for all safety analyses. Summaries will be presented by part 
and cohort, unless otherwise stated. 
7.2. 
Adverse Events 
All adverse events will be coded using MedDRA.  
Adverse events present before the first administration of study drug (PET tracer) will not be 
included in the summaries.  
The incidence of adverse events will be summarized using descriptive statistics by SOC and 
preferred term. Each subject 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 (ie, 
reasonable possibility) (overall and by severity), serious adverse events, and adverse events 
causing withdrawal from the study. For the summaries by severity, subjects are counted at the 
highest severity. Summaries will be presented by part, cohort and total by population for all 
subjects. 
All adverse events (including events started before the first administration of study drug) 
recorded on the CRF will be listed. Subject listings of serious adverse events and adverse events 
leading to withdrawal will also be presented. 
The following missing data will be imputed as defined (for calculations only, will not be 
presented): 
• Missing AE start and / or end times for the calculation of onset and duration will be assumed 
to be at 00:01 for a start time and 23:59 for end times 
• Missing AE severity or relationship will be assumed to be severe or related, respectively 
• Missing AE start times for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment 
• Missing AE start times for the determination of treatment assignment will be assumed to 
occur after treatment on the recorded date 
• 
Missing AE start date will be assumed to be after treatment for deaths and SAEs. 
7.3. 
Deaths 
If any subject dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the subject narrative included in the CSR. 
7.4. 
Clinical Laboratory Tests 
Laboratory test results will be presented in standard international (SI) units. All laboratory data 
will be listed. 


 
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Summary statistics for chemistry, hematology, and urinalysis laboratory tests will be presented 
for screening, visits 2 and 3, and for the follow-up visit. Summary statistics for coagulation 
laboratory test will be presented for screening. Laboratory tests values and changes from baseline 
(absolute) to each visit and time point will be summarized using descriptive statistics.  
All values will be compared with predefined criteria, as specified in Table 1, to identify 
potentially clinically significant values or changes. These values will be listed in the subject data 
listings. The incidence of potentially clinically significant abnormal values will be summarized 
for laboratory variables using subject counts as specified in Section 4.1. 
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 
  Bilirubin (total) 
≥34.2 µmol/L 
Hematology 
 
  Hematocrit 
Men 
<0.37 L/L 
  Hemoglobin 
Men 
≤115 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 
  Ketones 
≥2 unit increase from baseline 
  Total protein 
≥2 unit increase from baseline 
ULN=upper limit of normal range 


 
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7.4.1. 
Laboratory Values Meeting Hy’s Law Criteria 
All occurrences of possible drug-induced liver injury that meet Hy's law criteria as defined in 
protocol Section 7.1.5.1 will be included in adverse events reporting. 
7.4.2. 
Other Clinical Laboratory Tests 
At screening, subjects will be tested for human immunodeficiency virus (HIV)-1, HIV-2, 
hepatitis B surface antigen, and hepatitis C antibody. These results will be presented in the 
subject data listings. 
7.4.2.1. 
Urine Drug Screen 
A urine drug screen will be performed at screening and on visits 2 and 3. The drug screen will 
detect the presence of amphetamines, cocaine, opiates, cannabis, barbiturates, and 
benzodiazepine. The urine drug screen results will be presented in the subject data listings. 
7.4.2.2. 
Alcohol Screen 
An alcohol breath analyzer test will be performed at screening and on visits 2 and 3. These 
results will be presented in the subject data listings. 
7.4.2.3. 
Corticoid Plasma Levels 
Endogenous corticoid plasma levels will be measured on visits 2 and 3 (immediately before the 
tracer injection). The analysis will include measurement of DHEA, progesterone, testosterone, 
cortisol, and, where feasible, androstanolone, allopregnanolone, pregnenolone. These results will 
be presented in the subject data listings. 
7.5. 
Physical Examinations 
Physical examinations, including height and weight (to be measured at the screening visit only), 
will be performed at screening, and at follow-up. An abbreviated physical examination will be 
performed on visits 2 and 3. Any physical examination finding that is judged by the investigator 
as a clinically significant change (worsening) compared with a baseline value will be considered 
an adverse event and reported as such. 
Descriptive statistics for weight and height will be provided. Individual results will be presented 
in the subject data listings. 
7.6. 
Vital Signs 
Any vital sign that is judged by the investigator as clinically significant will be considered an 
adverse event and reported as such. 
All individual vital signs results (pulse, systolic and diastolic BP, body temperature, and 
respiratory rate) will be listed. 
Summary statistics for vital signs (pulse, systolic and diastolic BP, body temperature, and 
respiratory rate) in seated or supine position will be presented for screening, for visits 2 and 3, 
and for the follow-up visit. Vital signs values and changes from baseline to each visit and time 
point will be summarized using descriptive statistics. The incidence of potentially clinically 


 
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significant abnormal values will be summarized using subject counts and these values will be 
listed separately in the subject data listings. 
Vital sign measurements will be present graphically for nominal measurements and change from 
baseline.  Each graph will have measurement (e.g. systolic BP) per part of the study where y-axis 
is the measurement and x-axis is time.  There will be a mean line with SD bars for each dose and 
each subject group (healthy subjects or HD patients).   
Table 2 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. 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 mm Hg 
 
≤85 mm Hg 
Decrease of ≥20 mm Hg 
Diastolic blood pressure 
≥105 mm Hg 
Increase of ≥15 mm Hg 
 
≤40 mm Hg 
Decrease of ≥15 mm Hg 
7.7. 
Electrocardiography 
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event and reported as such. 
Summary statistics for ECG measurements will be presented for screening, days -1 and 1 of 
visit 2 and days -1, 1 and 2 of visit 3, and for the follow-up visit. ECG variables will be averaged 
in case of repeated measurements in a single visit. ECG variable results and changes from 
baseline  (Visit 2) to each visit and time point will be summarized using descriptive statistics and 
also presented graphically. 
ECG measurements will be present graphically for nominal measurements and change from 
baseline.  Each graph will have measurement (i.e. QT) per part of the study where y-axis is the 
measurement and x-axis is time.  There will be a mean line with SD bars for each dose and each 
subject group (healthy volunteers or HD patients).   
Shifts in ECG findings (normal and abnormal as evaluated by the investigator) from baseline to 
each visit and time point will be summarized using subject counts. For overall, the worst 
postbaseline finding (the abnormal finding if there are both normal and abnormal findings) for 
the subject will be summarized. 
 


 
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7.8. 
Concomitant Medications or Therapies  
All concomitant medications will be coded using the WHODD. 
Use of concomitant medication or treatment will be monitored throughout the study.  
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and preferred term. Subjects are counted only once in 
each therapeutic class, and only once in each preferred term category. Concomitant therapies and 
medications will include all medications up to the end of study as defined in the study protocol. 
A medication is classified as concomitant medication if one of the following conditions is met: 
• If the medication start date and the medication stop date is missing 
• If the medication start date is known and medication stop date is missing and 
medication start date is less than or equal to the study medication last date and flag 
for continuation is yes. 
• If the medication start date is missing and the medication stop date is known and is 
greater than or equal to the study medication first date  
• If the medication start date and the medication stop date are both known and the 
medication start date is less than or equal to the study medication last date and the 
medication stop date is greater than or equal to the study medication first date. 
The prior and concomitant medication or treatment used by HD patients will be listed only. 
 


 
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8. 
TOLERABILITY VARIABLES AND ANALYSIS 
Subject tolerability assessments (the number [%] of subjects who fail to complete the study, 
number [%] of subjects who fail to complete the study due to adverse events, and the number of 
subjects who experience treatment-emergent adverse events) will be summarized by part and 
cohort in the disposition table. 
 


 
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9. 
PHARMACOKINETIC ANALYSIS 
9.1. 
General 
The pharmacokinetic analysis set will be used for all pharmacokinetic analyses. No formal 
statistical analyses of the pharmacokinetic data will be performed. All data will be listed and 
summarized descriptively by part and cohort and presented in tabular and graphical form where 
appropriate.   
9.2. 
Pharmacokinetic Parameters 
The following pharmacokinetic parameters will be determined or calculated from the plasma 
concentration-time data using non-compartmental analysis for pridopidine and its metabolite 
TV-45065, when possible. Actual sampling times will be used in the analysis. 
Table 3: 
Pharmacokinetic Parameters 
Parameter 
Description 
SAS Programming 
Notes 
Cmax 
Maximum plasma concentration. Observed peak analyte 
concentration obtained directly from the experimental data 
without interpolation, expressed in concentration units 
CMAX from WinNonlin® 
(WNL) 
tmax 
Time to maximum plasma concentration. First observed 
time to reach peak analyte concentration obtained directly 
from the experimental data without interpolation, 
expressed in time units. 
TMAX from WNL 
AUC 
All AUC values will be calculated using the linear up / log 
down method, expressed in units of concentration x time. 
 
AUC0-24 
Area under the plasma concentration-time curve from time 
0 to 24 hours postdose. 
AUC0_24 from WNL 
where partial time =24 
AUC0-t 
Area under the plasma concentration-time curve (time 0 to 
time of last measurable analyte concentration). 
AUCLAST from WNL 
AUC0-inf 
Area under the plasma concentration-time curve (time 0 to 
infinity), calculated as: 
AUC0-inf = AUC0-t + Ctlast/kel, where Ctlast is the last 
measurable analyte concentration.   
AUCINF_obs from WNL 
 
%AUC 
Percentage of estimated part for the calculation of AUC0-inf. 
AUC_%Extrap_obs from 
WNL 
If AUC_%Extrap_obs > 
20% then associated 
parameters (AUC0-inf, kel, 
t1/2) are flagged 
t1/2 
Terminal elimination half-life, calculated as ln(2)/kel, 
expressed in time units.  
HL_Lambda_z from 
WNL 


 
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Parameter 
Description 
SAS Programming 
Notes 
Vd/F 
Apparent volume of distribution of the drug following 
extravascular administration 
Vz_F_obs   from WNL 
Additional pharmacokinetic parameters, including partial AUCs and respective average plasma 
concentration (Caverage) to be inclusive of the PET scan duration, may be calculated as well, as 
deemed necessary. 
 
 
9.3. 
Plasma Pharmacokinetic Analysis 
9.3.1. 
Plasma Pharmacokinetic Concentrations 
Plasma concentrations for pridopidine and its metabolite TV-45065 that are BQL of the assay 
will be substituted by half the lower limit of quantification (LLOQ) in the computation of mean 
concentration values. Missing values will be ignored when calculating mean concentrations. 
Descriptive statistics (n, mean, geometric mean, SD, CV, median, minimum, and maximum) will 
be used to summarize the plasma concentrations by part, cohort and nominal time point. If over 
half of the subjects at a given time point have values BQL then the descriptive statistics will not 
be presented and will instead display as BQL for the mean and missing for all other statistics 
(except the minimum and maximum value).  
Linear and semi-logarithmic plots of the geometric mean plasma concentration by scheduled 
sampling time will be provided by part and cohort. These plots will show time in hours. The 
plots will match the summary table results and will not have an observation at a given time point 
if more than half of the subjects have values BQL.  
Combined individual profiles of pridopidine and its metabolite TV-45065 in plasma by actual 
sampling time, showing all subjects in a single plot by part and cohort will be presented on both 
a linear and a semi-logarithmic scale (1 graph for each analyte and cohort).  
Linear and semi-logarithmic plots of the individual plasma concentration of pridopidine and its 
metabolite TV-45065 by actual sampling time will be provided by subject. These plots will show 
time in hours. Individual plots will use the BQL handling procedure described below for 
“Pharmacokinetic Parameters”. 
All individual subject plasma concentration data for pridopidine and its metabolite TV-45065 
will be listed by part, cohort and nominal time point. 
9.3.2. 
Plasma Pharmacokinetic Parameters 
The pharmacokinetic parameters will be estimated from the pridopidine and its metabolite 
TV-45065 (where data permit) plasma concentration-time profiles for all subjects in the 
pharmacokinetic analysis set. The concentration data as provided by the Bioanalytical 
Laboratory and (derived) actual blood sampling times will be used in the pharmacokinetic 
calculations.  
In estimating the pharmacokinetic parameters, BQL values at time 0, at a sampling time before 
the first quantifiable plasma drug concentration will be treated as zero. All other BQL values will 


 
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be treated as missing. Missing values will be ignored when calculating pharmacokinetic 
parameters.  
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. If the actual time or dose time is missing, the scheduled time may be 
substituted in order to calculate the pharmacokinetic parameter. 
The terminal elimination rate constant (kel) will be determined by plotting the concentration data 
versus time on a semi-logarithmic scale. The time interval of the terminal elimination phase will 
be determined by visual inspection. Linear regression on log-transformed concentrations within 
this interval will be used to calculate the terminal elimination rate constant. At least 3 non-BQL 
data points are required to retain a reliable kel and associated parameters. Points prior to and 
including Cmax will not be included in this interval. If the adjusted r2 from the regression is ≤0.80 
and the residual area of the AUC0-inf extrapolated is >20% then the associated pharmacokinetic 
parameters may be considered unreliable. The values will be included in the analysis, but will be 
flagged in the individual listing, accompanied by a footnote. 
Descriptive statistics (n, mean, geometric mean, SD, CV, median, minimum, and maximum) will 
be used to summarize the calculated pharmacokinetic parameters by part and cohort. All 
individual pharmacokinetic parameters will be listed. 
 


 
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10. 
PHARMACODYNAMIC ANALYSIS 
All pharmacodynamic analyses will be performed outside of the scope of this SAP and reported 
separately.  
 


 
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11. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
The pharmacokinetic/pharmacodynamic analyses will be performed outside of the scope of this 
SAP. The pharmacokinetic/pharmacodynamic results will be analyzed and reported separately.  
 


 
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12. 
PHARMACOGENETIC AND BIOMARKER ANALYSIS 
Results of the exploratory biomarker and pharmacogenetic analyses will be reported outside of 
the scope of this SAP and reported in a separate addendum report. 
 
 
 


 
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13. 
STATISTICAL SOFTWARE 
All data listings, graphs, summaries, and statistical analyses will be generated using SAS® 
version 9.4 or later. 
The pharmacokinetic parameters of pridopidine and its metabolite TV-45065 will be estimated 
using validated Phoenix™ WinNonlin®, Version 6.3 (Pharsight Corporation). 
 


 
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14. 
REFERENCES 
Clinical study protocol. A Phase I, Open-Label, Single-Dose, Adaptive (S)-(-)-[18F]fluspidine 
and [18F]fallypride Positron Emission Tomography Study to Evaluate Sigma-1 and Dopamine-2 
Receptor Occupancy by Pridopidine in the Human Brain of Healthy Volunteers and in Patients 
with Huntington’s Disease. Final with Amendment 01, Approval Date: 11 November 2016. 
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC.