Conditions: Parkinson Disease
Keywords: Levodopa Dyskinesia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, three-arm, parallel-group, double-blind, placebo-controlled, study to evaluate the efficacy, safety and pharmacokinetics (PK) of pridopidine vs. placebo for the treatment of Levodopa Induced Dyskinesia (LID) in patients with Parkinson Disease.

Detailed description:

Arms:
arm 1: Dose 1 (oral capsule) for 12 weeks following 2 or 4 week dosage regimen titration period arm 2: Dose 2 for (oral capsule) for 12 weeks following 2 or 4 week dosage regimen titration period arm 3: Matching placebo (oral capsule) for 16 weeks

Interventions: intervention 1: Pridopidine intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule

Protocol document:
Prot_000.pdf: 
Official Title: A Double-Blind, Randomized, Three-Arm, Parallel-Group Study to 
Assess the Efficacy and Safety of Two Doses of Pridopidine Versus Placebo for the 
Treatment of Levodopa-Induced Dyskinesia in Patients With Parkinson's Disease 
(gLIDe) 
NCT Numbers: NCT03922711 
Document Date: 19 Nov 2019 


 
 
CLINICAL STUDY PROTOCOL 
IND NUMBER: 141222 
A Double-Blind, Randomized, Three-Arm, Parallel-Group Study to Assess 
the Efficacy and Safety of Two Doses of Pridopidine versus Placebo for the 
Treatment of Levodopa-Induced Dyskinesia in Patients with Parkinson’s 
Disease (gLIDe) 
 
PL101-LID201 
Sponsor: 
Prilenia Therapeutics 
Sponsor Contact: 
 
Head of Clinical Operations 
  
 
Medical Monitor: 
 
 
 
 
 
 
Version of Protocol:  
2.0 (Protocol Amendment 1) 
Date of Protocol:  
19 Nov 2019 
Previous Versions and Dates: 
Original (1.0), 14 Jan 2019 
Final (1.1), 24 Jan 2019 
 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Prilenia 
Therapeutics. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in 
part 
without 
the 
expressed, 
written 
consent 
of 
Prilenia 
Therapeutics. 
The study will be conducted according to the International Council for Harmonisation 
(ICH) harmonized tripartite guideline E6 (R2) on Good Clinical Practice. 




Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2.0 
19 Nov 2019 
 
 
Protocol Approval – Sponsor Signatory 
 
Study Title 
A Double-Blind, Randomized, Three Arm, Parallel-Group Study to 
Assess the Efficacy and Safety of Two Doses of Pridopidine versus 
Placebo for the Treatment of Levodopa-Induced Dyskinesia in Patients 
with Parkinson’s Disease (gLIDe) 
Protocol Number PL101-LID201 
Protocol Date 
19 Nov 2019 
 
Protocol accepted and approved by: 
Chief Medical Officer (for Sponsor)  
 
Prilenia Therapeutics 
 
 
 
Date 


19


Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2.0 
19 Nov 2019 
 
Declaration of Investigator 
 
I have read and understood all sections of the protocol entitled “A Double-Blind, Randomized, 
Three Arm, Parallel-Group Study to Assess the Efficacy and Safety of Two Doses of 
Pridopidine versus Placebo for the Treatment of Levodopa-Induced  Dyskinesia in Patients 
with Parkinson’s Disease (gLIDe)” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 2.0, dated 19 Nov 2019, the International Council 
for Harmonisation harmonized tripartite guideline E6 (R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with Prilenia Therapeutics or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to patients. I agree to administer 
study treatment only to patients under my personal supervision or the supervision of a 
sub-investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or appear 
in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Prilenia Therapeutics. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2. 
19 Nov 2019 
 
Page 6 
Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
 
Version 
Date 
Reason for Amendment 
Version 1.0 
14 Jan 2019 
Original Protocol 
Version 1.1  
24 Jan 2019 
• Administrative updates were made to the cover page, signatory pages, 
synopsis, Section 5.7 (Blinding), Section 6.5.1.6 (Suspected Unexpected 
Serious Adverse Reactions and Nonserious Adverse Events of Special 
Interest), Section 9.1, (Independent Ethics Committee or Institutional 
Review Board), and Section 11.3 (Study Termination) 
• A summary of changes was added 
• Exclusion criterion 20 was updated to prohibit the use of cannabis 
within 3 months (instead of 6 months) prior to baseline.  
• Creatinine clearance stopping rules were added 
• It was added that patients with CrCL <50 mL/min/1.73 m2 at any time 
point after Baseline (Visit 2) will be requested to return to the clinic for 
an unscheduled visit 1 week later to repeat the CrCL test. If the repeated 
CrCL value is confirmed to be <50 mL/min/1.73 m2, the patient will be 
discontinued from the study treatment. Any decrease in CrCL that is 
judged by the investigator as a clinically significant change (worsening) 
from Baseline (Visit 2) result will be considered an AE. 
Version 2.0 
19 Nov 2019 
• Significant updates were made to the cover page, signatory pages, 
synopsis, Section 1.1.3 (Current Available Pharmaceutical Options for 
the Treatment of LID), Section 2 (Study Objectives), Section 3 
(Investigational Plan), Section 4.1.1 (Inclusion Criteria), Section 4.1.2 
(Exclusion Criteria), Section 4.2.1 (Reasons for 
Withdrawal/Discontinuation, Section 5.2 (Treatments Administered), 
Section 5.3 (Dose Modifications – new section), Section 5.4.1 (Study 
Treatment Packaging, Storage, and Dispensing), Section 5.4.3 (Study 
Treatment Accountability), Section 5.10 (Prior and Concomitant 
Therapy), Section 6, Table 4 (Schedule of Assessments), Section 6.2 
(Efficacy Assessments), Section 6.5.1.6 (Suspected Unexpected Serious 
Adverse Reactions and Nonserious Adverse Events of Special Interest, 
6.5.2 (ECG: QTc Parameters), 7.2 (Secondary Efficacy Endpoints), 
7.4 (Exploratory Endpoints), 7.10.3 (Analyses of Exploratory 
Endpoint), 8.1 (Data Management), Appendix 13.1 (Visit Assessments 
and Procedures Flow – Baseline [Visit 2]), Appendix 13.2 (Visit 
Assessments and Procedures Flow – Visit 3-Visit 7) 
• The protocol title was updated 
• The summary of changes was updated 
• Inclusion criterion 4 was updated to include patients with Hoehn and 
Yahr stage 4 or less, such that the patient can complete the study 
assessment 
• Inclusion criterion 5 was modified to remove the specification of mild 


Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2. 
19 Nov 2019 
 
Page 7 
Version 
Date 
Reason for Amendment 
to moderate LID 
• Inclusion criterion 6 was modified to remove the use of the Abnormal 
Involuntary Movement Scale during the screening (visit 1) and replace 
it with the Unified Dyskinesia Rating Scale, Part 4 – Disability Scale 
• Inclusion criterion 8 was updated to reflect that patients must 
experience all motor states during concordance testing 
• Inclusion criterion 9 was added to note that patients who are stable on a 
daily dose of ≤200 mg amantadine must be off this treatment at least for 
weeks prior to certain screening assessments 
• Inclusion criterion 10 was updated to reflect multiple anti-Parkinson’s 
disease treatments and specify stability during the 12-week maintenance 
period 
• Exclusion criterion 3, requiring documentation of severe dyskinesia by 
the investigator, was removed  
• Exclusion criterion 5 was updated to specify arterial hypotension as an 
orthostasis symptom 
• Exclusion criterion 11, excluding the use of amantadine products within 
6 weeks prior to Screening, was removed 
• Exclusion criterion 13 was modified to require a Mini-Mental State 
Examination (MMSE) score of <24 (not including dementia) 
• Exclusion criterion 20 was updated to prohibit the use of all oral 
cannabinoids, with the exception of topical formulations of cannabidiol, 
within 28 days prior to Baseline 
• Exclusion criterion 23 was updated to reflect the use of body surface 
area adjustment for creatinine clearance  
• Study design and duration was updated to reflect a minimum 3-week 
and up to 9-week screening period, a 4-week up-titration period, a 12-
week maintenance treatment period, and a 4-day down-titration period 
• The study design was updated to reflect the requirement for patients to 
complete dosing diaries to record their study treatment intake during the 
16-week active treatment period 
• The 39-item Parkinson’s Disease questionnaire, Parkinson’s Disease 
Sleep Scale, and Non-Motor Symptom Scale and all associated 
endpoints and analyses were removed 
• The study treatment, dosage, and packaging sections were updated to 
reflect amended study periods (4-week up-titration period, 12-week 
maintenance treatment period, and 4-day down-titration period) 
For details of Protocol Amendments 1 and 2, see Section 13.3. 


Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2. 
19 Nov 2019 
 
Page 8 
Table of Contents 
Summary of Changes .................................................................................................................6 
Table of Contents .......................................................................................................................8 
List of Tables ............................................................................................................................12 
List of Figures ..........................................................................................................................12 
Protocol Synopsis.....................................................................................................................13 
List of Abbreviations................................................................................................................24 
1 
Introduction ......................................................................................................................26 
1.1 
Levodopa-Induced Dyskinesia................................................................................26 
1.1.1 
Epidemiology ...........................................................................................26 
1.1.2 
Impact on Quality of Life ........................................................................26 
1.1.3 
Currently Available Pharmaceutical Options for the Treatment of LID ..26 
1.2 
Pridopidine ..............................................................................................................27 
1.2.1 
Pridopidine in PD-LID ............................................................................27 
1.2.1.1 
Proof of Concept ......................................................................................27 
1.2.1.2 
Potential Mechanism of Action ...............................................................28 
2 
Study Objectives...............................................................................................................31 
3 
Investigational Plan ..........................................................................................................32 
3.1 
Study Design ...........................................................................................................32 
3.1.1 
Minimum 3-Week and Up to 9-Week Screening Period .........................34 
3.1.2 
16-week Active Treatment Period (Up-titration and Maintenance) and 
Down-titration Period ..............................................................................35 
3.1.3 
Safety Follow-up Visit .............................................................................36 
3.1.4 
Efficacy ....................................................................................................36 
3.1.5 
Safety .......................................................................................................37 
3.1.6 
Pharmacokinetics .....................................................................................38 
3.1.7 
Pharmacogenetic and Plasma Biomarker Substudy.................................38 
3.1.8 
Rationale of Study Design .......................................................................38 
4 
Patient Selection and Withdrawal Criteria .......................................................................39 
4.1 
Selection of Study Population .................................................................................39 
4.1.1 
Inclusion Criteria .....................................................................................39 


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4.1.2 
Exclusion Criteria ....................................................................................40 
4.2 
Withdrawal of Patients from Study Treatment and/or the Study ............................42 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................43 
4.2.2 
Handling of Withdrawals .........................................................................43 
4.2.3 
Replacements ...........................................................................................44 
5 
Study Treatments ..............................................................................................................45 
5.1 
Method of Assigning Patients to Treatment Groups ...............................................45 
5.2 
Treatments Administered ........................................................................................45 
5.3 
Dose Modification ..................................................................................................49 
5.3.1 
Up-titration Period ...................................................................................49 
5.3.2 
Maintenance Period .................................................................................49 
5.4 
Management of Clinical Supplies ...........................................................................49 
5.4.1 
Study Treatment Packaging, Storage, and Dispensing ............................49 
5.4.2 
Storage Conditions for Study Treatment and Security ............................50 
5.4.3 
Study Treatment Accountability ..............................................................50 
5.4.4 
Other Supplies .........................................................................................50 
5.5 
Overdose Management ...........................................................................................51 
5.5.1 
Medication Errors ....................................................................................51 
5.5.2 
Treatment of Medication Errors ...............................................................51 
5.6 
Misuse for Illegal Purposes .....................................................................................51 
5.7 
Off-Label Use .........................................................................................................51 
5.8 
Blinding ..................................................................................................................51 
5.8.1 
Breaking the Blind ...................................................................................52 
5.9 
Treatment Compliance ............................................................................................52 
5.10 Prior and Concomitant Therapy ..............................................................................52 
5.10.1 
Prohibited Medications and Substitution Alternatives.............................53 
6 
Study Assessments and Procedures ..................................................................................56 
6.1 
Study Visits .............................................................................................................63 
6.2 
Efficacy Assessments ..............................................................................................63 
6.2.1 
UDysRS ...................................................................................................63 
6.2.2 
UPDRS ....................................................................................................63 
6.2.3 
“ON/OFF” Home Diary Assessments .....................................................63 


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6.2.4 
Patient Global Impression of Change (PGI-C) ........................................64 
6.2.5 
Clinical Global Impression (CGI-C) .......................................................64 
6.2.6 
Mini-Mental State Examination (MMSE) ...............................................64 
6.3 
Pharmacokinetics Assessments ...............................................................................64 
6.4 
Pharmacogenetic and Plasma Biomarker Assessments ..........................................64 
6.4.1 
Pharmacogenetic Assessments .................................................................65 
6.4.2 
Plasma Biomarker Assessment ................................................................65 
6.5 
Safety Assessments .................................................................................................65 
6.5.1 
Adverse Events ........................................................................................65 
6.5.1.1 
Definitions of Adverse Events .................................................................65 
6.5.1.2 
Serious Adverse Events ...........................................................................66 
6.5.1.3 
Eliciting and Documenting Adverse Events ............................................66 
6.5.1.4 
Reporting Adverse Events .......................................................................66 
6.5.1.5 
Reporting Serious Adverse Events, Pregnancy, and Overdose ................67 
6.5.1.6 
Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest ..........................................................68 
6.5.1.7 
Assessment of Severity ............................................................................69 
6.5.1.8 
Assessment of Causality ..........................................................................69 
6.5.1.9 
Exceptions ................................................................................................69 
6.5.1.10 Follow-Up of Patients Reporting Adverse Events ...................................70 
6.5.2 
ECG: QTc Parameters ..............................................................................70 
6.5.3 
Vital Signs ................................................................................................71 
6.5.4 
Physical and Neurological Examination ..................................................71 
6.5.5 
Concomitant Medications ........................................................................71 
6.5.6 
Assessment of Suicidal Ideation and Behavior (C-SSRS).......................71 
6.5.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's 
Disease-Rating Scale (QUIP-RS) ............................................................72 
6.5.8 
Other Assessments ...................................................................................72 
6.6 
Data Safety Monitoring Board ................................................................................72 
6.7 
Pregnancy ................................................................................................................73 
6.8 
Clinical Laboratory Analyses/Evaluations ..............................................................73 
6.9 
Sample Collections .................................................................................................74 
6.10 Eligibility Review ...................................................................................................75 
7 
Statistical and Analytical Plan ..........................................................................................76 


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7.1 
Primary Efficacy Endpoint .....................................................................................76 
7.2 
Secondary Efficacy Endpoints ................................................................................76 
7.3 
Safety Endpoints .....................................................................................................77 
7.4 
Pharmacokinetic Endpoints ....................................................................................77 
7.5 
Pharmacogenetic and Plasma Biomarker Endpoints ..............................................77 
7.6 
Sample Size Calculations ........................................................................................78 
7.7 
Analysis Sets ...........................................................................................................78 
7.8 
Description of Subgroups to be Analyzed ..............................................................78 
7.9 
Statistical Analysis Methodology ...........................................................................79 
7.9.1 
Analysis of Primary Endpoint .................................................................80 
7.9.2 
Analysis of Secondary Endpoint .............................................................81 
7.9.3 
Pharmacokinetic Analyses .......................................................................81 
7.9.4 
Safety Analyses ........................................................................................81 
7.9.5 
Interim Analyses ......................................................................................82 
8 
Data Quality Assurance ....................................................................................................83 
8.1 
Data Management ...................................................................................................83 
9 
Ethics ................................................................................................................................84 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................84 
9.2 
Ethical Conduct of the Study ..................................................................................84 
9.3 
Patient Information and Consent ............................................................................84 
10 Investigator’s Obligations ................................................................................................85 
10.1 Confidentiality ........................................................................................................85 
10.2 Financial Disclosure and Obligations .....................................................................85 
10.3 Investigator Documentation ....................................................................................85 
10.4 Study Conduct .........................................................................................................86 
10.5 Adherence to Protocol ............................................................................................86 
10.6 Adverse Events and Study Report Requirements ...................................................86 
10.7 Investigator’s Final Report .....................................................................................86 
10.8 Records Retention ...................................................................................................87 
10.9 Publications .............................................................................................................87 


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11 Study Management ...........................................................................................................88 
11.1 Monitoring ..............................................................................................................88 
11.1.1 
Independent Data Safety Monitoring Board ............................................88 
11.1.2 
Monitoring of the Study ...........................................................................88 
11.1.3 
Inspection of Records ..............................................................................88 
11.2 Management of Protocol Amendments and Deviations..........................................88 
11.2.1 
Modification of the Protocol ....................................................................88 
11.2.2 
Protocol Deviations .................................................................................88 
11.3 Study Termination ...................................................................................................89 
11.4 Final Report ............................................................................................................89 
12 Reference List...................................................................................................................90 
13 Appendices .......................................................................................................................91 
13.1 Visit Assessments and Procedures Flow – Baseline (Visit 2) .................................92 
13.2 Visit Assessments and Procedures Flow – Visit 3 – Visit 7 ....................................93 
 
 
List of Tables 
Table 1 
Pridopidine Binding Profile Ranked in Descending Order ............................. 29 
Table 2 
Estimated Occupancy of the Human and NHP σ1R and D2R Receptors at 
Various Pridopidine Doses .............................................................................. 30 
Table 3 
Prohibited Medications and Substitution Alternatives .................................... 53 
Table 4 
Schedule of Assessments ................................................................................ 57 
 
List of Figures 
S-Figure 1 
Study Design ................................................................................................... 23 
Figure 1 
Study Design ................................................................................................... 33 
Figure 2 
Summary of the Statistical Testing Strategy ................................................... 79 
 


Prilenia Therapeutics 
Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2. 
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Page 13 
Protocol Synopsis 
Protocol Number: 
PL101-LID201 
Title: 
A Double-Blind, Randomized, Three Arm, Parallel-Group Study to Assess the 
Efficacy and Safety of Two Doses of Pridopidine versus Placebo for the 
Treatment of Levodopa-Induced Dyskinesia in Patients with Parkinson’s 
Disease (gLIDe) 
Sponsor: 
Prilenia Therapeutics  
 
  
Study Phase: 
2B 
Study Sites: 
Approximately 42 sites in the United States  
Indication: 
Levodopa-induced dyskinesia in patients with Parkinson’s disease (PD-LID) 
Rationale: 
The most widely used and effective therapy for the treatment of Parkinson’s 
disease (PD) is a 3,4-dihydroxyphenylalanine (L-DOPA). Over time, however, 
chronic L-DOPA therapy is complicated by the development of levodopa-
induced dyskinesia (LID), which can severely impact function and quality of 
life. The first and only drug approved for the treatment of dyskinesia in patients 
with PD receiving levodopa therapy is amantadine (Gocovri™ extended-release 
capsules). However, Gocovri™ is associated with significant side-effects 
including hallucinations, narcolepsy, psychosis, impulse control/compulsive 
behavioral disturbances as well as withdrawal-emergent hyperpyrexia and 
confusion.  
There remains a significant need for effective, safe, and tolerable treatment 
options for patients with PD who suffer from LID. Preclinical studies using the 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model suggest 
pridopidine can effectively reduce PD-LID in a dose-dependent manner
 
 
Furthermore, this benefit is not associated with any worsening of Parkinsonian 
features. In previous clinical trials in Huntington Disease (HD), pridopidine at 
doses up to 112.5 mg BID was established to be safe and tolerable. Taken 
together, these preclinical and clinical data justify testing pridopidine for 
PD-LID in a clinical study. 
Objectives: 
Primary Objective: 
1. To evaluate the efficacy of 2 dosages of pridopidine (100 mg BID and 
150 mg BID) vs placebo for the treatment of PD-LID 
 
Secondary Objectives: 
1. To determine if any effects of 2 dosages of pridopidine (100 mg BID 
and 150 mg BID) on the reduction of LID are associated with changes 
(worsening or improvement) of Parkinsonian features 


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Pridopidine 
Protocol: PL101-LID201 Protocol Amendment 1/v2. 
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Page 14 
2. To evaluate the effect of 2 dosages of pridopidine (100 mg BID and 
150 mg BID) vs placebo on global improvement, and activities of daily 
living in patients with PD-LID 
 
Safety Objective: 
1. To evaluate the safety and tolerability of 2 dosages of pridopidine 
(100 mg BID and 150 mg BID) vs placebo in patients with PD-LID 
 
Pharmacokinetic (PK) Objectives: 
1. To evaluate the PK of pridopidine in patients with PD-LID 
2. To explore the relationship between pridopidine exposure and 
dyskinesia 
Study Population: 
Inclusion Criteria: 
Patients may be included in the study only if they meet all of the following 
criteria: 
1. Male or female patients between 30 and 85 years of age, inclusive 
2. Signed an institutional review board (IRB)-approved informed consent 
form 
3. Diagnosis of PD consistent with the UK Parkinson’s Disease Society 
(UKPDS) Brain Bank Clinical Diagnostic Criteria 
4. Hoehn and Yahr Stage 4 or less in the “ON” state such that the patient 
can complete the study assessments 
5. Documentation of LID by the investigator 
6.  A Score of 3 on 2 elements of the Unified Dyskinesia Rating Scale 
(UDysRS) part 4 – Disability Scale   
7. Using the three consecutive 24-hour “ON/OFF” home diaries completed 
prior to Baseline (Visit 2), at least two half-hour time periods between 
8:00 AM and 5:00 PM of each 24-hour period are indicated as “ON with 
dyskinesia” 
8. Patient and/or study partner must demonstrate during the screening 
period an ability to keep accurate home diary entries of PD symptoms 
(“ON, OFF, and dyskinesia”) with <75% concordance with the study 
rater. During the 4-hour concordance testing, patient must experience all 
motor states: “ON”, “OFF”, and at least one period of “ON with 
dyskinesia”  
9. Patients who are stable on a total daily dose of ≤200 mg amantadine 
must be off this treatment at least 4 weeks prior to the assessment of 
UDysRS part 4, the concordance testing and the completion of the 
three consecutive 24-hour “ON/OFF” home diaries which are 
performed during screening 


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10. All anti-PD treatments are stable for at least 28 days prior to Baseline 
(Visit 2), including a levodopa preparation administered no less than 
three times daily, with the same dosing regimen during the 12-week 
maintenance study treatment period 
11. If taking allowed antidepressant or antipsychotic medication, must be on 
a stable dose for at least 28 days prior to Baseline (Visit 2) and must be 
kept constant during the study 
12. Any other routine and allowed prescription/nonprescription medications 
and/or nutritional supplements taken regularly must be at stable dosages 
for at least 28 days prior to Baseline (Visit 2) and remain during study 
participation 
13. Willing and able to comply with study requirements 
14. Approval for entry into the study by an independent Enrollment 
Authorization Committee (EAC) 
 
Exclusion Criteria: 
Patients will be excluded from participation in this study if they meet any of 
the following criteria: 
1. Diagnosis of atypical Parkinsonism 
2. History of exclusively diphasic, “OFF” state, myoclonic, or dystonic 
dyskinesia without peak-dose choreiform dyskinesia 
3. Treatment with dopamine blocking drugs (e.g., neuroleptics, Reglan® 
[metoclopramide])  
4. History of surgical intervention related to PD (e.g., deep brain 
stimulation, carbidopa-levodopa intra-enteral suspension [CLES; 
DuopaTM]). 
5. Presence of clinically significant orthostasis symptoms, e.g., arterial 
hypotension 
6. Clinically significant medical, surgical, psychiatric, or laboratory 
abnormality in the judgment of the investigator 
7. Any physical impairment that by the judgment of the investigator 
impairs the ability of the patient to complete study assessments 
8. History 
of 
severe 
depression, 
psychosis 
or 
hallucinations 
within 6 months prior to Screening (Visit 1) 
9. History of active suicidal ideation as assessed by the investigator or 
measured by a score of 4 (Active Suicidal Ideation with Some Intent to 
Act, without Specific Plan) or 5 (Active Suicidal Ideation with Specific 
Plan and Intent) on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) within 6 months prior to Screening (Visit 1), or suicidal 
attempt within 5 years prior to Screening (Visit 1) 
10. History of cancer within 5 years prior to Screening (Visit 1), with the 
following exceptions if adequately treated: non-melanomatous skin 
cancers, localized bladder cancer, non-metastatic prostate cancer or in 
situ cervical cancer 


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19 Nov 2019 
 
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11. Presence of cognitive impairment, as evidenced by a Mini Mental State 
Examination (MMSE) score of <24 not including dementia during 
Screening (Visit 1) 
12. A prolonged Fridericia-corrected QT (QTcF) interval (defined as a 
QTcF interval of >450 msec) at Screening (Visit 1)  
13. Clinically significant heart disease at Screening (Visit 1), defined as 
follows:  
(i) 
significant cardiac event within 12 weeks prior to Baseline 
(Visit 2) (e.g., admission for myocardial infarction, unstable 
angina, or decompensated heart failure), angina pectoris or 
episode of congestive heart failure with symptoms > grade 2 
New York Heart Association classification, or presence of 
cardiac disease that in the opinion of the investigator increased 
the risk of ventricular arrhythmia 
(ii) 
history of complex 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) 
symptomatic bradycardia, sick sinus syndrome or 
atrioventricular block greater than first degree in the absence 
of a functioning pacemaker  
(iv) 
unexplained syncope  
(v) 
Brugada syndrome 
(vi) 
hypertrophic cardiomyopathy 
14. History of congenital long QT syndrome or a first degree relative with 
this condition  
15. History of epilepsy or of seizures within 5 years prior to Baseline 
(Visit 2) 
16. History of clinically significant deficit from stroke or transient ischemic 
attack within 6 months prior to Screening (Visit 1) 
17. Serum potassium, magnesium and/or calcium levels outside of the 
central laboratory’s reference range at Screening (Visit 1) and 
considered clinically significantly abnormal by the investigator. Repeat 
testing is allowed (up to a maximum of three tests) if required to 
establish whether values are within normal range or not clinically 
significant 
18. Use of all oral cannabinoids (including all preparations containing any 
cannabinoids, prescribed oral medical marijuana and oral cannabidiol) 
with the exception of topical formulations of cannabidiol, within 28 days 
prior to Baseline (Visit 2) 
19. Use of medications (within the last 6 weeks prior to Baseline [Visit 2]) 
that have been demonstrated to prolong the QT interval, or any patients 
who may require such medications during the course of the study such 
as but not limited to prohibited antipsychotic medications, tricyclic 


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antidepressants and/or Class I antiarrhythmic (see Table 3 and 
Section 5.10.1) 
20. Treatment with apomorphine during the 28 days prior to Screening 
(Visit 1) 
21. Body 
surface 
area 
(BSA)-adjusted 
creatinine 
clearance 
<50 mL/min/1.73 m2 at Screening (Visit 1), calculated using the 
Cockcroft-Gault equation: [(140 - age) × mass (kg) × [0.85 if female] / 
72 × serum creatinine (mg/dL) × BSA (m2)/1.73]. Repeat testing is 
allowed once, if clinically appropriate 
22. Alcohol and/or drug abuse within 6 months prior to Screening (Visit 1), 
as defined by Diagnostic and Statistical Manual – Fifth Edition Text 
Revision Criteria for Substance Abuse  
23. Female patients who are pregnant or breastfeeding 
24. Sexually active female patients, who are not surgically sterile or at least 
2 years postmenopausal prior to Screening (Visit 1), and do not agree to 
utilize a highly effective hormonal method of contraception (an 
intrauterine device or vasectomized male partner is also acceptable), in 
combination with a barrier method, from Screening (Visit 1) through at 
least 4 weeks after the completion of study treatment 
25. Male patients not using highly effective contraception or not agreeing to 
continue highly effective contraception through at least 90 days after the 
completion of study treatment 
26. Known allergy to any ingredients of the study treatment or placebo 
(pridopidine, silicified microcrystalline cellulose, magnesium stearate) 
27. Treatment with any investigational product within 30 days of Screening 
(Visit 1) or patients planning to participate in another clinical study 
assessing any investigational product during the study 
28. Planned elective surgery during study participation 
Study Design: 
Following a minimum of a 3-week and up to 9-week screening period, patients 
will be randomized in a 1:1:1 ratio into one of the three treatment arms: 
pridopidine 100 mg BID, pridopidine 150 mg BID or matching placebo. Patients 
randomly assigned to the active treatment arms will undergo a dosage regimen 
titration period during which they will be treated with pridopidine 75 mg once 
every other day (Q48h) for 1 week, followed by pridopidine 75 mg once daily 
(QD) for 1 week, pridopidine 75 mg twice daily (BID) for the following week, 
and 100 mg BID for the final fourth week of titration. Maintenance treatment 
with pridopidine 100 mg BID or 150 mg BID will then continue for an additional 
12 weeks. Patients randomly assigned to the placebo arm will receive matching 
placebo for the duration of the 16-week active treatment period. During the 
16-week active treatment period, patients will be requested to complete “Dosing 
diaries” to record their study treatment intake. Upon completion of the 16-week 
active treatment period, patients will undergo a 4-day down titration phase, 
which will be followed by a safety follow-up visit at Visit 8 (2 weeks after 
completion of the 16-week active treatment period). During the 4-week titration 
period, for patients who suffer from symptoms indicating worsening of PD, the 
levodopa regimen may be adjusted until the regimen is optimal according to the 


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Investigator’s judgment. This optimal regimen must be obtained within the 4 
weeks titration period and cannot be lower than the levodopa regimen at the time 
of screening. 
The study duration (from first patient randomized to last patient last visit) will 
be approximately 12 months. 
Estimated Study 
Duration: 
The total study duration will be 21 to 27 weeks and will consist of a minimum 
of a 3-week and up to 9-week screening period; a 16-week active treatment 
period, consisting of 4-week up-titration period and a 12-week maintenance 
period; a 4-day down titration period, and a safety follow-up visit (2 weeks after 
completion of the 16-week active treatment period). Study visits will be 
conducted at Screening (Visit 1), Baseline (Visit 2), at the beginning of Week 5 
(Visit 3) and Week 7 (Visit 4), and at the end of Week 10 (Visit 5), 
Week 13 (Visit 6), and Week 16/early termination (ET) (Visit 7) to assess 
efficacy, PK, and safety. Telephone contacts will be conducted during the 
titration period on Days 7 of Weeks 1-4 to remind patients to up-titrate their 
dosage and record any tolerability/safety reports from the patient , and on Days 
2 and 4 of Week 17 to remind patients to down-titrate and discontinue the dosing. 
A safety follow-up visit will be performed at Week 18 (Visit 8). In-clinic 
unscheduled visits can be performed for safety concerns at any time. 
The study duration (from first patient randomized to last patient last visit) will 
be approximately 12 months. 
Efficacy 
Endpoints: 
Primary and all secondary endpoints will be assessed for both the 100 mg BID 
and the 150 mg BID pridopidine dosages vs placebo in a hierarchical manner. 
 
Primary Endpoint / Outcome Measure: 
The primary endpoint is the mean change from Baseline (Visit 2) to Visit 7/ET 
in the sum of Parts 1, 3, and 4 of the Unified Dyskinesia Rating Scale (UDysRS) 
while the patient is the peak in “ON” state and judged to be experiencing peak 
dose dyskinesia. 
 
Secondary Endpoints / Outcome Measures: 
1. Mean change from Baseline (Visit 2) to Visit 7/ET in “ON time without 
troublesome dyskinesia” based on “ON/OFF” home diary completed by 
the patients during three consecutive 24-hour intervals 
2. Mean change from Baseline (Visit 2) to Visit 7/ET in the total UDysRS 
score (Parts 1 to 4)  
3. Proportion of patients improving based on the Patient Global Impression 
of Change (PGI-C) at Visit 7/ET  
4. Mean change from Baseline (Visit 2) to Visit 7/ET in “ON time without 
any dyskinesia” based on “ON/OFF” home diary  
5. Proportion of patients improving based on CGI-C at Visit 7/ET 
6. Mean change from Baseline (Visit 2) to Visit 7/ET in the Unified 
Parkinson's Disease Rating Scale (UPDRS) Part 2  


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7. Proportion of responders (improvement in dyskinesia and no worsening 
in motor function) at Visit 7/ET. The improvement in dyskinesia is 
defined as ≥30% improvement in UDysRS score (Parts 1, 3, and 4) from 
Baseline (Visit 2) and no worsening from Baseline (Visit 2) in “OFF” is 
defined as ≤30 minutes increase in “OFF time” from Baseline (Visit 2) 
per a 24-hour period  
8. Mean change from Baseline (Visit 2) to Visit 7/ET in “OFF time” based 
on “ON/OFF” home diary  
9. Mean change from Baseline (Visit 2) to Visit 7/ET in the UPDRS Part 3 
as measured immediately prior to the in-clinic L-DOPA dose  
Pharmacokinetic 
Endpoint: 
Plasma concentration of pridopidine and its metabolite TV-45065 before and 
after in-clinic pridopidine dose. 
Pharmacogenetic 
and Plasma 
Biomarker 
Endpoints: 
1. To analyze the correlation of potential genetic variations and plasma 
biomarkers with clinical treatment responses to study drug (e.g., 
efficacy, PK, tolerability, and safety features)  
2. To assess potential genetic variation and plasma biomarkers associated 
with disease progression and severity 
 
Safety Endpoints: 
1. Adverse events (AEs) occurring throughout the study 
2. QTc parameters: QTcF of >450 msec, >480 msec, and >500 msec mean 
QTcF, change in QTcF>30 msec and <60 msec or change in 
QTcF>60 msec throughout the study 
3. Clinical safety laboratory (clinical chemistry, hematology and 
urinalysis), 
vital 
signs 
(including 
assessment 
of 
orthostatic 
hypotension), physical and neurological examination, and concomitant 
medications throughout the study 
4. Change from Baseline (Visit 2) in suicidality as evaluated with the 
C-SSRS throughout the study 
5. Change from Baseline (Visit 2) in impulse control disorder (ICD) as 
evaluated by the Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease-Rating Scale (QUIP-RS) throughout the study 
 
Tolerability: 
1. The number (%) of patients who complete the study treatment 
2. The number (%) of patients who fail to complete the study treatment due 
to AEs 
3. The number (%) of patients who fail to complete the study treatment due 
to QTcF and QT stopping rules, seizures, or convulsions 
 
Study Treatment, 
Dosage, and Route 
of Administration: 
Study treatment: oral capsules containing 75 mg and 100 mg of pridopidine. 
Control treatment product: identical placebo capsules matching the pridopidine 
capsules. 


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Patients will be randomly assigned at Baseline (Visit 2) to receive pridopidine 
100 mg BID, 150 mg BID or placebo using a 1:1:1 allocation ratio. Capsules 
will be swallowed whole with water. 
Study treatments and matching placebo will be administered as oral capsules. 
During the 16-week active treatment period, the first study treatment daily dose 
will be taken between 6:00 and 8:00 AM and the second study treatment daily 
dose will be taken 6 to 10 hours after the first study treatment daily dose 
administration and not later than 5:00 PM. The second study treatment daily dose 
should be taken 0 to 120 minutes BEFORE the “scheduled levodopa dose” (NOT 
after). As much as possible, study treatment should be taken at the same time 
throughout the study. Patients assigned to active treatments will undergo a 
dosage regimen according to the following schedule (allowances for dose 
reduction are detailed in Section 5.3):  
1. Up-titration period:  
a. Week 1 - Patients will receive 75 mg of pridopidine and placebo 
Q48h  
b. Week 2 - Patients will receive 75 mg of pridopidine and placebo 
QD (total daily dose: 75 mg) 
c. Week 3 - Patients will receive 75 mg of pridopidine and placebo 
BID (total daily dose: 150 mg) 
d. Week 4 - Patients will receive 100 mg of pridopidine and 
placebo BID (total daily dose: 200 mg) 
2. Maintenance period:  
a.  Weeks 5-16 - • Patients will receive 100 mg BID of 
pridopidine (total daily dose: 200 mg) or 150 mg BID (total 
daily dose: 300 mg), as randomized, for 12 weeks. 
3. Down-titration period: 
a. Days 1 to 2 - Patients will receive 75 mg pridopidine and 
placebo BID (total daily dose: 150 mg) 
b. Days 3 to 4 - Patients will receive 75 mg and placebo QD (total 
daily dose: 75 mg) 
Patients randomly assigned to the placebo arm will receive matching placebo 
throughout the active treatment period in a double-blind fashion at the same 
dosing schedule as patients assigned to the active treatments.  
Based on the evaluation of the safety and tolerability of the 150 mg BID 
treatment arm by the Drug Safety Monitoring Board (DSMB), the sponsor 
reserves the right to allocate, in a random manner, newly enrolled patients and/or 
switch all patients who are still in the titration period to the 100 mg BID dose 
level.  


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Sample Size: 
A sample size of 38 randomized patients in each treatment group 
(114 randomized patients overall) will provide 80% power to detect a 
between-group difference of 8.5 points in the UDysRS score with standard 
deviation of 13 points using a two-sided significance level of 0.05, using an 
ordinary least squares model. Assuming a drop-out rate of 15%, a total of 
135 patients will be randomized. The sample size was calculated based on two 
sample t-test assuming equal variances in the two groups, using nQuery Advisor 
version 7.0. 
Statistical 
Methods: 
Details of the statistical analyses, methods, and data conventions will be 
described in the statistical analysis plan (SAP), which will be approved before 
breaking the blind of the study. 
 
Analysis Sets 
The efficacy analysis will be based on the modified intention to-treat (mITT) set. 
The mITT set will include all randomized patients who receive a dose of study 
treatment and have efficacy assessments both at Baseline (Visit 2) and at least 
one post-randomization time point. The patients will be grouped as randomized.  
Safety and tolerability analyses will be based on the safety set. The safety set 
will consist of all patients receiving at least one dose of study treatment. The 
patients will be grouped according to the treatment regimen actually received.  
Pharmacokinetic analyses will be based on the PK set. The PK set will consist 
of all patients in the safety set with at least one pridopidine concentration sample 
result reported. 
 
Statistical Testing Procedure 
Each primary and secondary endpoint includes the comparison of each of the 
two dosages of pridopidine vs placebo. The overall Type I error rate within the 
family of each primary and secondary endpoint will be maintained by using the 
Hochberg’s step-up method. Furthermore, the primary and secondary endpoint 
families will be evaluated in a hierarchical manner as described below and will 
be described in the SAP. For this purpose, the matched parallel gatekeeping 
procedure will be used. 
 
Primary Analysis 
The primary endpoint is the mean change from Baseline (Visit 2) to Visit 7/ET 
in the UDysRS sum score of Parts 1, 3, and 4, in the “ON” state, will be analyzed 
using a Mixed Model for Repeated Measures (MMRM) with no imputation 
using the mITT population. The Baseline (Visit 2) score will be included as a 
covariate and the treatment group (pridopidine 100 mg BID, pridopidine 150 mg 
BID or placebo), visit (Visit 4, Visit 5, Visit 6, or Visit 7/ET) and the interaction 
between treatment group and visit as fixed factors in the MMRM. The difference 
between each dosage of pridopidine vs placebo at Visit 7/ET will be estimated 
from the MMRM. 
 


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Secondary Analysis 
The continuous secondary endpoints (sum scores derived from UDysRS, 
UPDRS, and endpoints based on the “ON/OFF” home diaries) will be analyzed 
with MMRM models similar to those used for analysis of the primary endpoint. 
The mITT population will be used for these analyses. 
The categorical secondary endpoints (proportion of responders and proportion 
of patients improving based on PGI-C or CGI-C) will be analyzed in the mITT 
population using a generalized linear mixed model (using the using the 
GLIMMIX procedure from SAS for binomial data with logit link). 
 
PK Analysis 
The PK analysis will be conducted on the PK set. Plasma concentrations of 
pridopidine and its metabolite TV-45065 will be listed and summarized by visit 
and time point. Descriptive statistics will include the mean, coefficient of 
variation, geometric mean, minimum, median, and maximum. Relationships 
between plasma concentrations of pridopidine and TV-45065 at Visit 4, Visit 6, 
and Visit 7/ET vs key safety and efficacy measures will be explored graphically. 
 
Safety Analysis 
The safety analysis will be conducted on the safety set. The treatment-emergent 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
and summarized by treatment group, organ class and preferred term. Further 
summaries will be done -by seriousness, severity, relationship to study treatment 
and dose at the time of onset. Other safety endpoints will be summarized with 
descriptive statistics. 
Version and Date 
of Protocol: 
2.0 (Protocol Amendment 1); 19 Nov 2019 


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S-Figure 1 
Study Design  
 
 
Abbreviations: BID, twice daily; PK, pharmacokinetic; Q48h, once every 48 hours, QD, once daily; SFU, safety follow-up; UDysRS, Unified Dyskinesia Rating 
Scale; V, visit; Wk, week 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BID 
twice daily 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CI 
confidence interval 
CLES 
carbidopa-levodopa enteral suspensions 
Cmax 
observed maximum plasma or serum concentration after administration 
CrCL 
creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB 
Drug Safety Monitoring Board 
EAC 
Enrollment Authorization Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HD 
Huntington disease 
ICD 
impulsive-compulsive disorders 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intention-to-treat 
IWRS 
interactive web response system 
L-DOPA 
3,4-dihydroxyphenylalanine 
LID 
levodopa-induced dyskinesia 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention to-treat 
MMRM 
mixed model for repeated measures 
MMSE 
Mini-Mental State Examination 


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Abbreviation 
Definition 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
NHP 
nonhuman primates 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PD-LID 
levodopa-induced dyskinesia in patients with Parkinson-’s disease 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
Q48H 
once every 48 hours  
QD 
once daily 
QTcF 
Fridericia-corrected QT 
QUIP-RS 
Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease 
Rating-Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
UDysRS 
Unified Dyskinesia Rating Scale 
UPDRS 
Unified Parkinson's Disease Rating Scale 


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1 
Introduction 
1.1 Levodopa-Induced Dyskinesia 
1.1.1 
Epidemiology 
The most widely employed and effective therapy for the treatment of Parkinson’s disease (PD) 
is 3,4-dihydroxyphenylalanine (L-DOPA or levodopa). Over time, however, chronic L-DOPA 
therapy can be complicated by the development of levodopa-induced dyskinesia (LID), which 
can severely impact function and quality of life. After 5 years of treatment about 40 to 50% of 
patients will have developed dyskinesia (Rascol et al 2000), and after 10 years of treatment, 
the vast majority of patients will have developed dyskinesia depending on the levodopa dose 
employed (Hauser et al 2007). 
Levodopa dosage is one of the main risk factors for the development of dyskinesia. For 
example, in the ELLDOPA study, 16.5% of patients randomized to a daily dose of 600 mg 
developed dyskinesia after 9 months of treatment vs 2.3% of patients randomized to a daily 
dose of 300 mg (Fahn et al 2004). Estimates indicate approximately 40% of patients have 
dyskinesias after 4 to 6 years of levodopa use (Ahlskog and Muenter 2001). Duration of 
treatment has also been demonstrated to be an independent risk factor, although this may also 
reflect disease duration and severity which have been shown to correlate highly with both 
treatment duration and the rate of dyskinesia. It has also been recognized that LID tend to be 
more severe and occur more frequently and sooner in patients with a younger age of onset 
(before the age of 50) (Kumar et al 2005). 
1.1.2 
Impact on Quality of Life 
Dyskinesia can have a major impact on the quality of life of the PD patient. In a public meeting 
to hear perspectives from PD patients, caretakers and other patient representatives on the most 
significant effects of their disease, patients commented that despite the benefits of carbidopa-
levodopa, they experienced significant side effects. Many patients identified dyskinesia as 
“more of a problem than the actual symptom [the medication] was treating.” Some patients 
stated that they often questioned whether to continue treatment because of the severity of 
dyskinesia. Several perspectives were provided on ideal treatments for PD. The top three 
aspects of ideal treatment desired by commenters included medications with less “off” time 
(unpredictable exacerbation of symptoms during which medications were less effective), better 
symptom control, and fewer side effects (FDA 2016). 
1.1.3 
Currently Available Pharmaceutical Options for the Treatment of 
LID 
The first and only drug approved for the treatment of dyskinesia in patients with PD receiving 
levodopa therapy is amantadine (Gocovri™ extended-release capsules). In the two clinical 
studies that formed the basis of US Food and Drug Administration (FDA) approval in 
August 2017, significant between-group differences in the absolute value changes from 


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baseline were demonstrated in the mean Unified Dyskinesia Rating Scale (UDysRS) total 
score (reduction in dyskinesia) at Week 12 in patients treated with Gocovri™ compared with 
placebo. In Study 301, there was a between-group least-squares means’ (LSMEANS) 
difference in the absolute value changes from baseline between -amantadine and 
placebo- of -7.9 points (95% confidence interval [CI] = -12.5, -3.3), and in Study 304, there 
was a least-squares means difference of amantadine versus -placebo of -14.4 points (95% CI = 
-20.4, -8.3).  
However, Gocovri™ is associated with significant side-effects including hallucinations, 
narcolepsy, psychosis, impulse control/compulsive behavioral disturbances as well as 
withdrawal-emergent hyperpyrexia and confusion. In controlled studies, the incidence of, e.g., 
hallucinations was 21% in patients treated with Gocovri™ 274 mg and 3% in placebo-treated 
patients.  
Gocovri™ is also associated with a high incidence of dizziness and orthostatic hypotension - 
in controlled clinical studies, 16% of Gocovri™-treated patients and 1% of placebo-treated 
patients reported dizziness, 13% of Gocovri™-treated patients and 1% of placebo-treated 
patients experienced orthostatic hypotension. Overall 29% of Gocovri™-treated patients and 
2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, 
presyncope, postural dizziness or hypotension. 
There is clearly a major unmet need for additional treatment options for levodopa-induced 
dyskinesia in patients with Parkinson’s disease (PD-LID). 
1.2 Pridopidine 
Pridopidine may fulfill an unmet need in the treatment of dyskinesia based on preclinical 
studies that support the ability of pridopidine to reduce PD-LID without causing an adverse 
effect on Parkinsonian features. In addition, clinical studies in patients with Huntington 
Disease (HD) involving pridopidine at doses up to 112.5 mg twice daily (BID), was established 
to be safe and tolerable. 
1.2.1 
Pridopidine in PD-LID 
1.2.1.1 
Proof of Concept 
The gold standard model for the preclinical evaluation of compounds with antidyskinetic 
potential was used to assess the ability of pridopidine to reduce LID in nonhuman primates. 
Eight cynomolgus macaques were rendered Parkinsonian by once daily (QD) subcutaneous 
injection of 0.2 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), administered 
for 8 to 12 days, until the first appearance of Parkinsonism symptoms. The Parkinsonian 
syndrome was allowed to stabilize over the next 30 days. Additional administrations of MPTP 
were given to some animals to titrate to similar degrees of Parkinsonism in individuals across 
the group. The monkeys were allowed to recover for a minimum of an additional 30 days until 


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their Parkinsonism was demonstrated as being stable. Animals were then treated with L-DOPA 
(25 mg/kg) QD for at least 4 months to allow for LID to develop. 
Once LID was established, animals were treated with vehicle and three different doses of 
pridopidine (15, 20, and 30 mg/kg) that were administered via oral-gavage. Treatments were 
separated by a 1-week washout interval. Following treatment, animal behavior was recorded 
on HD-video during a 6-hour period. These recordings were used by a movement disorders 
neurologist blinded to treatment to rate animals for Parkinsonism and dyskinesia.   
Doses of 20 and 30 mg/kg demonstrated dose-related anti-LID effects up to 71% at the 
30 mg/kg dose. Pridopidine also decreased the duration of ON-time with disabling dyskinesia 
evoked by L-DOPA by 37% (20 mg/kg dose) and 60% (30 mg/kg dose). On the other hand, 
pridopidine did not compromise the anti-Parkinsonian benefit of L-DOPA at any of the doses 
tested.  
Effective doses of 20 and 30 mg/kg were associated with geometric mean observed maximum 
plasma or serum concentration after administration (Cmax) values of 1487 and 2676 ng/mL, 
respectively. It was concluded that in the macaque, a pridopidine minimal dose of 20 mg/kg is 
needed to produce a significant decrease in LID, with higher doses (30 mg/kg) having stronger 
effect. Pridopidine was shown not to compromise the anti-Parkinsonian benefit of L-DOPA 
(Johnston et al 2018). The observed dose-response in the macaque model suggests higher 
efficacy at higher doses. The correlation of the macaque pharmacokinetic (PK) parameters 
(Cmax) at effective doses (20 and 30 mg/kg) with known human pridopidine exposure (Table 
2) indicates that the 20 mg/kg macaque dose correlates with the human 90 mg BID dose 
(Cmax 1487 ng/mL and 1480 ng/mL, respectively),
 
 
 
 Safety and tolerability of pridopidine 
in humans has been demonstrated up to 112.5 mg BID (highest dose tested). 
1.2.1.2 
Potential Mechanism of Action 
In vitro binding assays to assess pridopidine’s affinity to a range of receptors were conducted. 
Pridopidine was tested in the range of 10 nM – 100 µM. 


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Table 1 
Pridopidine Binding Profile Ranked in Descending Order 
Target 
IC50 (µM) 
Ki (µM) 
nH 
Sigma-1 (σ1R) 
0.14 
0.057 
0.87 
Adrenergic α2C 
3.56 
1.58 
0.76 
Dopamine D3 
4.79 
1.63 
0.90 
Serotonin 5-HT1A 
6.36 
3.63 
0.72 
Sigma-2 (σ2R) 
7.16 
5.45 
0.80 
Serotonin 5-HT2A 
24.5 
7.00 
0.81 
Serotonin 5-HT7 
14.8 
8.51 
1.02 
Adrenergic α2A 
22.0 
11.0 
0.98 
Histamine-H3 
37.6 
18.3 
0.85 
Muscarinic-M2 
58.1 
24.4 
0.62 
Dopamine D2 
88.4 
29.5 
0.94 
Abbreviations: IC50, half maximum inhibitory concentration; Ki, inhibition constant calculated using the equation of Cheng 
and Prusoff; nH, Hill coefficient, defining the slope of the competitive binding curve, was calculated using MathIQTM. 
Pridopidine was found to have the highest affinity for the sigma-1 receptor (σ1R), with a Ki of 
57 nM. Moderate affinity binding in the micromolar-range was also evident for adrenergic α2C, 
dopamine-D3 and serotoninergic 5-HT1A receptors, with lower-affinity binding to 5-HT2A, 
5-HT7, α2A, histamine-H3 and muscarinic-M2 (Table 1). There was only negligible binding of 
pridopidine to D2R (Ki 29.5 µM). Additional targets were tested including the N-methyl-
D-aspartate, 5-HT6 and tachykinin NK1 receptors along with the dopamine, norepinephrine 
and the serotonin-transporters, all of which exhibited no detectable levels of binding (Johnston 
et al 2018). 
In vivo σ1R and D2R occupancies were calculated using (i) known binding-affinities of 
pridopidine to human and rodent receptors in-vitro; (ii) in vivo positron-emission tomography 
imaging in humans and monkeys; and (iii) the extensive PK profiling of pridopidine in the 
different species.  


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Table 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUC, area under the curve; BID, twice daily; Cmax, observed maximum plasma or serum concentration after 
administration; NHP, nonhuman primate; PET, positron-emission tomography; PO, per os.  
Cmax and AUC values for NHP as a function of oral pridopidine dose measured in the macaque (Johnston et al 2018; 
DPR-2017-016; DPR-2017-099). Human Cmax and AUC values for 45 and 90 mg BID are from Pride-HD (Study 
TV7820-CNS-20002) and simulated for 150 mg BID. Human σ1R and D2R occupancy at 45 mg BID derived from human 
PET study TV7820-IMG-10082 and estimated for higher doses. NHP D2R occupancy data is based on in vivo PET imaging 
with pridopidine (subcutaneous) using specific D2R ligand 11C-raclopride (PHA070005). NHP σ1R occupancy data 
extrapolated from in vitro binding investigations with 3H-fluspidine, a specific σ1R tracer, (Johnston et al 2018, 
supplementary) 
a 
Simulated data using the population pharmacokinetic modeling 
 
From Table 2, it is clear that in the macaques, plasma exposures following the ineffective 
pridopidine dose (15 mg/kg) are associated with full σ1R (>85%) suggesting σ1R engagement 
alone is unlikely to account for the antidyskinetic benefits of pridopidine that were observed. 
Exposures following effective doses (20 to 30 mg/kg), while still providing full σ-1-occupancy, 
provide only modest D2R-occupancy (25-40%). On the other hand, effective pridopidine doses 
clearly engage a range of receptors (including adrenergic-α2C, dopamine-D3 and 
serotoninergic-5-HT1A sites) to a greater degree than D2 (Johnston et al 2018).  
It is hypothesized that the ability of pridopidine to reduce PD-LID possibly involves- a 
complex pharmacological profile, associated with high σ1R occupancy together with multiple 
nonsigma receptors, including adrenergic α2C, 5-HT1A, and DA receptors. 


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2 
Study Objectives  
Primary Objective: 
1. To evaluate the efficacy of 2 dosages of pridopidine (100 mg twice daily [BID] and 150 
mg BID) vs placebo for the treatment of PD-LID 
Secondary Objectives: 
1. To determine if any effects of 2 dosages of pridopidine (100 mg BID and 150 mg BID) 
on the reduction of LID are associated with changes (worsening or improvement) of 
Parkinsonian features 
2. To evaluate the effect of 2 dosages of pridopidine (100 mg BID and 150 mg BID) vs 
placebo on global improvement, and activities of daily living in patients with PD-LID  
Safety Objective: 
1. To evaluate the safety and tolerability of 2 dosages of pridopidine (100 mg BID and 
150 mg BID) vs placebo in patients with PD-LID 
Pharmacokinetic Objectives: 
1. To evaluate the PK of pridopidine in patients with PD-LID 
2. To explore the relationship between pridopidine exposure and dyskinesia 


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3 
Investigational Plan 
3.1 Study Design 
This is a Phase 2B, multicenter, randomized, three-arm, parallel-group, double-blind, placebo-
controlled study to evaluate the efficacy, safety, and PK of pridopidine 100 mg BID and 
150 mg BID vs placebo for the treatment of PD-LID, experiencing dyskinesia. 
Following a minimum of a 3-week and up to 9-week screening period, patients will be 
randomized in a 1:1:1 ratio into one of the three treatment arms: pridopidine 100 mg BID, 
pridopidine 150 mg BID or exactly matching placebo. Patients randomly assigned to the active 
treatment arms will undergo a dosage regimen titration period during which they will be treated 
with pridopidine 75 mg once every other day (Q48h) for 1 week, followed by pridopidine 
75 mg once daily (QD) for 1 week, pridopidine 75 mg BID for 1 week, and finally by 100 mg 
BID for the fourth and final week of titrations. Maintenance treatment with pridopidine 100 mg 
BID or 150 mg BID will then continue for an additional 12 weeks. Patients randomly assigned 
to the placebo arm will receive a matched placebo for the duration of the 16-week active 
treatment period. Upon completion of the 16-week active treatment period, patients will 
undergo a 4-day down titration phase, which will be followed by a safety follow-up visit at 
Visit 8 (2 weeks after completion of the16-week active treatment period).  
During the 4-week titration period, for patients who suffer from symptoms indicating 
worsening of PD, the levodopa regimen may be adjusted until the regimen is optimal according 
to the Investigator’s judgment. This optimal regimen must be obtained within the 4 weeks 
titration period and cannot be lower than the total daily levodopa dose regimen at the time of 
screening. 
The study duration (from first patient randomized to last patient last visit) will be 
approximately 12 months.  
The study design is presented in Figure 1. 


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Figure 1 
Study Design 
Abbreviations: BID, twice daily; PK, pharmacokinetic; Q48h, once every 48 hours, QD, once a day; SFU, safety follow-up; UDysRS, Unified Dyskinesia Rating 
Scale; V, visit; Wk, week 


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Study visits will be conducted at Screening (Visit 1), Baseline (Visit 2), at the beginning of 
Week 5 (Visit 3) and Week 7 (Visit 4), and at the end of Week 10 (Visit 5), Week 13 (Visit 6), 
and Week 16/early termination (ET, Visit 7) to assess efficacy, PK, and safety. Telephone 
contacts will be conducted on Days 7 of Week 1-4 to remind patients to up-titrate their dosage 
and record any tolerability/safety reports from the patients. Patients will be contacted by the 
site team on Days 2 and 4 of Week 17 to remind them to down-titrate and discontinue the 
dosing. A safety follow-up visit will be performed at Week 18 (Visit 8). In-clinic unscheduled 
visits can be performed for safety concerns at any time, per the discretion of the investigator. 
During the study, an independent Drug Safety Monitoring Board (DSMB) will perform an 
ongoing review of serious adverse events (SAEs) and periodically review accumulating 
unblinded safety data. Further details are provided in Section 6.6. 
3.1.1 
Minimum 3-Week and Up to 9-Week Screening Period 
After signing an institutional review board (IRB)-approved informed consent document, 
screening will be performed within a minimum of 21 (3 weeks) days and up to 63 days 
(9 weeks) prior to Baseline (Visit 2). A review of screened patients to ensure safety and to 
confirm eligibility will be performed by an Enrollment Authorization Committee (EAC) prior 
to randomization (see Section 4.1 and Section 6.10). 
For patients requiring an amantadine washout period, two screening visits will be required 
during the screening period: Visit 1 and Visit 1.1. Visit 1, the first screening visit, will be 
performed up to 9 weeks/63 days prior to Baseline (Visit 2) and Visit 1.1 will be performed no 
later than on 3 weeks/ Day -21 days prior to Baseline (Visit 2) as defined in Table 4. 
For patients not requiring a washout period for any prohibited medication (see Section 5.10.1), 
only one screening visit will be required during the screening period: Visit 1. As much as 
possible, this visit should be performed 3 weeks/ 21 days prior to Baseline (Visit 2) as defined 
in Table 4. 
During the screening period (either during Visit 1 or Visit 1.1 depending on the need for 
amantadine washout), potential patients and any involved caregivers or study partners will be 
trained by a rater, a qualified study staff member to recognize the different motor states (“ON 
without dyskinesia,” “ON with no troublesome dyskinesia,” “ON with troublesome 
dyskinesia,” and “OFF”), and to complete a corresponding “ON/OFF” home diary.  
After training, the study rater and the patient will complete an “ON/OFF” diary at half-hour 
intervals over a 4-hour period to ensure concordance of >75% between the evaluations (e.g., 
“ON, OFF and dyskinesia”) of the rater and the patient. During this concordance testing, 
patients must experience each of the motor states and at least one time period rated as “ON 
with dyskinesia”. After assurance of >75% concordance, the patients will complete the 
“ON/OFF home diary” at home during three consecutive 24-hour periods (72 hours total). The 
patients will send the completed diaries to the site (e.g., via fax, email) up to 1 week before 


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end of the screening period because these diaries will serve as the baseline motor home diary 
and for eligibility to participate in the study. Training may be repeated during the screening 
period to ensure concordance with the rater.  
Patients’ existing anti-PD medication regimen, including, but not limited to, levodopa oral 
preparations, must be maintained at a stable dose for at least 28 days prior to Baseline (Visit 2) 
and for the entire duration of the maintenance treatment duration period.  Allowed 
antidepressant or antipsychotic medication and any other routine allowed prescription/over-
the-counter medications and/or nutritional supplements taken regularly, must also maintained 
at a stable dose for at least 28 days prior to Baseline (Visit 2) and for the entire duration of the 
treatment duration period.  
Details of all assessments performed at the Screening period (Visit 1 and Visit 1.1) are provided 
in Section 6, Table 4. 
3.1.2 
16-week Active Treatment Period (Up-titration and Maintenance) 
and Down-titration Period 
IRB-consented- patients who meet eligibility criteria will be randomly assigned at Baseline 
(Visit 2) to receive pridopidine 100 mg BID, 150 mg BID or placebo using a 1:1:1 allocation 
ratio. Study treatment and matching placebo will be administered as oral capsules. During the 
16-week active treatment period, the first study treatment daily dose will be taken between 
6:00 and 8:00 AM and the second study treatment daily dose will be taken 6 to 10 hours after 
the first study treatment dose administration and not later than 5:00 PM. The second study 
treatment daily dose should be taken 0 to 120 minutes BEFORE the “scheduled levodopa dose” 
(NOT after). As much as possible, study treatment should be taken at the same time throughout 
the study. If a patient misses the morning study treatment dose on an in-clinic day, the visit 
should be rescheduled. 
Patients in the active treatment arms will undergo a 4-week dosage regimen titration period 
during which they will be treated with pridopidine 75 mg Q48h for 1 week, followed by 
pridopidine 75 mg QD for 1 week, followed by pridopidine 75 mg BID for 1 week, followed 
by 100 mg BID for 1 week. Telephone contacts will be conducted on Days 3 and 7 of Weeks 1 
through 4 to remind patients to up-titrate their dosage and ask them to provide details on AEs 
and concomitant medication changes. A one-time dose reduction for up to 7 days, to the prior 
dosing level will be permitted, at the Investigator’s discretion. Further details of the dosing 
schedule are provided in Section 5.2. 
See Figure 1 for up-titration. The up-titration is the same for both groups to maintain the blind 
and effectively the 100 mg BID group is in maintenance at the end of the Week 1. 
During the 4-week titration period, for patients who suffer from symptoms indicating 
worsening of PD, the levodopa regimen may be adjusted until the regimen is optimal according 


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to the Investigator’s judgment. This optimal regimen must be obtained within the 4-week 
titration period and cannot be lower than the levodopa regimen at the time of screening. 
Maintenance treatment with pridopidine 100 mg BID or 150 mg BID will then be continued 
for an additional 12 weeks. During the maintenance period, patients unable to tolerate the study 
treatment will be allowed a 3-day reduction from BID to QD dosing. This down titration is not 
permitted in the 7 days before the patient’s next site visit and on the day of the site visit itself. 
Patients will be discontinued if they cannot tolerate the study treatment after the 3-day down-
titration during maintenance phase. Further details of the dosing schedule are provided in 
Section 5.2. 
At the end of the maintenance period or at ET, active-treatment patients will undergo a down-
titration period during which they will receive one capsule of pridopidine 75 mg and one 
capsule of placebo BID on Days 1 and 2 followed by one capsule of pridopidine 75 mg and 
one capsule of placebo QD on Days 3 and 4 of Week 17. Telephone contacts will be conducted 
on Days 2 and 4 of Week 17 to remind patients to down-titrate, discontinue the dosing, and ask 
them to provide details on AEs and concomitant medication changes  
Patients randomly assigned to the placebo arm will receive matching placebo throughout the 
treatment period in a double-blind fashion at the same dosing schedule as patients assigned to 
the active treatments. Details of all assessments performed at during the 16-week active 
treatment period are provided in Section 6, Table 4.  
Based on the evaluation of the safety and tolerability of the 150 mg BID treatment arm by the 
DSMB, the sponsor reserves the right to allocate, in a random manner, newly enrolled patients 
to the 100 mg BID dose level and placebo. Patients randomly assigned to the 150 mg BID arm 
who are still in the titration period could also be switched to the 100 mg BID arm.  
3.1.3 
Safety Follow-up Visit  
A safety follow-up visit will be performed 2 weeks after Visit 7/ET. 
3.1.4 
Efficacy  
Onsite/in-clinic assessments will be scheduled around the second (PM) study daily treatment 
dose from 11:00 AM through 5:00 PM at time points consistent with each patient’s usual 
levodopa dosing. The “scheduled levodopa dose” is defined as the afternoon levodopa dose 
prior to which the UPDRS assessment is performed and after which the UDysRS Parts 3+4 
assessment is performed. The second study treatment dose should be taken 0 to 120 minutes 
BEFORE the “scheduled levodopa dose” (NOT after). A consistent effort will be made to 
ensure that all study visits for an individual patient will occur at approximately the same time 
of the day. The same in-clinic procedural timing will be kept as best as possible for all visits 
for each patient. Every effort should be made to ensure that, for a given efficacy assessment, 
all measurements are performed by the same rater for each individual patient for all visits. 


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An in-clinic assessment of dyskinesia according to UDysRS will be conducted by the study 
rater at the time points noted in the schedule of assessments (Table 4). At Baseline (Visit 2), 
all UDysRS parts (Parts 1 to 4) must be assessed before the initial study treatment dose (refer 
to Appendix 13.1). For the rest of the time points, UDysRS must be assessed as per the in-clinic 
visit procedural flow in Appendix 13.2. The historical parts of the UDysRS (Parts 1 and 2) will 
be performed at any time during the visit (at Baseline [Visit 2], at any time before the initial 
study treatment dose). The objective score (Parts 3 and 4) will be performed at least 30 minutes 
following the patient’s in-clinic dose of levodopa (the “scheduled levodopa dose”), at a time 
when the patients are normally in an “ON” state and experiencing their peak dose dyskinesia.  
Patients will complete an “ON/OFF” home diary for 3 consecutive days before the in-clinic 
visit at the time points noted in the schedule of assessments (Table 4). The patients will record 
their motor state (“OFF”, “ON with no dyskinesia”, “ON with no troublesome dyskinesia”, 
“ON with troublesome dyskinesia”, and “asleep”) every 30 minutes during the 24-hour period. 
During this period, patients will also record their anti-PD and study treatment doses. A phone 
call will be made 4 days before each of these in-clinic visits to remind patients to complete 
their “ON/OFF” home diaries and bring them to the clinic. 
The Unified Parkinson’s Disease Rating Scale (UPDRS) Parts 2 and 3 and Patient Global 
Impression of Change (PGI-C) will be conducted at the time points noted in the schedule of 
assessments (Table 4). At Baseline (Visit 2), UPDRS Parts 2 and 3 must be assessed before the 
initial study treatment dose (refer to Appendix 13.1). For the rest of the time points, UPDRS 
Part 2 and Part 3 must be assessed as per the in-clinic visit procedural flow in Appendix 13.2. 
UPDRS Part 3 will be measured before the in-clinic levodopa dose (the “scheduled levodopa 
dose”). Part 2 can be measured at any time during the visit (at Baseline [Visit 2], at any time 
before the initial study treatment dose). 
Additional assessments to be performed include the Clinical Global Impression of 
Change (CGI-C) and the Patient Global Impression of Change (PGI-C). These additional 
scales will be assessed at the time points noted in the schedule of assessments (Table 4) and 
can be measured at any hour during the visit. Details of all efficacy assessments performed 
during the study are provided in Section 6, Table 4. 
3.1.5 
Safety  
Concomitant medications, laboratory tests, and safety assessments including adverse events 
(AEs), 
Columbia-Suicide 
Severity 
Rating 
Scale 
(C-SSRS), 
Questionnaire 
for -Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS), and 
vital signs (including orthostatic assessment) will be performed at all visits. A 12-lead 
electrocardiogram (ECG) will be conducted at Screening (Visit 1) and then at Baseline (Visit 2) 
and every visit thereafter; three consecutive 12-lead electrocardiogram (ECG) evaluations will 
be conducted before and 1 to 2 hours after the study treatment dose administered at the clinic 
(approximate Cmax). 


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All AEs and concomitant medications will be recorded from Screening (Visit 1) until the last 
study visit. During all telephone contacts, patients will be asked to provide details on AEs and 
concomitant medication changes.  
Details of all safety assessments performed during the study are provided in Section 6, Table 4. 
3.1.6 
Pharmacokinetics  
PK sampling for levels of pridopidine and its metabolite TV-45065 will be performed at the 
time points noted in the schedule of assessments (Table 4) (approximately 1 hour before and 1 
to 2 hours after the PM pridopidine dose). When coincident with ECG monitoring, PK samples 
will be collected within 30 minutes after the ECG recording.  
Details of all PK assessments performed during the study are provided in Section 6, Table 4. 
3.1.7 
Pharmacogenetic and Plasma Biomarker Substudy 
Patients will sign a separate informed consent form (ICF) for pharmacogenetic and plasma 
biomarker assessments before any are performed. Participation in this assessment is voluntary 
and patients can opt out at any time.  
Sampling analyses for DNA extraction will be performed only once during the study at 
Screening (Visit 1) or Baseline (Visit 2). Plasma samples for potential biomarkers research will 
be collected at the time points noted in the schedule of assessments (Table 4). 
3.1.8 
Rationale of Study Design 
A randomized, double-blind, placebo-controlled, three-arm, parallel-group study design was 
chosen for this Phase 2B study to allow comparison of safety, tolerability, efficacy, and PK for 
2 dosages of the study treatment versus the placebo control arm.  
The starting dose was chosen based on prior clinical experience demonstrating that the 
initiation of treatment with a pridopidine dose of 67.5 mg BID in healthy volunteers 
(135 mg/day, multiple-ascending dose study) was well tolerated, and that a dose of 45 mg BID 
(90 mg/day) has a safety profile similar to that of placebo as seen in HD patients. 
Pridopidine has the potential to fulfill an unmet need in the treatment of dyskinesia based on 
preclinical studies that support the ability of pridopidine to reduce LID without causing an 
adverse effect on Parkinsonian symptoms and in clinical studies of patients with HD involving 
pridopidine at doses up to 112.5 mg BID, that demonstrate an overall good safety and 
tolerability profile. 
The variables used for assessing PK, safety and efficacy are standard measures in clinical study 
in PD patients. 


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4 
Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 135 patients will be enrolled at 42 sites in the US (45 randomized patients in 
each treatment group). Patients will be assigned to study treatment only if they meet all the 
inclusion criteria and none of the exclusion criteria. 
4.1.1 
Inclusion Criteria 
Patients may be included in the study only if they meet all of the following criteria: 
1. Male or female patients between 30 and 85 years of age, inclusive 
2. Signed an IRB-approved ICF 
3. Diagnosis of PD consistent with the UK Parkinson’s Disease Society (UKPDS) Brain 
Bank Clinical Diagnostic Criteria 
4. Hoehn and Yahr Stage 4 or less in the “ON” state such that the patient can complete 
the study assessments 
5. Documentation of LID by the investigator 
6. A score of 3 on 2 elements of the Unified Dyskinesia Rating Scale (UDysRS) part 4 – 
Disability Scale 
7. Using the three consecutive 24-hour “ON/OFF” home diaries completed prior to 
Baseline (Visit 2), at least two half-hour time periods one between 8:00 AM and 
5:00 PM of each 24-hour period are indicated as “ON with dyskinesia” 
8. Patient and/or study partner must demonstrate during the screening period an ability to 
keep accurate home diary entries of PD symptoms (“ON, OFF, and dyskinesia”) with 
>75% concordance with the study rater. During the 4-hour concordance testing, patient 
must experience all motor states: “ON”, “OFF” and at least one period of “ON with 
dyskinesia”  
9. Patients who are stable on a total daily dose of ≤200 mg amantadine must be off this 
treatment at least 4 weeks prior to the assessment of UDysRS part 4, the concordance 
testing and the completion of the three consecutive 24-hour “ON/OFF” home diaries 
which are performed during screening   
10. All anti-PD treatments are stable for at least 28 days prior to Baseline (Visit 2), 
including a levodopa preparation administered no less than three times daily, with the 
same dosing regimen during the 12-week maintenance study treatment period 


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11. If taking allowed antidepressant or antipsychotic medication, must be on a stable dose 
for at least 28 days prior to Baseline (Visit 2) and must be kept constant during the 
study 
12. Any other routine and allowed prescription/nonprescription medications and/or 
nutritional supplements taken regularly must be at stable dosages for at least 28 days 
prior to Baseline (Visit 2) and remain during study participation  
13. Willing and able to comply with study requirements 
14. Approval for entry into the study by an independent EAC (see Section 6.10) 
4.1.2 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Diagnosis of atypical Parkinsonism 
2. History of exclusively diphasic, “OFF” state, myoclonic, or dystonic dyskinesia 
without peak-dose choreiform dyskinesia 
3. Treatment 
with 
dopamine 
blocking 
drugs 
(e.g., 
neuroleptics, 
Reglan® 
[metoclopramide]) 
4. History of surgical intervention related to PD (e.g., deep brain stimulation, carbidopa-
levodopa intra-enteral suspension [CLES; DuopaTM]) 
5. Presence of clinically significant orthostasis symptoms, e.g., arterial hypotension  
6. Clinically significant medical, surgical, psychiatric, or laboratory abnormality in the 
judgment of the investigator 
7. Any physical impairment that by the judgment of the investigator impairs the ability of 
the patient to complete study assessments 
8. History of severe depression, psychosis or hallucinations within 6 months prior to 
Screening (Visit 1) 
9. History of active suicidal ideation as assessed by the investigator or measured by a 
score of 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or 
5 (Active Suicidal Ideation with Specific Plan and Intent) on the Columbia-Suicide 
Severity Rating Scale (C-SSRS) within 6 months prior to Screening (Visit 1), or 
suicidal attempt within 5 years prior to Screening (Visit 1)  


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10. History of cancer within 5 years prior to Screening (Visit 1), with the following 
exceptions if adequately treated: non-melanomatous skin cancers, localized bladder 
cancer, non-metastatic prostate cancer or in situ cervical cancer 
11. Presence of cognitive impairment, as evidenced by a Mini Mental State Examination 
(MMSE) score of <24 not including dementia at Screening (Visit 1) 
12. A prolonged Fridericia-corrected QT (QTcF) interval (defined as a QTcF interval of 
>450 msec ) at Screening (Visit 1) 
13. Clinically significant heart disease at Screening (Visit 1), defined as follows:  
(i) 
significant cardiac event within 12 weeks prior to Baseline (Visit 2) (e.g., 
admission for myocardial infarction, unstable angina, or decompensated heart 
failure), angina pectoris or episode of congestive heart failure with symptoms 
> grade 2 New York Heart Association classification, or presence of cardiac 
disease that in the opinion of the investigator increased the risk of ventricular 
arrhythmia 
(ii) 
history of complex 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) 
symptomatic bradycardia, sick sinus syndrome or atrioventricular block greater 
than first degree in the absence of a functioning pacemaker 
(iv) 
unexplained syncope  
(v) 
Brugada syndrome  
(vi) 
hypertrophic cardiomyopathy 
14. History of congenital long QT syndrome or a first degree relative with this condition  
15. History of epilepsy or of seizures within 5 years prior to Baseline (Visit 2) 
16. History of clinically significant deficit from stroke or transient ischemic attack 
within 6 months prior to Screening (Visit 1) 
17. Serum potassium, magnesium and/or calcium levels outside of the central laboratory’s 
reference range at Screening (Visit 1) visit and considered clinically significant by the 
investigator. Repeat testing is allowed (up to a maximum of three tests) if required to 
establish whether values are within normal range or not clinically significant 
18. Use of all oral cannabinoids (including all preparations containing any cannabinoids, 
prescribed oral medical marijuana and oral cannabidiol) with the exception of topical 
formulations of cannabidiol, within 28 days prior to Baseline (Visit 2) 


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19. Use of medications (within the last 6 weeks prior to Baseline [Visit 2]) that have been 
demonstrated to prolong the QT interval, or any patients who may require such 
medications during the course of the study such as but not limited to prohibited 
antipsychotic medications, tricyclic antidepressants and/or Class I antiarrhythmic (see 
Table 3 and Section 5.10.1) 
20. Treatment with apomorphine during the 28 days prior to Screening (Visit 1)  
21. Body surface area (BSA)-adjusted creatinine clearance <50 mL/min/1.73 m2 at 
Screening (Visit 1), calculated using the Cockcroft-Gault equation: [(140 - age) × mass 
(kg) × [0.85 if female] / 72 × serum creatinine (mg/dL) × BSA (m2)/1.73]. Repeat 
testing is allowed once, if clinically appropriate 
22. Alcohol and/or drug abuse within 6 months prior to Screening (Visit 1), as defined by 
Diagnostic and Statistical Manual – Fifth Edition Text Revision Criteria for Substance 
Abuse  
23. Females who are pregnant or breastfeeding 
24. Sexually active female patients, who are not surgically sterile or at least 2 years 
postmenopausal prior to Screening (Visit 1), and do not agree to utilize a highly 
effective hormonal method of contraception (an intrauterine device or vasectomized 
male partner is also acceptable), in combination with a barrier method, from Screening 
(Visit 1) through at least 4 weeks after the completion of study treatment 
25. Male patients not using highly effective contraception or not agreeing to continue 
highly effective contraception through at least 90 days after the completion of study 
treatment 
26. Known allergy to any ingredients of the study treatment or placebo (pridopidine, 
silicified microcrystalline cellulose, magnesium stearate) 
27. Treatment with any investigational product within 30 days of Screening (Visit 1) or 
patients planning to participate in another clinical study assessing any investigational 
product during the study 
28. Planned elective surgery during study participation 
4.2 Withdrawal of Patients from Study Treatment and/or the Study 
The duration of the study is defined for each patient as the date signed written informed consent 
is provided through the last safety follow-up visit at Visit 8. If a patient discontinues treatment, 
they will be encouraged to remain in the study and continue study visits and procedures for the 
full course of the study without receiving study treatment. Patients who withdraw from the 


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study before the Visit 7/ET visit and are not willing to continue study visits and procedures for 
the full course of the study will be asked, to undergo an ET visit that will include all evaluations 
that were intended to be performed at the final visit. 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Patients are free to withdraw from the study at any time and for any reason without prejudice. 
The investigator also has the right to withdraw a patient from the study if an intercurrent illness 
or AE occurred, if the patient did not cooperate, or for any reason concerning the health or 
well-being of the patient. The reasons for patients not completing the study will be recorded. 
Among other reasons, a patient may be discontinued from the study treatment or the study if 
they meet any of the following stopping rules: 
QTcF stopping rules 
• QTcF >500 msec (based on the mean value from the triplicate ECG measurements) 
• QTcF >480 msec with concurrent increase in QTcF >60 msec (ΔQTcF, based on the 
mean value from the triplicate ECG measurements) from Baseline (Visit 2) 
• Patients with QTcF >480 msec or with an increase of QTcF >60 msec from Baseline 
(Visit 2) will return to the clinic within 48 to 72 hours for repeat evaluation of electrolyte 
levels and repeat triplicate ECGs to demonstrate reversibility of the effect on QTcF. 
Decision on discontinuation will be determined by EAC 
Creatinine clearance stopping rule 
Patients with an adjusted CrCL <50 mL/min/1.73 m2 calculated by CrCL * BSA/1.73, where 
CrCL is calculated using the Cockcroft-Gault equation [(140 - age) × mass (kg) × [0.85 if 
female] / 72 × serum creatinine (mg/dL)] at any time point after Baseline (Visit 2) will be 
requested to return to the clinic for an unscheduled visit 1 week later to repeat the CrCL test 
one more time for confirmation. If the repeated CrCL value is confirmed to be 
<50 mL/min/1.73 m2, the patient will be discontinued from the study treatment. 
The investigator will also withdraw a patient if Prilenia Therapeutics or regulatory authorities 
terminate the study. If a patient is discontinued because of an AE, the event will be followed 
until it has resolved.  
4.2.2 
Handling of Withdrawals 
The reason(s) for withdrawal will be documented in the patient’s electronic case report form 
(eCRF). Patients withdrawing from the study will be encouraged to complete the same final 
evaluations as patients completing the study according to this protocol, particularly safety 
evaluations. The aim is to record data in the same way as for patients who completed the study. 
Reasonable efforts will be made to contact patients who are lost to follow-up. These efforts 


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must be documented in the patient’s file. The sponsor has the right to terminate the study at 
any time in case of serious AEs (SAEs) or if special circumstances concerning the study 
treatment or the company itself occur, making further treatment of patients impossible. In this 
event, the investigator(s) will be informed of the reason for study termination. 
4.2.3 
Replacements 
Patients who withdraw, are withdrawn by the investigator, or are lost to follow-up after 
randomization will not be replaced. 


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5 
Study Treatments 
The study treatment will be oral capsules containing 75 mg and 100 mg of pridopidine and 
matching placebo capsules (as the control treatment product) identical in appearance. 
Pridopidine capsules contain the active ingredient pridopidine (75 mg or 100 mg) and inactive 
excipients. The excipients are 
. 
The investigational product will be produced and packed in 60 count bottles provided by 
  
The secondary packaging and labeling of study treatment will be performed by 
 
 All packaging and labeling operations for study treatment will be performed 
according to Good Manufacturing Practice for Medicinal Products and the relevant regulatory 
requirements. 
Bottles containing the investigational product or placebo capsules will be packed in kits. Each 
medication kit will contain two distinct labeled bottles in accordance with the associated 
treatment arm. Both outer pack and bottles will be labeled with a unique pack number. 
Four types of kit will be prepared for use in this study: 
• 
Kit type 1: One bottle of 75 mg pridopidine and one bottle of placebo 
• 
Kit type 2: One bottle of 100 mg pridopidine and one bottle of placebo 
• 
Kit type 3: Two bottles of 75 mg pridopidine 
• 
Kit type 4: Two bottles of placebo 
 
5.1 Method of Assigning Patients to Treatment Groups 
Patients will be randomly assigned at Baseline (Visit 2) to receive pridopidine 100 mg BID, 
150 mg BID or placebo using a 1:1:1 allocation ratio.  
An interactive web response system (IWRS) will be used to administer the randomization 
schedule. Biostatistics will generate the randomization schedule using SAS software 
Version 9.4 or later (SAS Institute Inc, Cary, North Carolina) for IWRS, which will link 
sequential patient randomization numbers to treatment codes.  
5.2 Treatments Administered 
Study treatments and matching placebo will be administered as oral capsules. During the 
16-week active treatment period, the first study treatment daily dose will be taken between 
6:00 and 8:00 AM and the second study treatment daily dose will be taken 6 to 10 hours after 


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the first study treatment dose administration and not later than 5:00 PM. The second study 
treatment daily dose should be taken 0 to 120 minutes BEFORE the “scheduled levodopa dose” 
(NOT after). As much as possible, study treatment should be taken at the same time throughout 
the study. 
Capsules will be swallowed whole with water. Study treatment can be taken irrespective of 
meals.  
If a patient misses a study treatment dose(s) on a non-clinic day, the following guidelines 
should be followed: 
• If the first study daily treatment dose is missed, it can be taken up to 11:00 AM that 
day. If it is not taken by 11:00 AM, the first study daily treatment dose should be 
skipped, and the patient continues to the normal dosing schedule  
• If the second study daily treatment dose is missed, it can be taken up to 5:00 PM that 
day. If it is not taken by 5:00 PM, the second study daily treatment dose should be 
skipped, and the patient continues to the normal dosing schedule the following day  
If a patient misses the morning study treatment dose on an in-clinic day, the visit should 
be re-scheduled. 
Patients randomized to each of the active treatment arms, pridopidine 100 mg BID or 150 mg 
BID will receive the following during these designated periods in the study (as per the schedule 
detailed in Section 5.4.1): 
1. Up-titration-period (Weeks 1 through 4) 
a. Week 1-3: One kit type 1 (one bottle of 75 mg pridopidine capsules and one 
bottle of placebo capsules in a blinded fashion): 
i. 
Week 1 (Days 1-7) - patients will receive one capsule of study 
medication from each of the 2 bottles, every other day (Q48h) 
(either AM or PM). 
ii. 
Week 2 (Days 8-14) - patients will receive one capsule of study 
medication from each of the 2 bottles, once per day (QD) (either 
AM or PM). The total daily dose will be 75 mg pridopidine.   
iii. 
Week 3 (Days 15-21)- patients will receive one capsule of study 
medication from each of the 2 bottles, twice per day (BID). The 
total daily dose will be 150 mg pridopidine. 
b. Week 4: One kit type 2 (one bottle of 100 mg pridopidine and one bottle of 
placebo in a blinded fashion):  


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i. Week 4 (Days 22-28) - patients will receive one capsule of study 
medication from each of the 2 bottles, BID. The total daily dose will be 
200 mg pridopidine. 
2. Maintenance period (Weeks 5 to 16) –   
a. 100 mg BID arm, patients will receive 3 kits type 2 (each comprises one bottle 
of 100 mg pridopidine capsules and one bottle of placebo capsules in a blinded 
fashion), in total 3 kits for 12 weeks.  
i.  Weeks 5 -16 (Days 29 to 112) - patients will receive one capsule of 
100 mg pridopidine and one capsule of placebo, one capsule from each 
of the 2 bottles, BID (total daily dose of 200 mg pridopidine). On Day 
1 of Week 5 (Day 29), the first daily dose patients will take before 
coming to Visit 3 is from the up-titration kit they used during Week 4. 
b. 150 mg BID arm, patients will receive 3 kits type 3 (each comprises 2 bottles 
of 75 mg pridopidine capsules in a blinded fashion), in total 3 kits for 12 weeks.  
i. Weeks 5-16 (Days 29 to 112) - patients will receive 2 capsules of 75 mg 
pridopidine, one capsule from each of the 2 bottles, BID (total daily 
dose of 300 mg pridopidine). 
3. Down-titration period (Week 17)-  
a. Patients will receive one kit type 1 (one bottle of 75 mg pridopidine capsules 
and one bottle of placebo capsules in blinded fashion): 
i. Week 17 (Days 1 to 2) - patients will receive one capsule of study 
medication from each of the 2 bottles, BID.  The total daily dose will be 
150 mg pridopidine. 
ii. Week 17 (Days 3 to 4) - patients will receive one capsule of study 
medication from each of the 2 bottles, QD (either AM or PM).  The total 
daily dose will be 75 mg pridopidine. 


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Patients randomized to the placebo treatment arm will receive the following during these 
designated periods in the study (as per schedule detailed in Section 5.4.1): 
1. Up- titration period (Weeks 1 through 4) 
a. Weeks 1 – 3: One kit type 4 (two bottles of placebo in blinded fashion): 
i) Week 1 (Days 1-7) - patients will receive 2 capsules of placebo 
(one capsule from each of the 2 bottles), every other day (Q48h) (either 
AM or PM). 
ii) Week 2 (Days 8-14) - patients will receive 2 capsules of placebo 
(one capsule from each of the 2 bottles), once per day (QD) (either AM 
or PM). 
iii) Week 3 (Days 15-21) - patients will receive 2 capsules of placebo (one 
capsule from each of the 2 bottles), twice per day (BID). 
b. Week 4: One kit type 4 (two bottles of placebo in blinded fashion):  
i) Week 4 (Days 22-28) - patients will receive 2 capsules of placebo 
(one capsule from each of the 2 bottles), twice per day (BID). 
2. Maintenance period (Weeks 5 to 16) –   
a. Patients will receive 3 kits type 4 (each comprises 2 bottles of placebo) , in total 
3 kits for 12 weeks. 
i) Week 5-16 (Days 29 to 112) - patients will receive 2 capsules of placebo 
(one capsule from each of the 2 bottles), BID. On Day 1 of Week 5 
(Day 29), the first daily dose patients will take before coming to Visit 3 
is from the up-titration kit they used during Week 4. 
3. Down-titration period (Week 17):  
a. Patients will receive one kit type 4 (two bottles of placebo in blinded fashion): 
i. Week 17 (Days 1 to 2) -  patients will receive two capsules of placebo 
(one capsule from each of the two bottles), BID. 
ii. Week 17 (Days 3 to 4) - patients will receive 2 capsules of study 
medication (one capsule from each of the 2 bottles), QD (either AM or 
PM). 


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5.3 Dose Modification 
5.3.1 
Up-titration Period 
During the 4-week titration, a one-time dose reduction, for up to 7 days, to the prior dosing 
level will be permitted, at the Investigator’s discretion. After this down-titration, the normal 
up-titration schedule must be resumed, and patients who still do not tolerate study treatment 
will be discontinued. 
• If the dose reduction occurs during Weeks 1 through 3, the Investigator should instruct 
the patient to continue to use the same kit  
• If the dose reduction occurs in the fourth week of the up-titration period (Week 4), the 
Investigator should instruct the patient to dose from the kit used during Weeks 1 
through 3.  
5.3.2 
Maintenance Period 
During the maintenance period, patients unable to tolerate the study treatment will be allowed 
a 3-day reduction from BID to QD dosing. This down titration is not permitted in the 7 days 
before the patient’s next site visit and on the day of the site visit itself. Patients will be 
discontinued if they cannot tolerate the study treatment after the 3-day down-titration during 
maintenance phase. 
5.4 Management of Clinical Supplies 
5.4.1 
Study Treatment Packaging, Storage, and Dispensing 
Pridopidine and matching placebo will be prepared in bottle packs and shipped by 
 
. Each patient will receive a total of 6 different kits during the following periods 
of the study:  
At Baseline (Visit 2) – 2 kits for the up-titration- (Weeks 1 to 4) 
Maintenance period of 12 weeks – Visits 3, 5, 6, and 7 
1. At Visit 3 (Week 5) – patients will return the 2 kits used during up-titration (Visit 2) and 
2 new kits will be dispensed for a period of 8 weeks (Weeks 5-12). 
2. At Visit 5 (Week 10)– patients will return the 2 kits dispensed at Visit 3 for 
accountability. Bottle with unused capsules will be returned to the patient to continue 
using during Weeks 11 and 12, and a new kit will be dispensed to use during Weeks 13, 
14, 15, and 16. The patient will be sent home with 2 kits; a used kit that was originally 
dispensed at Visit 3, and a new dispensed kit. 


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1. At Visit 6 (Week 13) – patients will return the two kits provided to them from Visit 5 for 
accountability. Unused bottles will be re-dispensed to the patients following the accountability 
to use during Weeks 14, 15, and 16. The patient will be sent home with one kit that was 
dispensed at Visit 5.  
At Visit 7/ET– Patients will return the one kit from Visit 6. An additional kit will be dispensed 
for the down-titration- period (Week 17, Days 1 to 4) 
5.4.2 
Storage Conditions for Study Treatment and Security 
All medication supplied in connection with this study (pridopidine and placebo) must be used 
only for this study and no other purpose. 
At each investigational site, the study treatments will be kept at 15 to 25 ºC in a secure, limited-
access, controlled storage area. Only authorized personnel will have access to the study 
treatments. The study personnel at each site will be responsible for the correct storage and 
handling of the study treatments.  
Study treatment is packed in drug kits. Patients will be provided with sufficient drug supplies 
to cover the period until their next study visit. Each drug kit for maintenance period will contain 
drug capsules sufficient for 28 + 2 days to accommodate the flexible visit windows. 
Each drug kit will be labelled with the protocol number, storage information, warning language 
(i.e., as required by local legislation for investigational drug products), dosing and storage 
instructions.  
The Investigator is responsible for recording the receipt and use of all drugs supplied, and for 
ensuring the supervision of the storage and allocation of these supplies. Full accountability will 
be performed for all used and unused study treatment. 
5.4.3 
Study Treatment Accountability 
During the 16-week active treatment period, patients will be requested to complete “Dosing 
diaries” to record their study treatment intake. The diaries will be dispensed at Visits 2, 3, 4, 5, 
6, and 7. Diaries will be returned at each subsequent visit. 
The investigator will maintain accurate records of receipt of all study treatment, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test article 
is dispensed and used by each patient in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all study treatment will be reconciled and retained 
or destroyed according to applicable regulations. 
5.4.4 
Other Supplies 
Study sites will be supplied with the home diaries and all scales.  


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5.5 Overdose Management 
The determination of an overdose will be left to the discretion of the investigator, based on the 
quantity of overdose, emergence of any clinical signs and symptoms suggestive of toxic 
administration, as well as his/her own clinical judgment as it applies to each individual case. 
Discovery of overdose within 1 hour may warrant induction of emesis, followed by supportive 
care and observation in a controlled medical setting. 
Any overdose, with or without associated AEs, must be promptly reported to the Sponsor
 
 in an expedited manner using the SAE Report form and following the 
procedure described in Section 6.5.1.5. 
5.5.1 
Medication Errors 
A medication error is an unintended failure in the drug treatment process that leads to, or has 
the potential to lead to, harm to the patient. A failure in the drug treatment process does not 
refer to lack of efficacy of the drug, rather to human or process mediated failures.  
In the event of medication error, appropriate therapy for the patient’s symptoms and clinical 
status should be provided. 
5.5.2 
Treatment of Medication Errors 
Not applicable. 
5.6 Misuse for Illegal Purposes 
Not applicable. 
5.7 Off-Label Use 
Not applicable. 
5.8 Blinding 
This is a double-blind study. Patients, investigators, the treating physician who will view 
clinical laboratory reports and assess AEs, and safety information and an independent 
evaluating physician, responsible for performing efficacy assessments, and anyone else 
involved in the study, with the exception of the individuals responsible for sample bioanalysis 
and PK analysis, will all be blinded. The prolactin should be blinded to all the clinical staff, 
Prilenia Therapeutics and/or its designee. The individuals responsible for sample bioanalysis 
and PK analysis and other responsible staff members supporting the unblinded data review by 
the DSMB will know who received study treatment and who received placebo during the study. 
The DSMB will review the data in an unblinded fashion. 


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The PK scientist will not have access to randomization codes. Unblinding can be performed 
upon request for reasons related to safety as described in Section 5.8.1.  
5.8.1 
Breaking the Blind 
If a patient is unblinded they will not receive further study treatment but will be encouraged to 
continue in the study until their final visit. 
The study blind may be broken for an individual patient using the IWRS only in the case of an 
emergency when knowledge of the study treatment is essential for the clinical management of 
the patient. The Investigator must make every effort to contact the 
 prior 
to breaking the study blind. The breaking of the blind shall be based solely on the Investigator’s 
medical judgment. In the case of unblinding, the Investigator must inform 
 immediately 
without revealing to 
personnel the result of the code break. The Investigator must record 
in the patient’s eCRF and source documents the date of the code break and reason for requiring 
a code break, in the event of a medical emergency, as soon as possible. It may be discussed 
with the 
Medical Monitor and the Sponsor if needed, but the final decision is the 
Investigator’s. 
If a suspected unexpected serious adverse reaction (SUSAR) or SAE is reported, the
 
may unblind the treatment assignment for the individual patient. In such cases, 
access to the code will only be permitted by authorized drug safety representatives.  
5.9 Treatment Compliance 
Patients will be instructed to bring with them the used and unused drug kits at Visit 3, Visit 5, 
Visit 6, Visit 7/ET, and at Visit 8, in which treatment compliance will be evaluated. 
Treatment compliance at the Visit 3, Visit 5, Visit 6, Visit 7/ET, and Visit 8 and overall for the 
16-week active treatment period will be calculated using the following formula: 
Compliance (%) = [Total number of administered doses/Total number of scheduled 
doses] × 100 
The total number of scheduled doses will be calculated based on the extent (days) of exposure 
of each patient. A range between 80% to 120% will be taken as reference limits for a 
satisfactory level of compliance. In addition, compliance will be assessed by tablet count. 
During the in-clinic days, the levodopa doses will be recorded and tracked during the 
“ON/OFF” diary completion days. 
5.10 Prior and Concomitant Therapy  
To be eligible for entering this study, patients must have dyskinesia and be taking at least three 
doses/day of oral levodopa. This treatment has to be stable for at least 28 days prior to Baseline 


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(Visit 2). Patients must be stable on their anti-PD medications and dosage regimens for at least 
28 days prior to Baseline (Visit 2) and continue anti-PD medications without change 
throughout the treatment period.  
During the 4-week titration period, for patients who suffer from symptoms indicating 
worsening of PD, the levodopa regimen may be adjusted until the regimen is optimal according 
to the Investigator’s judgment. This optimal regimen must be obtained within the 4 weeks 
titration period and cannot be lower than the levodopa regimen at the time of screening. 
Use of all prior medications 28 days prior to Baseline (Visit 2) and concomitant medications 
will be recorded in the patient’s eCRF. The minimum requirement is that drug name and the 
dates of administration are to be recorded. This will include all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter (OTC) medications. Any changes in 
concomitant medications also will be recorded in the patient’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the investigator. However, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the eCRF. 
Non-emergent levodopa rescue is not permitted during the screening and maintenance periods. 
In cases of medical emergency, levodopa rescue may be used (based on investigator decision) 
but not on the days of clinic visits or “ON-OFF” diary completion as much as possible. Use of 
levodopa must be reported and recorded.  
5.10.1 
Prohibited Medications and Substitution Alternatives 
The medications in the excluded medications column of Table 3 are not allowed within 
6 weeks before Baseline (Visit 2) or during the study. By-class substitution alternatives (if 
available) are also provided in Table 3.  
Enrolled patients must be provided with all contact information in order to allow any prescriber 
to discuss medication changes with the clinical investigator team/medical monitor before 
making therapeutic decisions and prescribing new medications during the study. 
 
Table 3 
Prohibited Medications and Substitution Alternatives 
Medication Class 
Excluded medications 
Substitution Alternatives 
Anti PD/ PD-LID  
apomorphine, mucuna pruriens, 
topiramate, amantadine, levodopa 
injection/infusion 
Not applicable 


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Medication Class 
Excluded medications 
Substitution Alternatives 
Antipsychotics 
ziprasidone, clozapine, haloperidol, 
mesoridazine, thioridazine, pimozide, 
zuclopenthixol, chlorpromazine, 
paliperidone, iloperidone, 
fluphenazine, prochlorperazine, 
trifluoperazine/trifluroperazine, 
flupentixol, benperidol, amisulpride, 
and sulpiride 
aripiprazole, risperidone, 
olanzapine, quetiapine, 
thiothixene, 
acetophenazine, 
triflupromazine, loxapine, 
tiapride, chlorprothixene, 
bromperidol 
Antidepressants 
Any tricyclic/tetracyclic 
antidepressant (e.g., amitriptyline, 
nortriptyline, imipramine, 
desipramine, doxepin, clomipramine, 
protriptyline, and amoxapine),  
Escitalopram, citalopram, trazodone 
>100 mg/day 
All triple reuptake inhibitors 
 lithium (mood stabilizer) 
SSRI/SNRIs: venlafaxine, 
paroxetine, duloxetine, 
sertraline, omipramol 
(opipramol), moclobemide, 
tranylcypromine, buspiron, 
reboxetine, dibenzepin, 
fluvoxamine 
Bupropion: special caution 
re: seizure risk, maximum 
3 × 150 mg/day  
Antiarrhythmics 
disopyramide, procainamide, 
quinidine, flecainide, propafenone, 
amiodarone, dofetilide, ibutilide, 
sotalol 
mexiletine, tocainide 
Dopamine 
antagonists 
All dopamine antagonists are 
prohibited (e.g., Reglan 
[metoclopramide]) 
Not applicable 
Othera 
astemizole, terfenadine, azithromycin, 
erythromycin, moxifloxacin, 
pentamidine, sparfloxacin, 
clarithromycin, chloroquine, 
halofantrine, bepridil, cisapride, 
domperidone, droperidol, 
levomethadyl, codeine, sevoflurane, 
tamoxifen, anagrelide, budipine, 
cotrimoxazole, fluconazole, 
levofloxacin, lidoflazine, loratadine, 
ondansetron, probucol, sertindole, 
terodiline, vandetanib 
Clinician’s choice and 
decision on a specific base-
basis.  


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Abbreviations: PD, Parkinson’s disease; PD-LID, levodopa-induced dyskinesia in patients with Parkinson’s 
disease; SNRI, serotonin-noepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor;  
a Due to either QT prolongation effects or metabolism by CYP2D6 into active metabolites 
 
** Fluoxetine is allowed as it carries a conditional risk only for patients with congenital Long 
QT, hypokalemia or metabolic inhibitors. 
Other: 
• 
Use of all oral cannabinoids (including all preparations containing any cannabinoids, 
including cannabidiol, as well as prescribed oral medical marijuana and oral 
cannabidiol) with only an exception for topical formulations of cannabidiol, are 
prohibited within 28 days prior to Baseline (Visit 2) and during the study 
• 
Amantadine is not allowed within 4 weeks prior to  the UDyRS Part 4 assessment for 
eligibility, concordance testing, and completion of the 3 consecutive 24 hour 
“ON/OFF” home diaries during the screening period 
• 
Apomorphine is not allowed within 28 days prior to screening and during the study 
 


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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential patients will sign an IRB-approved- ICF. 
Patients will have the opportunity to have any questions answered before signing the ICF. The 
investigator must address all questions raised by the patient. The investigator or designee will 
also sign the ICF. 
On-site (in-clinic) visits should be scheduled around the second (PM) study treatment daily 
dose within the time window of 11:00 AM through 5:00 PM and at consistent time points. 
Attempts will be made to schedule all study visits for an individual patient at approximately 
the same time of the day. The same in-clinic procedural timing will be kept for each of the in-
clinic- visits for each patient. The in--clinic procedural flow for Baseline (Visit 2) is presented 
in Appendix 13.1. The in-clinic procedural flow for Visits 3 to 7 is presented Appendix 13.2. 
The second (PM) study treatment daily dose (at clinic) should be taken 6-10 hours after the 
first (AM) study treatment daily dose, which is taken at home, and not later than 5:00 PM. 
A detailed schedule of study procedures/assessments is provided in Table 4. 
 


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Table 4 
Schedule of Assessments 
Study Perioda 
Screening 
Treatment Period 
Down-
titration 
Safety 
Follow-Up 
Up-titration 
Maintenance 
Study Week 
 
Week 1b 
Week 5 
Week 7 
Week 10 
Week 13 
Week 
16/ETc 
Week 
17d 
Week 18 
Visit # 
Visit 1  
Visit 1.1gg 
Visit 2e 
Visit 3ee 
Visit 4 ee 
Visit 5 ee 
Visit 6 ee 
Visit 7 ee 
TC 
Visit 8 
Study Visit Day 
(window) 
-63 
daysff 
-21 days 
(none) 
1 
(none) 
29 
(±1 day) 
43 
(±1 day) 
70 
(±1 day) 
91 
(±1 day) 
112 
(±1 day) 
119 
(none) 
126 
(±1 day) 
Study Phone Call Day 
 
 
7, 14, 21, f 
25g 
52g 
73g 
94g 
 
114, 116h 
 
Visit Descriptor 
SCR 
SCR 
BSL 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
PK 
Phone 
call 
Final 
Safety 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomization to 
treatment groups 
 
 
X 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
MMSE  
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Psychiatric history  
X 
 
 
 
 
 
 
 
 
 
Medication historyj 
X 
 
 
 
 
 
 
 
 
 
Alcohol/ illicit drug use 
inquiry 
X 
 
 
 
 
 
 
 
 
 
Hoehn and Yahr scale 
X 
 
 
 
 
 
 
 
 
 
Training on recognizing 
motor sates and diary 
documentationk 
Xhh 
X 
 
 
 
 
 
 
 
 
Motor state concordance 
testingl 
Xhh 
X 
 
 
 
 
 
 
 
 
“ON/OFF” Home diaries 
dispensing 
Xhh 
X 
 
X 
X 
X 
X 
 
 
 


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Study Perioda 
Screening 
Treatment Period 
Down-
titration 
Safety 
Follow-Up 
Up-titration 
Maintenance 
Study Week 
 
Week 1b 
Week 5 
Week 7 
Week 10 
Week 13 
Week 
16/ETc 
Week 
17d 
Week 18 
Visit # 
Visit 1  
Visit 1.1gg 
Visit 2e 
Visit 3ee 
Visit 4 ee 
Visit 5 ee 
Visit 6 ee 
Visit 7 ee 
TC 
Visit 8 
Study Visit Day 
(window) 
-63 
daysff 
-21 days 
(none) 
1 
(none) 
29 
(±1 day) 
43 
(±1 day) 
70 
(±1 day) 
91 
(±1 day) 
112 
(±1 day) 
119 
(none) 
126 
(±1 day) 
Study Phone Call Day 
 
 
7, 14, 21, f 
25g 
52g 
73g 
94g 
 
114, 116h 
 
Visit Descriptor 
SCR 
SCR 
BSL 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
PK 
Phone 
call 
Final 
Safety 
Follow-up 
“ON/OFF” Home diaries 
assessments 
 
 
Xm 
 
Xg 
Xg 
Xg 
Xg 
 
 
Prior and concomitant 
medications reviewn 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
Xo 
 
 
 
 
Xp 
 
Xp 
Vital signsq 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Neurological examination 
Xhh 
X 
Xo 
 
 
 
 
Xp 
 
Xp 
Body weight and heightr  
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Clinical laboratory tests  
(Serum haematology and 
biochemistry)s  
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis (dip stick)  
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum pregnancy test  
(if applicable)t  
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test  
(if applicable)u 
 
 
X 
X 
X 
X 
X 
X 
 
X 
ECG (12-lead) 
Consecutive triplicate of 
10 secondsv 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRS 
Xhh 
X 
X 
X 
X 
X 
X 
X 
 
X 
QUIP-RS 
Xhh 
X 
X 
X 
X 
X 
X 
X 
 
X 


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Study Perioda 
Screening 
Treatment Period 
Down-
titration 
Safety 
Follow-Up 
Up-titration 
Maintenance 
Study Week 
 
Week 1b 
Week 5 
Week 7 
Week 10 
Week 13 
Week 
16/ETc 
Week 
17d 
Week 18 
Visit # 
Visit 1  
Visit 1.1gg 
Visit 2e 
Visit 3ee 
Visit 4 ee 
Visit 5 ee 
Visit 6 ee 
Visit 7 ee 
TC 
Visit 8 
Study Visit Day 
(window) 
-63 
daysff 
-21 days 
(none) 
1 
(none) 
29 
(±1 day) 
43 
(±1 day) 
70 
(±1 day) 
91 
(±1 day) 
112 
(±1 day) 
119 
(none) 
126 
(±1 day) 
Study Phone Call Day 
 
 
7, 14, 21, f 
25g 
52g 
73g 
94g 
 
114, 116h 
 
Visit Descriptor 
SCR 
SCR 
BSL 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
Efficacyi 
Safety 
PK 
Efficacyi 
Safety 
PK 
Phone 
call 
Final 
Safety 
Follow-up 
UDysRS (Part 4 for 
eligibility) 
Xhh 
X 
 
 
 
 
 
 
 
 
UDysRS (Parts 1, 2, 3, 4)w 
 
 
X 
X 
X 
X 
X 
X 
 
 
UPDRS (Parts 2 and 3)x 
 
 
X 
 
X 
X 
X 
X 
 
 
PGI-C 
 
 
 
 
X 
X 
X 
X 
 
 
CGI-C 
 
 
Xy 
 
 
X 
 
X 
 
 
Treatment initiationz  
 
 
X 
 
 
 
 
 
 
 
Assign and dispense study 
treatment (bottles and kits)  
 
 
X 
X 
 
X 
 
X 
 
 
Collect returned kits and 
bottles and assess 
complianceaa 
 
 
 
X 
 
X 
X 
X 
 
X 
Dispense and/or return 
dosing diaries 
 
 
X 
X 
X 
X 
X 
X 
 
 
PK sampling (two 
samples)bb 
 
 
 
 
X 
 
X 
X 
 
 
Pharmacogenetic samplecc 
X 
 
X 
 
 
 
 
 
 
 
Plasma Biomarker 
samplingdd 
X 
 
X 
 
 
X 
 
X 
 
 
Safety including AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations: AE, Adverse events; BID, twice daily; BSL, baseline; CGI-C, Clinical Global Impression of Change; C-SSRS, Columbia-Suicide Severity Rating 
Scale; ECG: electrocardiogram; MMSE, Mini-Mental State Examination; PD, Parkinson’s disease; PGI-C, Patient Global Impression of Change; PK, 
pharmacokinetics; QD, once daily; QUIP-RS, Questionnaire for Impulsive / -Compulsive Disorders in Parkinson’s Disease- Rating Scale; SCR, screening; TC, 
telephone contact; UDysRS, Unified Dyskinesia Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. 
a. 
In-clinic unscheduled visits can be performed for safety concerns at any time per the discretion of the investigator. 
b. Four-week up-titration period. Patients randomly assigned to active treatment will receive 75 mg of pridopidine every other day (Q48h) for one week 
either AM or PM; then 75 mg of pridopidine once daily (QD) either AM or PM for 1 week; then 75 mg of pridopidine twice daily (BID) for one week; 
then 100 mg of pridopidine for one week in a blinded fashion. Patients randomly assigned to the placebo arm will receive matching placebo at the same 
dosing schedule as patients assigned to the active treatments. Refer to Section 5.2. 
c. 
An early termination (ET) visit should be performed for patients who discontinue prematurely within 1 week of ET. 
d. Down-titration period. At the end of the maintenance period or at ET, active treatment patients will undergo a down-titration- period in which they will 
receive pridopidine 75 mg BID on Days 1 to 2 followed by pridopidine 75 mg QD on Days 3 to 4 of Week 17. Patients randomly assigned to the placebo 
arm will receive matching placebo at the same dosing schedule as patients assigned to the active treatments. Refer to Section 5.2. 
e. 
All efficacy and safety measures, except the ECG after the second study treatment dose must be assessed before the first study treatment dose. Refer to the 
in-visit procedural flow for Baseline (Visit 2) in Appendix 13.1. 
f. 
Telephone contacts will be conducted on Day 1 of Week 1-4 (up-titration period) to remind patients to up-titrate their dosage and ask them to provide 
details on AEs and concomitant medication changes. 
g. Patients will be called 4 days before each of the relevant visits to remind them to complete the “ON/OFF” home diary every 30 minutes during the 3 
consecutive days before the visit and to bring them to the clinic.  
h. Telephone contacts will be conducted on Days 2 and 4 of Week 17 to remind patients to down-titrate and discontinue the dosing. 
i. 
Onsite/in-clinic assessments will be scheduled around the second (PM) study daily treatment dose from 11:00 AM through 5:00 PM and will use time 
points consistent with each patient’s usual levodopa dosing. On clinic visit days, the “scheduled levodopa dose” is defined as the in-clinic afternoon 
levodopa dose prior to which the UPDRS assessment is performed and after which the UDysRS parts 3+4 assessment is performed. The study treatment 
afternoon dose should be taken 0 to 120 minutes BEFORE the “scheduled levodopa dose” (NOT after). As much as possible, all study visits for an 
individual patient will occur at approximately the same time of the day. The same in-clinic procedural timing will be kept for all visits for each patient. 
j. 
Patients’ existing anti-PD medication regimens, including, but not limited to, levodopa oral preparations, must be maintained at a stable dose for at least 
28 days prior to Baseline (Visit 2) and for the entire duration of the treatment duration period. During the 4-week titration period, for patients who suffer 
from symptoms indicating worsening of PD, the levodopa regimen may be adjusted until the regimen is optimal according to the Investigator’s judgement. 
This optimal regimen must be obtained within the 4-week titration period and cannot be lower than the levodopa regimen at the time of screening. 
Allowed antidepressant or antipsychotic medication and any other routine allowed prescription/nonprescription medications and/or nutritional supplements 
taken regularly, must also maintained at stable dose for at least 28 days prior to Baseline (Visit 2) for the entire duration of the maintenance treatment 
duration period.  
k. Training of patients and study partners on recognition of motor state and “ON/OFF” home diary documentation to ensure concordance with the 
investigator rating may be repeated as many times as needed throughout the screening period. 


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l. 
After motor state recognition training, the patient will be invited to the clinic, and both the study rater and the patient will complete an “ON/OFF” home 
diary, at half hour intervals over a 4-hour period, to obtain concordance of >75% between the evaluations (e.g., “ON, OFF and “dyskinesia”) of the rater 
and the patient. 
m. After assurance of >75% concordance between the rater and patient, the patients will complete at their homes the “ON/OFF” home diary during three 
consecutive 24-hour periods (72 hours total) and send the completed diaries to the site (e.g., via fax, email). The patients will send the completed diaries to 
the site (e.g., via fax, email) up to one week before the end of the screening period because these diaries will serve as the baseline motor home diary and 
for eligibility to participate in the study. 
n. Prior and concomitant medication during 28 days prior to Baseline (Visit 2). 
o. The purpose of the assessment at Visit 2 is to confirm that there are no changes since Screening (Visit 1). 
p. The assessment will be performed at Visit 7/ET or at Visit 8. 
q. Vital signs include supine (after resting for at least 5 minutes), supine, and standing BP, pulse rate, and body weight.  
r. 
Height will be recorded at Screening (Visit 1) only. 
s. 
Prolactin will be assessed at Baseline (Visit 2) and Visit 7/ET only. 
t. 
Human chorionic gonadotropin (HCG) serum test will be performed for all women not surgically sterile or at least two years postmenopausal at Screening 
(Visit 1). An indeterminate reading for the serum pregnancy test should be checked twice (urine test) and discussed with the medical monitor if 
persistently indeterminant; no study treatment will be administered until this is resolved. 
u. A dipstick urine pregnancy test will be performed for all female patients who are not surgically sterile or who are not at least two years postmenopausal.  
v. Three consecutive 12-lead ECG evaluations will be assessed before, and 1 to 2 hours after the study treatment dose administered at the clinic (approximate 
Cmax). A single ECG may be used for screening purposes if the QTcF is normal. 
w. An in-clinic assessment of dyskinesia according to UDysRS will be conducted by the study rater. At Screening, only Part 4 will be assessed in order to 
determine eligibility. At Baseline (Visit 2), all UDysRS parts (Parts 1 to 4) must be assessed before the initial study treatment dose (refer to 
Appendix 13.1). For the rest of the time points, UDysRS must be assessed as per the in-clinic visit procedural flow in Appendix 13.2. The historical parts 
of the UDysRS (Parts 1 and 2) will be performed at any time during the visit (at Baseline [Visit 2] at any time before the initial study treatment dose). The 
objective score (Parts 3 and 4) will be performed at least 30 minutes following the patient’s in-clinic dose of levodopa (the “scheduled levodopa dose”), at 
a time when the patients are normally in an “ON” state and experiencing their peak dose dyskinesia. Every effort will be made to ensure that all 
assessments of UDysRS are performed by the same rater for each individual patient. 
x. At Baseline (Visit 2), UPDRS Part 2 and 3 must be assessed before the initial study treatment dose (refer to Appendix 13.1). For the rest of the time points, 
UPDRS Part 2 and 3 must be assessed as per the in-clinic visit procedural flow in Appendix 13.2. UPDRS Part 3 will be measured before the in-clinic 
levodopa dose (the “scheduled levodopa dose”); Part 2 can be measured at any time during the visit (at Baseline [Visit 2] at any time before the initial 
study treatment dose). 
y. Investigators must complete a detailed case note at Visit 2 to document the patient’s condition before starting study drug. This will be the baseline in 
which to compare changes in the patients’ global condition after receiving study drug for rating the CGI-C. 
z. 
During the 16-week active treatment period, the first study treatment daily dose will be taken between 6:00 and 8:00 AM and the second study treatment 
daily dose will be taken 6 to 10 hours after the first study treatment dose administration and not later than 5:00 PM. The second study treatment daily dose 
should be taken 0 to 120 minutes BEFORE the “scheduled levodopa dose” (NOT after). As much as possible, study treatment should be taken at the same 


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time throughout the study. Capsules will be swallowed whole with water. Study treatment can be taken irrespective of meals. If a patient misses the 
morning study treatment dose on an in-clinic day, the visit should be rescheduled. 
aa. Study treatment kit for down-titration purposes. At the end of the maintenance period or at ET, active treatment patients will undergo a down-titration  
period in which they will receive one capsule of pridopidine 75 mg and one capsule of placebo BID on Days 1 to 2 followed by one capsule of pridopidine 
75 mg and one capsule of placebo QD on Days 3 to 4 of Week 15.Patients receiving placebo will receive matching placebo at the same dosing schedule as 
patients assigned to the active treatments. 
bb. Pharmacokinetic sampling will be performed at Visit 4, Visit 6, and Visit 7/ET approximately 1 hour before and 1 to 2 hours after the PM study treatment 
dose. When concomitant with ECG recording, PK samples will be collected within 30 minutes after the ECG recording. The timing of UDysRS and 
UDPRS should be prioritized before PK sampling. 
cc. Sampling analyses for DNA extraction will be performed only once during the study at the Screening (Visit 1) or at Baseline (Visit 2). 
dd. Sampling analyses will be performed at Screening (Visit 1) or Visit 2, Visit 5, and Visit 7/ET. 
ee. If a patient misses the morning study treatment dose on an in-clinic day, the visit should be rescheduled. 
ff. For patients requiring an amantadine washout period, two screening visits will be required during the screening period: Visit 1 and Visit 1.1. Visit 1, the 
first screening visit, will be performed up to 9 weeks/63 days prior to Baseline (Visit 2) and Visit 1.1 will be performed no later than 3 weeks/ 21 days 
prior to Baseline. For patients not requiring an amantadine washout period, only one screening visit will be required during the screening period: Visit 1. 
As much as possible, this visit should be performed 3 weeks/ 21 days prior to Baseline. 
gg. Additional visit only required for patients requiring an amantadine washout period.  
hh. If Visit 1.1 is required due to necessity for amantadine washout, this assessment shall only be performed at Visit 1.1 and not at Visit 1. 
 


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6.1 Study Visits 
The schedule of assessments by study visit is presented in Table 4. Detailed instructions for the 
conduct of study assessments and procedures will be provided in the study manual provided to 
investigators. 
6.2 Efficacy Assessments 
Every effort should be made to ensure that, for a given efficacy assessment, all measurements 
are performed by the same rater for each individual patient for all visits.  
6.2.1 
UDysRS 
The UDysRS is designed to evaluate involuntary movements often associated with treated PD. 
The scale comprises two primary sections: 
• 
Historical [Part 1 (ON-Dyskinesia) and Part 2 (OFF-Dystonia)] 
• 
Objective [Part 3 (Impairment) and Part 4 (Disability)] 
ON-Dyskinesia refers to the choreic and dystonic movements described to the patient as 
“jerking or twisting movements that occur when your medicine is working.” OFF-Dystonia 
should be described to the patient as “spasms or cramps that can be painful and occur when 
your Parkinson’s disease medications are not taken or are not working”. The assessments will 
be carried out at the time points noted in the schedule of assessments (Table 4). Every effort 
should be made to ensure that all UDysRS assessments are performed by the same rater for 
each individual patient. 
6.2.2 
UPDRS 
The UPDRS scale is divided into 4 parts. Part 1 is designed to rate mentation, behavior and 
mood (questions 1 to 4). It is to be collected as historical information without direct relevance 
to “ON” or “OFF” periods experienced by the patient. Part 2 (questions 5 to 17) is designed to 
rate activities of daily living for both “ON” and “OFF” periods. Part 3 (questions 18 to 31) is 
done as a motor examination at the time of a visit. Part 4 (questions 32 to 42) is historical 
information designed to rate complications of therapy. The various items to be rated are scored 
using a 5-point system (i.e., 0 is normal and 4 indicates a severe abnormality). UPDRS Part 2 
and Part 3 will be measured at the time points noted in the schedule of assessments (Table 4).  
6.2.3 
“ON/OFF” Home Diary Assessments 
The “ON/OFF” home diary assessments are assessed during three consecutive 24-hour periods. 
During the screening period, potential patients and any involved caregivers or study partners 
if applicable will be trained to recognize the different motor states (“ON without dyskinesia,” 
“ON with no troublesome dyskinesia,” “ON with troublesome dyskinesia,” and “OFF”), and 
to complete a corresponding “ON/OFF” home diary. Training will be conducted by a well-


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Page 64 
trained rater. After training, the patients will be invited to the clinic; the study rater and the 
patients will complete an “ON/OFF” diary at half-hour intervals over a 4-hour period to ensure 
concordance of >75% between the evaluations (e.g., “ON, OFF and dyskinesia”) of the rater 
and the patient. After assurance of >75% concordance between the rater and patient, the 
patients will complete at their homes the “ON/OFF Home Diary” during three consecutive 
24-hour periods (72 hours total). The patients will send the completed diaries to the site (e.g., 
via fax, email) during the first two weeks of the screening period because these diaries will 
serve as the baseline motor home diary and for eligibility to participate in the study. Training 
may be repeated during the screening period to ensure concordance with investigator ratings. 
The assessments will be carried out at the time points noted in the schedule of assessments 
(Table 4). 
6.2.4 
Patient Global Impression of Change (PGI-C) 
Global improvement will be rated by the patient using the PGI-C. Whenever feasible, 
assessments should be made by the same assessor in an individual patient. The assessments 
will be carried out at the time points noted in the schedule of assessments (Table 4). 
6.2.5 
Clinical Global Impression (CGI-C) 
Global improvement will also be rated by the investigator or designee separately using the 
CGI-C. Whenever feasible, assessments should be made by the same assessor in an individual 
patient. The assessments will be carried out at the time points noted in the schedule of 
assessments (Table 4). 
6.2.6 
Mini-Mental State Examination (MMSE)  
The MMSE is a scale for eligibility. It comprises a 30-point questionnaire that is used 
extensively in clinical and research settings to measure cognitive impairment. It is used to 
estimate the severity and progression of cognitive impairment and to follow the course of 
cognitive changes in an individual over time; thus, making it an effective way to document an 
individual’s response to treatment. The assessments will be carried out at Screening. 
6.3 Pharmacokinetics Assessments 
The PK measure will be the determination of plasma concentration of pridopidine and its 
metabolite TV-45065 using a validated liquid chromatography–mass spectrometry method. 
Details on PK sample collection are detailed in Section 6.9. 
6.4 
Pharmacogenetic and Plasma Biomarker Assessments 
Details on pharmacogenetic and plasma biomarker sample collection are detailed in 
Section 6.9. 


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6.4.1 
Pharmacogenetic Assessments 
Pharmacogenetic assessments may include the analysis of DNA variations (e.g., known 
polymorphism in the σ1R gene and the catechol-O-methyltransferase [COMT] gene) with a 
potential relationship with clinical responses to study drug (e.g., efficacy, PK, tolerability, 
safety features or disease susceptibility, and severity features). The final list of genes that might 
be investigated will be selected at a later stage before the analysis to allow updating with new 
scientific information. Genetic analysis could also include sequencing of the whole genome if 
required. The genetic sample analysis will be performed if and when required. Since new 
techniques continue to be developed, the method and laboratory that will be used for the genetic 
analysis cannot be defined at present. The bioanalytical laboratory will be identified at a later 
stage. 
6.4.2 
Plasma Biomarker Assessment 
The following biomarker candidate assessments will be evaluated: neurofilament light chain 
protein (NFL), α-synuclein, and DJ-1. Other blood biomarkers may be evaluated for future 
exploratory purposes upon new scientific knowledge. 
6.5 
Safety Assessments 
Safety assessments include AEs, concomitant medications, laboratory tests (clinical chemistry, 
haematology, and urinalysis), C-SSRS, 12-lead ECG, QUIP-RS, vital signs (including 
assessment of orthostatic hypotension), and physical and neurological examination. The 
assessments will be carried out at the time points noted in the schedule of assessments 
(Table 4). Every effort should be made to ensure that, for a given safety assessment, all 
measurements are performed by the same rater for each individual patient for all visits. 
6.5.1 
Adverse Events 
6.5.1.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, from the signing of the IRB-approved ICF to the last study visit or until satisfactory 
resolution, regardless of their relationship to study treatment or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study treatment. Patients will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
treatment or any event already present that worsens in either intensity or frequency after 
exposure to study treatment.  


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6.5.1.2 
Serious Adverse Events 
An SAE is defined as any event that: 
• 
results in death 
• 
is immediately life-threatening 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.5.1.3 
Eliciting and Documenting Adverse Events 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) and 
up to visit of the safety follow-up period (Visit 8). 
Serious AEs that occur more than 30 days after the reporting period need not be reported unless 
the investigator considers them related to study treatment. 
At every study visit, patients will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. Patients will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and OTC medications). 
In addition to patient observations, any abnormal laboratory test results (haematology, clinical 
chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital sign 
measurements), including those that worsen from Visit 2, felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. In 
addition, AEs identified from review of other documents (e.g., patient diaries) that are relevant 
to patient safety will be documented on the AE page in the eCRF. 
6.5.1.4 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 


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• 
drug treatment 
• 
dose 
• 
event term 
• 
time of onset 
• 
investigator-specified assessment of severity and relationship to study treatment 
• 
time of resolution of the event 
• 
seriousness 
• 
any required treatment or evaluations 
• 
outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions 
to concurrent medications, or progression of disease states must also be reported. All AEs will 
be followed to appropriate resolution. The Medical Dictionary for Regulatory Activities 
(MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. Pharmacodynamic symptoms of the treatment are not 
considered as an AE. Overdoses without signs or symptoms do not need to be recorded as AEs; 
in case of any AEs associated with the overdose, these should be reported on relevant AE/SAE 
sections in the eCRF (Section 5.5). 
6.5.1.5 
Reporting Serious Adverse Events, Pregnancy, and Overdose 
Any AEs reported or observed during the study from informed consent that meets SAE criteria 
(Section 6.5.1.2) must be reported to the 
 immediately (i.e., within 
24 hours) after the time site personnel first learn about the event. Any pregnancy that occurs 
during study participation must be reported using the same procedures as an SAE, i.e., within 
24 hours of first knowledge using a pregnancy report form. The investigator should also be 
notified of pregnancy occurring during the study but confirmed after completion of the study. 
In the event that a patient is found to be pregnant after inclusion in the study, any pregnancy 
will be followed to term, and after delivery, the status of mother and child will be reported to 
the sponsor after delivery. Full details will be recorded on the withdrawal page of the eCRF. 
Any overdose, with or without associated AEs, must be promptly reported to the Sponsor
 
 in an expedited manner using the SAE Report Form, and following the 
procedure described in this section and from 
. The patient may be 
hospitalized for observation and appropriate supportive treatment administered. Any 
concerning overdose (i.e., with an associated AEs or any lab abnormalities) will be reported 


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via 
. Any AE/SAEs or any lab abnormalities considered related to 
the overdose should be reported as appropriate.  
The determination of an overdose will be left to the discretion of the investigator, based on the 
quantity of overdose, emergence of any clinical signs and symptoms suggestive of toxic 
administration, as well as his/her own clinical judgment as it applies to each individual case. 
Overdoses without signs or symptoms do not need to be recorded as AEs; in case of any AEs 
associated with the overdose, these should be reported on relevant AE/SAE sections in the 
eCRF. 
The following contact information is to be used for SAE reporting: 
 
 
 
 
 
Investigators must report SAEs and follow-up information to their responsible IRB or 
independent ethics committee (IEC) as applicable per institutional policy. 
The sponsor or designee will provide regulatory authorities, IRBs, IECs, and principal 
investigators with clinical safety updates/reports according to local requirements. 
6.5.1.6 
Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest 
The sponsor will promptly evaluate all SUSARs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to investigators, 
IRBs/IECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the study treatment investigator's brochure. 
Prilenia Therapeutics will compare the severity of each SUSAR and the cumulative event 
frequency reported for the study with the severity and frequency reported in the applicable 
reference document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. All AEs will be evaluated 
with equal interest.  
Events of discontinuation due to meeting the QTcF stopping rules (defined in Section 4.2.1) 
will be considered AEs of special interest. 


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6.5.1.7 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria:  
Mild: 
These events require minimal or no treatment and do not interfere with the 
patient’s daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with normal 
functioning. 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
These events interrupt a patient’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode. 
6.5.1.8 
Assessment of Causality 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, to the 
study treatment. Investigators should use their knowledge of the patient, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether or not an AE is considered to be related to the study treatment. Causality should be 
assessed using the categories presented below: 
Related:  
Adverse event judged by the Investigator as having a reasonable suspected 
causal relationship to the investigational medicinal product 
Unrelated:  
Adverse event judged by the Investigator as NOT having a reasonable suspected 
causal relationship to the investigational medicinal product 
6.5.1.9 
Exceptions 
In this protocol, symptoms and signs related to PD will not be considered as AEs or captured 
on the eCRF, however, unexpected worsening of PD should be reported as an AE.  The 
following hospitalization scenarios will not be considered AEs:  
• 
Hospitalization for a preexisting condition, provided that the following criteria are met:  
o The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal 
progression of the disease or 
o The patient has not experienced an AE 


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6.5.1.10 
Follow-Up of Patients Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable. 
6.5.2 
ECG: QTc Parameters 
At Baseline (Visit 2) and at every visit thereafter, triplicate 12-lead ECG evaluations will be 
assessed before, and 1 to 2 hours after the study treatment dose administered at the clinic 
(approximate Cmax). A triplicate 12-lead ECG measure is comprised of three 10-second ECG 
recordings. The time interval between each of the three individual ECG recordings should be 
approximately 60 seconds. When concomitant with ECG recording, PK samples will be 
collected within 30 minutes after the ECG recording. 
At Screening (Visit 1), a single resting 12-lead ECG will be conducted after at least 5 minutes 
of supine rest. If there is evidence of a prolonged QTcF interval (defined as a QTcF interval of 
>450 msec), then the ECG will be repeated twice within 10 minutes of the first ECG recording. 
The time interval between the two additional ECGs should be approximately 60 seconds. The 
mean of the three screening measurements will be used to determine whether or not the patient 
is suitable for inclusion in the study. The decision to repeat an ECG will be made by the 
investigator and/or the physician assessing the ECG. 
At Baseline (Visit 2) and at every clinic visit thereafter, a triplicate 12-lead ECG evaluation 
(three 10-second recordings) will be conducted before and 1-2 hours after study treatment dose 
administration. When applicable, PK samples will be collected within 30 minutes after the 
ECG recording. The QTcF values will be determined by the average of the 12-lead ECG 
triplicate.  
The patient must be in a supine position and resting for at least 5 minutes prior to each ECG 
measurement. Where applicable, ECG measurements should be taken prior to vital sign 
measurements and blood being drawn for clinical laboratory or PK evaluations. A qualified 
physician at the central ECG vendor will be responsible for interpreting the ECG and send 
results within 24 hours. However, every ECG should be reviewed immediately at site for the 
purpose of determining any gross abnormality (like new atrial fibrillation or QTcF 
prolongation) that might affect patient safety and not allow dosing. If the local ECG reading 
results at the site match any of the discontinuation criteria (see Section 4.2.1), the patient 
should stop taking study treatment until the central ECG reader’s report is received. If the 
central reader does not report a QTcF interval that would lead to discontinuation according to 
the above, then the patient should restart study treatment. Any ECG finding that is judged by 
the investigator or the physician from the central ECG vendor as a clinically significant change 
(worsening) compared with a Visit 2 value will be considered an AE, recorded on the source 
documentation and transcribed onto the eCRF and monitored as described in Section 6.5.1.4. 


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6.5.3 
Vital Signs 
Vital signs including supine and standing blood pressure (BP), pulse rate, and body weight will 
be measured at every clinic visit. Height will be measured at Screening (Visit 1) only. 
Measurements for orthostatic hypotension will be taken at every study visit and at specific time 
points as described in Table 4. Orthostatic measurements (supine and standing BP and seconds 
of pulse rate) can be measured manually or using an automated BP machine; the same method 
of measurement should, however, be used throughout the study for a particular patient. The 
patient’s BP and pulse rate will be measured after the patient has been supine for approximately 
5 minutes. The patient will be instructed to rise to a standing position, and a BP measurement 
will be taken after the patient has been standing for two minutes. Orthostatic hypotension is 
defined as a reduction of 20 mmHg or more in systolic BP, or a reduction of 10 mmHg or more 
in diastolic BP, the standing measurement compared to the supine measurement. 
At Baseline (Visit 2), three sets of orthostatic vital signs will be collected, at least 25 to 20 
minutes apart, to minimize the potential impact of biological variability of a single baseline 
measurement and use the average of the three orthostatic vital signs measurements for 
comparison to all post-treatment measurements. 
Blood pressure should be measured in seated position after 5 minutes resting (for individual 
patients, measurements at different visits should be taken in the same position and the same 
arm). Blood pressure should be repeated in the opposite arm if an abnormal reading is obtained. 
6.5.4 
Physical and Neurological Examination 
The physical and neurological examination of all major body parts (excluding a genitourinary 
exam) will be carried out by an Investigator (who is a neurologist by medical training) at the 
time points noted in the schedule of assessments (Table 4). Any clinically significant changes 
during the treatment period will be recorded on the eCRF. 
6.5.5 
Concomitant Medications 
The concomitant medication assessments will be carried out at the time points noted in the 
schedule of assessments (Table 4). 
6.5.6 
Assessment of Suicidal Ideation and Behavior (C-SSRS) 
Suicidal ideation and behavior will be assessed using the “Screening” part of the C-SSRS. Each 
part of the C-SSRS consists of three question groups (suicidal ideation, intensity of ideation, 
suicidal behavior). It is intended for use by individuals who have been trained in its 
administration. Ultimately the presence of suicidality depends on clinical judgment.  
Throughout the clinical study patients will be monitored for suicidality potential using the 
C-SSRS scale. Patients who have a C-SSRS suicidal ideation score > 2 will be sent for further 
evaluation by a mental health care specialist who will assess for imminent risk. The score alone 


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will not serve as a reason for immediate treatment discontinuation. The assessments will be 
carried out at the time points noted in the schedule of assessments (Table 4). 
6.5.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's 
Disease-Rating Scale (QUIP-RS) 
QUIP-RS is a rating scale designed to measure severity of impulsive-compulsive disorders 
(ICD) symptoms and support a diagnosis of ICD and related disorders in PD. Four subscales 
for ICDs (gambling, sexual compulsions, compulsive buying and compulsive eating) have 
possible scores between 0 and 16 and suggested cut-offs (scores validated as indicative of ICDs 
via clinical interview) as follows: gambling (≥6); compulsive buying (≥8); sexual compulsions 
(≥8); compulsive eating (≥7); and combined ICDs (≥10). The QUIP-RS also includes measures 
for hobbyism (involvement in organized activities like writing or computer use) and punding 
(repeating activities like cleaning). The assessments will be carried out at the time points noted 
in the schedule of assessments (Table 4). 
6.5.8 
Other Assessments 
An eligibility review of screened patients to help protect the safety of patients and confirm 
eligibility will be performed by independent neurologists serving on the EAC (Clintrex) to 
determine if a patient is correctly diagnosed and to ensure that patient meets the criteria for 
enrollment in order to avoid unnecessary risks for the patients. Potential patients will be 
reviewed at least 24 hours before a potential randomization to ensure they meet the criteria for 
enrollment. 
6.6 Data Safety Monitoring Board   
During the study, an independent Drug Safety Monitoring Board (DSMB) consisting of a 
neurologist, a cardiologist and a statistician will periodically review accumulating unblinded 
safety data. The DSMB will meet when first 30 patients have been enrolled and have completed 
2 weeks of maintenance treatment on 150 mg BID, 100 mg BID dose or placebo (Visit 3) 
Thereafter the DSMB will determine the meeting frequency as they deem necessary. 
Additionally, DSMB will evaluate all SAEs in real-time. 
If a significant safety concern emerges in the high dose treatment, the DSMB will have the 
authority to discontinue individual patients from the study, discontinue an arm and/or halt the 
study. In case the 150 mg BID arm is discontinued, all patients who are on maintenance 
treatment with 150 mg BID arm will immediately be discontinued from the study and will 
undergo a down-titration period. Patients, randomly assigned to the 150 mg BID arm but still 
in the titration period, will be switched to the 100 mg BID arm. Newly enrolled patients will 
be randomized to the 100 mg BID dose or placebo Further details will be provided in the 
DSMB charter. 


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6.7 Pregnancy 
Human chorionic gonadotropin (HCG) serum test will be performed for all women not 
surgically sterile or at least two years postmenopausal at Screening (Visit 1). An indeterminate 
reading for the serum pregnancy test should be checked twice (urine test) and discussed with 
the medical monitor if persistently indeterminant; no study treatment will be administered until 
this is resolved. HCG urine tests will be performed for all women not surgically sterile or at 
least two years postmenopausal as per schedule described in Table 4.  
Any patient who becomes pregnant during the study will be withdrawn. Patients will be 
instructed that known or suspected pregnancy occurring during the study, in female patients or 
female partners of male patients, should be confirmed and reported to the investigator, who 
will withdraw a pregnant patient from the study without delay and report the pregnancy within 
24 hours of first knowledge using a pregnancy report form. The investigator should also be 
notified of pregnancy occurring during the study but confirmed after completion of the study. 
In the event that a patient is found to be pregnant after inclusion in the study, any pregnancy 
will be followed to term, and after delivery, the status of mother and child will be reported to 
the sponsor after delivery.  
Pregnancy is not regarded as an AE unless there is a suspicion that a study treatment may have 
interfered with the effectiveness of contraceptive medication. Any pregnancy that occurs 
during study participation must be reported using the same procedures as an SAE 
(Section 6.5.1.5). 
6.8 Clinical Laboratory Analyses/Evaluations 
A laboratory test result that has significantly worsened (according to medical judgment) from 
Visit 2 result will be recorded on the source documentation, transcribed onto the eCRF as an 
AE, and monitored as described in Section 6.5.1.4.  
Clinical laboratory tests will be performed using a central laboratory, as identified in the 
Laboratory Procedures Manual provided in the study file documents.  
The safety laboratory tests will include:  
Haematology: white cell count and differential count, red cell count, hemoglobin, hematocrit, 
mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count.  
Clinical Serum Chemistry: calcium, sodium, potassium, magnesium chloride, bicarbonate or 
carbon dioxide, glucose, blood urea nitrogen (BUN), creatinine, cholesterol,  uric acid, total 
bilirubin, 
alkaline 
phosphatase, 
gamma 
glutamyl 
transpeptidase 
(GGT), 
alanine 
aminotransferase, aspartate aminotransferase, total protein, albumin, lactate dehydrogenase, 
creatinine phosphokinase (in case of elevated creatinine phosphokinase, the muscle/brain [MB] 
fraction should be measured), direct bilirubin, indirect bilirubin, prolactin. The prolactin should 


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be blinded to all the clinical staff, Prilenia Therapeutics and/or its designee. In case of a safety 
concern, the Investigator will be notified by the central laboratory. 
Urinalysis: protein, glucose, ketones, blood (hemoglobin), pH, specific gravity, leukocyte 
esterase, microscopic (bacteria, red blood cells, white blood cells, casts, crystals). A dipstick 
urine pregnancy test will be performed as noted in the schedule of assessments (Table 4). 
Patients with CrCL <50 mL/min/1.73 m2 calculated using the Cockcroft-Gault equation 
[(140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)] at any time point 
after Baseline (Visit 2) will be requested to return to the clinic for an unscheduled visit 1 week 
later to repeat the CrCL test one more time for confirmation. If the repeated CrCL value is 
confirmed to be <50 mL/min/1.73 m2, the patient will be discontinued from the study 
treatment. 
Any decrease in CrCL that is judged by the investigator as a clinically significant change 
(worsening) from Baseline (Visit 2) result will be considered an AE, recorded on the source 
documentation, transcribed onto the eCRF, and monitored as described in Section 6.5.1.4. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the patient’s 
condition, are not to be reported as AEs or SAEs. 
6.9 Sample Collections 
Blood samples for the determination of laboratory parameters will be collected as per the 
schedule of assessments (Table 4) and according to the procedures described in the Laboratory 
Procedures Manual provided in the study file documents. 
Blood samples for the determination of plasma concentrations will be collected at three visits 
during the study; Visit 4, Visit 6 and Visit 7/ET. Samples will be collected via venipuncture or 
indwelling catheter in the morning before study treatment administration per the schedule of 
assessment (Table 4). Plasma concentration of pridopidine will be measured approximately 1 
hour before, and approximately 1 to 2 hours after the PM study treatment dose (approximate 
Cmax). When concomitant with ECG recording, PK samples will be collected within 30 minutes 
after the ECG recording. The timing of UDysRS and UPDRS should be prioritized before PK 
sampling.  
The date and time of each PK sample and the dates and times of the last drug administration 
prior to any collected PK sample will be recorded on the source documentation and transcribed 
onto the eCRF. Only major deviations (>5%) from the scheduled blood sampling time points 
will be commented on the respective page of the eCRF. 
Samples will be analyzed by 
 using an appropriate validated 
method for pridopidine and its main metabolite TV-45065. 


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Blood samples for DNA extraction will be collected only once during the study at Screening 
(Visit 1) or at Baseline (Visit 2). Plasma samples for potential biomarkers research will be 
collected at the time points noted in the schedule of assessments (Table 4). The details of the 
sample collection and handling are described in the Laboratory Procedures Manual provided 
in the study file documents. 
6.10 Eligibility Review 
An eligibility review will be conducted by the EAC to determine suitability of screened 
subjects for the study, including review of screening safety data and fulfillment of enrollment 
criteria. Screened subjects will be reviewed within 48 hours of potential randomization to 
ensure that they meet the criteria for enrollment. 


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7 
Statistical and Analytical Plan 
Details of the statistical analyses, methods, and data conventions will be described in the 
statistical analysis plan (SAP), which will be approved before breaking the blind of the study.  
Primary and all secondary endpoints will be assessed for both the 100 mg BID and the 150 mg 
BID pridopidine dosage vs. placebo in a hierarchical manner. 
7.1 Primary Efficacy Endpoint 
The primary endpoint is the mean change from Baseline (Visit 2) to Visit 7/ET in the sum of 
Parts 1, 3, and 4, of the UDysRS while the patient is in the peak “ON” state and judged to be 
experiencing peak dose dyskinesia.  
7.2 Secondary Efficacy Endpoints 
The following secondary endpoints will be evaluated: 
1. Mean change from Baseline (Visit 2) to Visit 7/ET in “ON time without troublesome 
dyskinesia” based on “ON/OFF” home diary completed by the patients during three 
consecutive 24-hour intervals  
2. Mean change from Baseline (Visit 2) to the end of Visit 7/ET in the total UDysRS 
score (Parts 1 to 4)  
3. Proportion of patients improving based on PGI-C at Visit 7/ET 
4. Mean change from Baseline (Visit 2) to Visit 7/ET in “ON time without any 
dyskinesia” based on “ON/OFF” home diary  
5. Proportion of patients improving based on CGI-C at Visit 7/ET 
6. Mean change from Baseline (Visit 2) to Visit 7/ET in the score of UPDRS Part 2  
7. Proportion of responders (improvement in dyskinesia and no worsening in motor 
function) at Visit 7/ET. The improvement in dyskinesia is defined as ≥30% 
improvement in UDysRS score (Parts 1, 3, and 4) from Baseline (Visit 2) and no 
worsening from Baseline (Visit 2) in “OFF” which is defined as ≤30 minutes increase 
in “OFF” time from Baseline (Visit 2) per a 24 hours period 
8. Mean change from Baseline (Visit 2) to Visit 7/ET in “OFF time” based on 
“ON/OFF” home diary  
9. Mean change from Baseline (Visit 2) to Visit 7/ET in the UPDRS Part 3 as measured 
immediately prior to the in-clinic L-DOPA dose 


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7.3 Safety Endpoints 
The following safety and tolerability endpoints will be evaluated: 
Safety: 
1. AEs occurring throughout the study 
2. QTc parameters: absolute QTcF of >450 msec, >480 msec, and >500 msec, mean 
QTcF, change in QTcF>30 msec and <60 msec, or changes in QTcF>60 msec 
throughout the study 
3. Clinical safety laboratory (clinical chemistry, haematology and urinalysis, vital signs 
(including assessment of orthostatic hypotension), physical and neurological 
examination, concomitant medications throughout the study 
4. Change from Baseline (Visit 2) in suicidality as evaluated with the C-SSRS 
throughout the study  
5. Change from Baseline (Visit 2) in impulse control disorder (ICD) as evaluated by the 
QUIP-RS throughout the study 
Tolerability: 
1. The number (%) of patients who complete the study treatment 
2. The number (%) of patients who fail to complete the study treatment due to AEs 
3. The number (%) of patients who fail to complete the study treatment due to QTcF and 
QT stopping rules, seizure or convulsions (Section 4.2.1) 
7.4 Pharmacokinetic Endpoints 
The PK measure will be the determination of plasma concentration of pridopidine and its 
metabolite TV-45065 before and after in-clinic pridopidine dose. 
7.5 Pharmacogenetic and Plasma Biomarker Endpoints 
The following pharmacogenetic and plasma biomarker endpoints may be evaluated:  
1. To analyze the correlation of potential genetic variations and plasma biomarkers with 
clinical treatment responses to study drug (e.g., efficacy, PK, tolerability and safety 
features).  
2. To assess for potential genetic variation and plasma biomarkers associated with 
disease progression and severity. 


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7.6 Sample Size Calculations 
A sample size of 38 randomized patients in each treatment group (114 randomized patients 
overall) will provide 80% power to detect a between-group difference of 8.5 points in the 
UDysRS score with standard deviation of 13 points using a two-sided significance level of 
0.05, using an ordinary least squares model. Assuming a drop-out rate of 15%, a total of 135 
patients will be randomized. The sample size was calculated based on two sample t-test 
assuming equal variances in the two groups, using nQuery Advisor version 7.0. 
7.7 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Intent-to-Treat (ITT) Set: The ITT set will include all randomized patients. The patients will 
be grouped as randomized. Retrieved drop-out data (data captured from the drop-outs after the 
end-of-study visit when the patient is free of study treatment) will not be included in the ITT 
set. The ITT set will be used for the sensitivity analysis of the primary endpoint. 
Modified Intent-to-Treat (mITT) Set: The mITT set will include all randomized patients who 
receive a dose of study treatment and have efficacy assessments both at Baseline (Visit 2) and 
at least one post-randomization time point. The patients will be grouped as randomized. 
Retrieved drop-out data (data captured from the drop-outs after the end-of-study visit when the 
patient is free of study treatment) will not be included in the determination of the mITT set. 
The mITT set will be used for the efficacy analysis.  
Completer Set: The completer set is a subset of the mITT set and includes the subsets of 
patients with efficacy data at Visit 7/ET. 
The patients will be grouped as randomized. The completer set will be used for the sensitivity 
analysis of the primary endpoint. 
Safety Set: The safety set will consist of all patients receiving at least one dose of study 
treatment. The patients will be grouped according to the treatment regimen actually received 
at Visit 3. The safety set will be used for the safety analyses. 
PK Set: The PK set will consist of all patients in the safety set with at least one pridopidine 
concentration sample result reported. The PK set will be used for the PK analyses. 
7.8 Description of Subgroups to be Analyzed 
Subgroup analyses may be conducted as deemed necessary and will be defined in the SAP.  


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7.9 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.3 or later. Continuous 
variables will be summarized using the mean, the standard deviation, median, minimum value, 
and maximum value. Categorical variables will be summarized using frequency counts and 
percentages. All collected data will be listed in data listings. 
Each primary and secondary endpoint includes the comparison of each of the two dosages of 
pridopidine vs placebo. The overall Type I error rate within the family of each primary and 
secondary endpoint will be maintained by using the Hochberg’s step-up method. Furthermore, 
the primary and secondary endpoint families will be evaluated in a hierarchical manner as 
outlined above. For this purpose, a matched parallel gatekeeping procedure will be used.  
The testing strategy is summarized in Figure 2 and detailed below. 
Figure 2 
Summary of the Statistical Testing Strategy 
 
The primary endpoint family (F1) consists of two null hypotheses H11 and H12 for comparisons 
of pridopidine 100 mg BID and pridopidine 150 mg BID, respectively, with placebo in regard 
to the primary endpoint. That is, F1 = {H11, H12}. Similarly, the first secondary endpoint family 
F2 = {H21, H22} consists of H21 and H22 for comparisons of pridopidine 100 mg BID and 
pridopidine 150 mg BID, respectively, with placebo in regard to the secondary endpoint ranked 
first in the hierarchy. The family F1 serves as a gatekeeper for F2 such that F2 will be examined 
only when the gatekeeper F1 has been successfully passed, i.e., at least one of the hypotheses 
in the F1 family is rejected. The significance in the secondary endpoint ranked first for a dose 
level cannot be claimed unless its corresponding primary hypothesis is significant. The same 
procedure will continue to the next families of secondary endpoints according to the hierarchy 
defined for the endpoints. The procedure will go on as long as the previous gatekeeper has 
been successfully passed. 


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Each family of primary and secondary endpoints includes the comparison of each of the two 
dosages of pridopidine vs placebo. The overall Type I error rate within the family of each 
primary and secondary objective with respect to the two active dosages will be maintained by 
using the Hochberg’s step-up method. According to Hochberg’s step-up method, the higher of 
the two p-values will be compared to a two-sided significance level of 0.05. In case the higher 
p-value is <0.05, both of the two comparisons will be judged as statistically significant. In case 
the higher p-value is not <0.05, the lower p-value will be compared to a two-sided significance 
level of 0.025. In case the higher p-value is not <0.05 and the lower p--value is <0.025, only 
the comparison related to the lower p-value will be judged as statistically significant. The 
testing will continue if at least one dose level was statistically significant in the previous family. 
Statistical significance will only be claimed if the dose level in question was statistically 
significant in the previous family. 
In case not all endpoints are compared as a part of the hierarchical testing procedure, the 
statistical tests will be reported in any case and interpreted in an explorative manner. 
7.9.1 
Analysis of Primary Endpoint 
The primary endpoint will be analyzed using a Mixed Model for Repeated Measures (MMRM 
with no imputation using the mITT population. The Baseline (Visit 2) score will be included 
as a covariate and the treatment group (pridopidine 100 mg BID, pridopidine 150 mg BID or 
placebo), Visit 4, Visit 5, Visit 6 or Visit 7/ET, and the interaction between treatment group and 
visit as fixed factors in the MMRM. An unstructured covariance structure will be applied for 
MMRM. In case the model will not converge with the unstructured covariance structure, the 
heterogeneous Toeplitz structure (TOEPH) will be used instead. In case the model will not 
converge with the heterogeneous Toeplitz structure, heterogeneous compound symmetry will 
be used. The denominator degrees of freedom will be computed using the Kenward-Roger 
method. The difference between each dosage of pridopidine vs placebo at Visit 7/ET along 
with the 95% CIs and associated p-value will be estimated from the MMRM. The differences 
at Visit 4 and Visit 6 will be estimated as well from the same model.  
Sensitivity analyses of the primary endpoint will be conducted in the ITT set with multiple 
imputation methods, both assuming that data are missing at random and not missing at random. 
The analysis assuming that data are not missing at random will be conducted with the Copy-
Reference approach, i.e., assuming that the patients who have missing data will follow the 
trajectories of the placebo-treated patients after the first visit with missing data. Further 
sensitivity analysis will be conducted in the completer set with MMRM. In addition, sensitivity 
analyses will be conducted by including the retrieved drop-out data (data captured from the 
drop-outs after the end-of-study visit when the patient is free of study treatment) to the mITT 
analysis. All efforts will be made to perform scheduled efficacy assessments after patients 
discontinue. 


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7.9.2 
Analysis of Secondary Endpoint 
The continuous secondary endpoints (sum scores derived from UDysRS, UPDRS, and 
endpoints based on the “ON/OFF” home diaries) will be analyzed with MMRM models similar 
to those used for analysis of the primary endpoint. The mITT population will be used for these 
analyses. 
The categorical secondary endpoints (proportion of responders and proportion of patients 
improving based on PGI-C or CGI-C) will be analyzed in the mITT population using the 
generalized linear mixed model (using the GLIMMIX from SAS for binomial data with logit 
link). This analysis will model the response data from each postbaseline visit with treatment 
group (pridopidine 100 mg BID, pridopidine 150 mg BID or placebo), visit (Visit 4, Visit 5, 
Visit 6 or Visit 7/ET), and interaction between the treatment group and visit. An unstructured 
covariance structure will be used for the repeated measures model. In case the model will not 
converge with the unstructured covariance structure, the heterogeneous Toeplitz structure 
will be used instead. In case the model will not converge with the heterogeneous Toeplitz 
structure, heterogeneous compound symmetry will be used instead. The odds ratio for the 
treatment difference, 95% CIs for the odds ratio and p-value will be provided. 
7.9.3 
Pharmacokinetic Analyses 
The PK analysis will be conducted on the PK set. Plasma concentrations of pridopidine and its 
metabolite TV-45065 will be listed and summarized by visit and time point. Descriptive 
statistics will include the mean, coefficient of variation, geometric mean, minimum, median, 
and maximum. Relationships between plasma concentrations of pridopidine and TV-45065 at 
Visit 4, Visit 6, and Visit 7/ET vs key safety and efficacy measures will be explored graphically. 
Additional details will be provided in the SAP. 
7.9.4 
Safety Analyses 
The safety analysis will be conducted on the safety set. The AEs will be coded according to 
the MedDRA and treatment-emergent adverse events (TEAEs) summarized by treatment 
group, system organ class and preferred term. Further summaries will be done by seriousness, 
severity, relationship to study treatment and actual dose at the time of onset.  
Vital signs, ECG data and laboratory tests at baseline (last non-missing results prior to the first 
dose of study drug, each postbaseline visit, and changes from baseline to each of the 
postbaseline visits will be summarized with descriptive statistics. Shift tables for the laboratory 
tests based on a classification of values as low, normal, or high with respect to the reference 
range will be summarized.  
For vital signs, orthostatic hypotension is defined as a reduction of 20 mmHg or more in 
systolic blood pressure, or a reduction of 10 mmHg or more in diastolic blood pressure, for the 
standing measurement compared to the supine measurement. The proportion of patients with 
orthostatic hypotension will be summarized with shift tables.  


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For ECG data, absolute QTcF of >450 msec, >480 msec, and >500 msec, changes from 
baseline in QTcF>30 msec and <60 msec, and changes in QTcF>60 msec throughout the study 
will be summarized. 
All other safety data will be summarized with descriptive methods. 
7.9.5 
Interim Analyses 
No interim analyses are planned for the study. 


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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6 (R2) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management (ICH Q9). 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include, but are not limited to, diary 
cards/laboratory reports/ECG strips/rater scales, etc. 
Investigative site personnel will enter patient data into Medidata RAVE. The analysis data sets 
will be a combination of these data and data from other sources (e.g., laboratory data). 
Clinical data management will be performed in accordance with applicable Prilenia 
Therapeutics standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. Adverse event terms will be coded using the 
MedDRA, an internal validated medical dictionary, and concomitant medications will be coded 
using the World Health Organization Drug Dictionary (WHODRUG). 
After database lock, each study site will receive a CDROM containing all of their site specific 
eCRF data as entered into Medidata RAVE for the study, including full discrepancy and audit 
history. Additionally, a CDROM copy of all of the study site’s data from the study will be 
created and sent to the sponsor for storage. 
 will maintain a duplicate CDROM copy for 
their records. In all cases, patient initials will not be collected or transmitted to the sponsor. 


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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/ IEC 
before participation of human patients in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study patients, and any 
other written information regarding this study to be provided to the patient or the patient’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of 
the IRB/IEC compliance with ICH harmonized tripartite guideline E6 (R2): Good Clinical 
Practice (GCP) will be maintained by the site and will be available for review by the sponsor 
or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. The investigator is responsible 
for providing written summaries of the progress and status of the study at intervals not 
exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must promptly 
supply Prilenia Therapeutics or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study 
or increasing the risk to patients. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Patient Information and Consent 
Written informed consent in compliance with regulatory authority regulations shall be obtained 
from each patient before entering the study or performing any unusual or nonroutine procedure 
that involves risk to the patient. An informed consent template may be provided by the sponsor 
to investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the sponsor or its designee or 
both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating patients must sign the 
revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to participate 
in the study by signing the ICF. The investigator shall retain the signed original ICF(s) and 
give a copy of the signed original form to the patient or legal guardian. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be patient to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written 
permission of the patient (or the patient’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the US Food and Drug Administration (FDA), or the 
IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 Code 
of Federal Regulations (CFR) 54. In addition, the investigator must provide to the sponsor a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year following the completion of the study. 
Neither the sponsor nor 
is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the sponsor nor 
 is financially responsible for further 
treatment of the patient’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 (R2) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol 


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• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
• Curriculum vitae (CV) for the investigator and each subinvestigator listed on Form 
FDA 1572  
• Medical License (ML) for the investigator and each applicable subinvestigator listed 
on Form FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the patient or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the site, 
in accordance with 42 CFR 493 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6 (R2). The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical study registers before enrollment of patients begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 (R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the sponsor and regulatory authority(ies) with any reports required. 


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10.8 Records Retention 
Essential documents should be retained until at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the study treatment. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting 
or for publication in a scientific journal. In these cases, the sponsor will be responsible for 
these activities and will work with the investigators to determine how the manuscript is written 
and edited, the number and order of authors, the publication to which it will be submitted, and 
other related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization from 
the sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
The administrative structure will include a DSMB and EAC.  
11.1 Monitoring 
11.1.1 
Independent Data Safety Monitoring Board 
During the study, an independent DSMB will periodically review accumulating unblinded 
safety data and SAE/AE in real time. The detailed description is provided in Section 6.6. 
11.1.2 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In 
the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, must be reviewed and approved by the sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB/IEC for 
approval before patients can be enrolled into an amended protocol. 
11.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the patient’s source documentation 
any deviation from the approved protocol. The investigator may implement a deviation from, 


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or a change of, the protocol to eliminate an immediate hazard to study patients without prior 
IRB/IEC approval. As soon as possible after such an occurrence, the implemented deviation or 
change, the reasons for it, and any proposed protocol amendments should be submitted to the 
IRB/IEC for review and approval, to the sponsor for agreement, and to the regulatory 
authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the procedures 
or processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A 
significant deviation occurs when there is nonadherence to the protocol by the patient or 
investigator that results in a significant, additional risk to the patient. Significant deviations 
can include nonadherence to inclusion or exclusion criteria, or nonadherence to FDA 
regulations or ICH GCP guidelines, and will lead to the patient being withdrawn from the study 
(Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
11.3 Study Termination 
Although Prilenia Therapeutics has every intention of completing the study, Prilenia 
Therapeutics reserves the right to discontinue the study at any time for clinical or 
administrative reasons.  
The end of the study will be defined as the final date on which data were (or are expected to 
be) collected. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report is prepared and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonized tripartite guideline 
E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with the 
full summary of the study results. The investigator is encouraged to share the summary results 
with the study patients, as appropriate. The study results will be posted on publicly available 
clinical trial registers. 


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12 Reference List 
Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations 
as estimated from the cumulative literature. Mov Disord. 2001;16(3):448-58. 
Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the 
progression of Parkinson's disease. N Engl J Med. 2004;351(24):2498-508. 
Food and Drug Administration. The Voice of the Patient, Parkinson’s Disease. Public Meeting, 
22 Sep 2015. Report date Apr 2016 [cited 21 Dec 2018]. Available from: 
https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm498266.pdf 
Hauser R, Rascol O, Korczyn AD, Jon Stoessl A, Watts RL, Poewe W, et al. Ten-year follow-up 
of Parkinson's disease patients randomized to initial therapy with ropinirole or levodopa. Mov 
Disord. 2007;22(16):2409-17. 
Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, et al. Pridopidine, 
a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in 
parkinsonian macaques. Mov Disord. Epub 2018 Dec 21.  
Kumar N, Van Gerpen JA, Bower JH, Ahlskog JE. Levodopa-dyskinesia incidence by age of 
Parkinson's disease onset. Mov Disord. 2005;20(3):342-4. 
Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of 
the incidence of dyskinesia in patients with early Parkinson's disease who were treated with 
ropinirole or levodopa. N Engl J Med. 2000;342(20):1484-91. 
 


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13 Appendices 


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13.1 Visit Assessments and Procedures Flow – Baseline (Visit 2) 
 
Abbreviations: AE, adverse event; CGI-C, Clinical Global Impression of Change; C-SSRS, Columbia-Suicide Severity Rating Scale; ECG, electrocardiogram; L-
DOPA, 3,4-dihydroxyphenylalanine; max, maximum; min, minute; PD, Parkinson’s disease; QUIP-RS, Questionnaire for Impulsive Compulsive Disorders in 
Parkinson’s Disease Rating Scale; UDysRS, Unified Dyskinesia Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. 


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13.2 Visit Assessments and Procedures Flow – Visit 3 – Visit 7 
Abbreviations: AE, adverse event; CGI-C, Clinical Global Impression of Change; C-SSRS, Columbia-Suicide Severity Rating Scale; ECG, electrocardiogram; L-
DOPA, 3,4-dihydroxyphenylalanine; lab, laboratory; max, maximum; min, minute; PD, Parkinson’s disease; PGI-C, Patient Global Impression of Change; PK, 
pharmacokinetic; QUIP-RS, Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease Rating Scale; UDysRS, Unified Dyskinesia Rating Scale; 
UPDRS, Unified Parkinson’s Disease Rating Scale; V, visit.

SAP_001.pdf: 
Official Title: A Double-Blind, Randomized, Three-Arm, Parallel-Group Study to 
Assess the Efficacy and Safety of Two Doses of Pridopidine Versus Placebo for the 
Treatment of Levodopa-Induced Dyskinesia in Patients With Parkinson's Disease 
(gLIDe) 
NCT Numbers: NCT03922711 
Document Date: 23 Jul 2020 
 


 
 
 
A DOUBLE-BLIND, RANDOMIZED, THREE ARM, PARALLEL GROUP STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF TWO DOSES OF PRIDOPIDINE VERSUS 
PLACEBO FOR THE TREATMENT OF LEVODOPA INDUCED DYSKINESIA IN 
PATIENTS WITH PARKINSON’S DISEASE (gLIDe) 
 
 
Study code: PL101-LID201 
 
Phase 2B study (Modified Post-COVID-19 to a Phase 2 PoC Study) 
 
 
 
STATISTICAL ANALYSIS PLAN,  
VERSION 1.0 
 
23 July 2020 
 
 
DocuSign Envelope ID: 2CD5B7F8-9C42-4D3C-AC08-B1ACF5DB9C1A


 
Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
2 
 
Signature Page 
 
 
Statistical Analysis Plan was prepared by: 
 
23 July 2020 
Date 
Principal Statistician, 
 
 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 
 
 
 
Date 
 
 
 
           
           
           
                              
 
 
 23 July, 2020 
 
 
Date 
Head of Research, Prilenia Neurotherapeutics 
 
 
  
 
 
 
 
 
23 July, 2020 
 
 
 
Date 
Head of Clinical Operations, Prilenia Neurotherapeutics 
 
DocuSign Envelope ID: 2CD5B7F8-9C42-4D3C-AC08-B1ACF5DB9C1A
8/30/2020


 
Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
3 
  
Contents 
1 
Abbreviations ........................................................................................................................................ 5 
2 
Introduction .......................................................................................................................................... 7 
3 
Study Objectives ................................................................................................................................... 7 
3.1 
Primary Objective .......................................................................................................................... 7 
3.2 
Secondary Objectives ..................................................................................................................... 7 
3.3 
Safety Objective ............................................................................................................................. 7 
3.4 
Pharmacokinetic (PK) Objectives: ................................................................................................. 7 
4 
Design and Type of the Study .............................................................................................................. 8 
4.1 
Visit Structure ................................................................................................................................ 8 
4.2 
Study Treatment ............................................................................................................................. 9 
4.3 
Study Population .......................................................................................................................... 10 
5 
Analysis Populations .......................................................................................................................... 10 
5.1 
Efficacy Evaluable (EE) Population ............................................................................................ 10 
5.2 
Safety Population ......................................................................................................................... 10 
5.3 
PK Population .............................................................................................................................. 10 
6 
Endpoints ............................................................................................................................................ 10 
6.1 
Primary Endpoint: Sum of Parts 1, 3, and 4 of UDysRS ............................................................. 11 
6.2 
Secondary Endpoints ................................................................................................................... 11 
6.2.1 
ON time without troublesome dyskinesia and other endpoints based on “ON/OFF” home 
diary 
12 
6.2.2 
The above analysis will be generated for the EE1 and EE2 populations. Total UDysRS score 
-Sum of Parts 1 to 4................................................................................................................................ 13 
6.2.3 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2 ................................................. 13 
6.2.4 
Proportion of Responders ...................................................................................................... 14 
6.2.5 
UPDRS Part 3 as Measured Immediately Prior to the In-clinic L-DOPA Dose ................... 14 
6.2.6 
Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change 
(CGI-C) 15 
6.2.7 
Parkinson’s Disease Questionnaire -39 (PDQ-39) ................................................................ 15 
6.3 
Exploratory Efficacy Endpoints ................................................................................................... 15 
6.4 
Safety and tolerability endpoints ................................................................................................. 15 
6.5 
PK Endpoints ............................................................................................................................... 16 
7 
Sample Size Considerations ............................................................................................................... 16 
8 
Statistical Hypotheses ......................................................................................................................... 16 
9 
General Statistical Considerations ...................................................................................................... 16 
9.1 
Adjustment for Covariates ........................................................................................................... 17 
9.2 
Handling of Drop-Outs or Missing Data...................................................................................... 17 
9.2.1 
Imputation of Incomplete Data within a Visit or Timepoint ................................................. 18 
9.2.2 
Handling of Missing Longitudinal Data ................................................................................ 18 
9.3 
Interim Analyses and Data Monitoring ........................................................................................ 18 
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Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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9.4 
Multiple Comparison/Multiplicity ............................................................................................... 18 
10 
Subjects Disposition, Demographic and Other Baseline Characteristics ........................................ 19 
11 
Prior and Concomitant Medications ................................................................................................ 19 
12 
Medical History ............................................................................................................................... 19 
13 
Protocol Deviations ......................................................................................................................... 20 
14 
Analysis of Efficacy ........................................................................................................................ 20 
14.1 
Primary Endpoint .................................................................................................................. 20 
14.2 
Secondary Endpoints ............................................................................................................. 21 
14.2.1 
Continuous Secondary Endpoints ......................................................................................... 21 
15 
Analysis of Safety and Tolerability ................................................................................................. 21 
15.1 
Extent of Exposure ................................................................................................................ 21 
15.2 
Compliance ............................................................................................................................ 22 
15.3 
Adverse Events ...................................................................................................................... 22 
15.4 
Laboratory Safety Parameters ............................................................................................... 23 
15.5 
Vital Signs ............................................................................................................................. 23 
15.6 
ECG ....................................................................................................................................... 24 
15.7 
Physical and Neurological Examination ............................................................................... 24 
15.8 
Other Safety Variables .......................................................................................................... 25 
15.8.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................. 25 
15.8.2 
Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS) ........... 25 
15.9 
Tolerability ............................................................................................................................ 25 
16 
Analysis of PK ................................................................................................................................ 25 
17 
Deviations from the Analyses Planned in the Study Protocol ........................................................ 26 
18 
Execution of Statistical Analyses .................................................................................................... 26 
19 
Hardware and Software ................................................................................................................... 26 
20 
References ....................................................................................................................................... 26 
21 
Appendices ...................................................................................................................................... 27 
21.1 
Table of Contents of Tables, Figures and Listings ................................................................ 27 
 
 
 
 
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Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
5 
 
1 
Abbreviations 
 
Term             Description 
AE 
 
Adverse Event 
AIMS  
Abnormal Involuntary Movement Scale 
ATC  
Anatomical Therapeutic Chemical 
BID 
 
Twice daily 
BP 
 
Blood Pressure 
CGI-C  
Clinical Global Impression of Change 
CI 
 
Confidence Interval 
COVID-19 
Coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB  
Data Safety Monitoring Board 
ET 
 
Early Termination 
ITT 
 
Intention-To-Treat 
LID 
 
Levodopa-Induced Dyskinesia 
LS 
 
Least Square 
MAR  
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
 
Multiple Imputation 
mITT  
Modified Intention-To-Treat 
MMRM 
Mixed Model for Repeated Measures 
MMSE 
Mini–Mental State Examination 
NMSS  
Non-Motor Symptom Scale 
PD 
 
Parkinson’s Disease 
PDQ-39 
39-item Parkinson’s Disease Questionnaire 
PDSS-2 
Parkinson’s Disease Sleep Scale 
PGI-C  
Patient Global Impression of Change 
PK 
 
Pharmacokinetic 
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Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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PT 
 
Preferred Term 
QD 
Once daily 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale 
SAE 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SI 
 
International System of Units 
SOC  
System Organ Class 
TEAE  
Treatment-Emergent Adverse Event 
UDysRS 
Unified Dyskinesia Rating Scale 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
WHO-DD  
World Health Organization Drug Dictionary 
 
DocuSign Envelope ID: 2CD5B7F8-9C42-4D3C-AC08-B1ACF5DB9C1A


 
Statistical Analysis Plan 
 
Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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2 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis, shortly after the decision to 
terminate the study due to coronavirus disease 2019 (COVID-19) pandemic and other reasons. The SAP 
will serve as a complement to the study protocol and supersedes it in case of differences. The study is still 
ongoing, and this SAP is being finalized prior to locking the database and unblinding the study. 
3 
Study Objectives 
The objectives of the study as indicated in the protocol are described below. Since the study is being 
terminated early, there may not be a sufficient number of subjects within each treatment arm. Therefore, 
the objectives may also include evaluation of only pridopidine 100 mg BID dose at the end of titration at 
Week 3/5 (Visit 3), the pooled active doses (pridopidine 100 mg BID and 150 mg BID) at Week 8/10 
(Visit 5) and potentially comparing results with placebo data from historical data. 
Study weeks are further explained in Section Error! Reference source not found.. 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of 2 dosages of pridopidine administered 
twice daily (BID), 100 mg BID and 150 mg BID (individually and combined) vs placebo BID for the 
treatment of levodopa-induced dyskinesia (LID) in subjects with Parkinson’s disease (PD) at Week 8/10 
(Visit 5).  
The primary objective will also evaluate subjects on 100 mg BID as compared to placebo at Week 
3/5(Visit 3), since both 100 mg BID and 150 mg BID groups are on 100 mg BID at the end of titration. 
3.2 
Secondary Objectives 
1. To determine if the effect of pridopidine (100 mg BID, 150 mg BID and pooled 100+150 mg BID) vs 
placebo is associated with changes (worsening or improvement) in parkinsonian features at Weeks 3/5 
and 8/10 (Visits 3 and 5). 
2. To evaluate the effect of pridopidine (100 mg BID, 150 mg BID and pooled 100+150 mg BID)  vs 
placebo on measures of global improvement, activities of daily living, and quality of life in subjects 
with PD LID at Weeks 3/5 and 8/10 (Visits 3 and 5). 
3.3 
Safety Objective 
To evaluate the safety and tolerability of 2 dosages of pridopidine (100 mg BID and 150 mg BID) vs 
placebo in patients with PD LID. 
3.4 
Pharmacokinetic (PK) Objectives: 
1. To evaluate the PK of pridopidine and its main metabolite TV-45065 in subjects with PD-LID 
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Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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2. To explore the relationship between pridopidine exposure and dyskinesia 
4 
Design and Type of the Study 
The study was originally designed as a 16-week study with a 2 week titration phase (January 24th, 2019 
original protocol, v1.1) and was modified on 15th October 2019 (Amendment 1) via Safety Urgent 
Measures letter to increase the titration period from 2 to 4 weeks. This change along with other changes 
were implemented in Amendment 1 (19th  November 2019, v2.0). The duration of the study was thus 
increased from 16 to 18 weeks. 
The study was designed as a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, three-
arm, parallel-group study to evaluate the efficacy, safety, and PK of pridopidine 100 mg BID and 150 mg 
BID vs placebo for the treatment of PD LID.  
Due to COVID-19 the study was terminated early and is now considered a Phase 2 proof of concept (PoC) 
study. The study will evaluate efficacy and safety of the two doses of pridopidine vs placebo as well as 
the pooled active doses vs. placebo. 
4.1 
Visit Structure 
Study visits in the original and Amendment 1 (amended as per the Oct 15th Safety letter) are as below: 
 
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Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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4.2 
Study Treatment 
Subjects who met eligibility criteria were randomly assigned at Baseline (Visit 2) to receive pridopidine 
100 mg BID, 150 mg BID or placebo using a 1:1:1 randomization. No stratification factors were used in 
the randomization. During the 14/16-week active treatment period, two oral capsules were taken in the 
morning (at 7:00 AM ±1 hour) and 2 oral capsules in the afternoon (at 1:00 PM ±1 hour). The time 
difference between the 2 administrations was 6-8 hours apart. 
Subjects in the active treatment arms underwent either a 2-week (original amendment) or a 4-week 
(Amendment 1) dosage titration period as described below:  
 Original protocol: Subjects who underwent a 2-week titration period were treated for 3 days with 
pridopidine 75 mg QD (once daily), 4 days of pridopidine 75 mg BID, and 1 week with pridopidine 
100 mg BID.  
 Amendment 1: Subjects who underwent a 4-week titration period were treated with pridopidine 75 
mg on alternate days (Q48h) during one week, 75 mg QD during 1 week ,75 mg BID during 1 
week , and 100 mg BID during one week.  
Under both protocol versions, maintenance treatment with pridopidine 100 mg BID or 150 mg BID 
was then continued for an additional 12 weeks.  
Subjects randomly assigned to the placebo arm  received matching placebo throughout the treatment 
period in a double-blind fashion at the same dosing schedule as subjects assigned to the active 
treatments.  
At the end of the maintenance period or at early termination (ET), all subjects underwent a down-titration 
period in which they received 1 capsule of pridopidine 75 mg (or the matching placebo) and 1 capsule of 
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placebo BID on Days 1 to 2 followed by one capsule of pridopidine 75 mg (or the matching placebo) and 
one capsule of placebo QD on Days 3 to 4 of Week 17. 
4.3 
Study Population 
PD subjects with a documentation of mild to moderate LID (subjects with severe LID were included after 
Amendment 1) by the investigator and by home diary were enrolled in the study. The full list of inclusion 
criteria can be found in Section 4.1.1 of the study protocol and exclusion criteria in Section 4.1.2 of the 
study protocol. 
5 
Analysis Populations 
The following analysis populations (analysis sets) will be used for the analysis of the disposition, 
demographic, efficacy, safety and PK data. 
Subjects will be grouped according to the actual treatment received if there were inaccuracies in study 
drug taken compared to what treatment subjects were randomized to.  
5.1 
Efficacy Evaluable (EE) Population 
The Efficacy Evaluable 1 (EE1)  population includes all subjects that were randomized, received at least 
80% of their dose of study drug and were on treatment at Visit 3 (Week 3/5) and have a post-randomization 
assessment of the primary endpoint.  
The Efficacy Evaluable 2 (EE2) population includes all subjects who were on treatment at Visit 5 (Week 
8/10), have at least 80% compliance to study drug and have a valid assessment of the primary endpoint. 
5.2 
Safety Population 
The Safety Population will include all subjects receiving at least one dose of study treatment. The subjects 
will be grouped according to the highest treatment regimen actually reached.. Anyone with mean total 
daily dose > 0 and ≤ 100 mg BID will be included in the 100 mg BID group, anyone with mean total daily 
dose > 100 mg BID will be included in the 150 mg BID group. The Safety Population will be used for the 
safety analyses. 
5.3 
PK Population 
The PK Population will include all subjects in the safety population with at least one pridopidine 
concentration sample result reported. The PK population will be used for the PK analyses. The PK analyses 
may or may not be performed based on outcome of other analyses and availability of PK data. 
6 
Endpoints 
The following endpoints are pre-defined for this study.  
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6.1 
Primary Endpoint: Sum of Parts 1, 3, and 4 of UDysRS 
The primary endpoint is the mean change and % change from Baseline (Visit 2) to Week 3/5 (Visit 3) and 
Week 8/10 (Visit 5) in the sum of Parts 1, 3, and 4 of the Unified Dyskinesia Rating Scale (UDysRS) 
while the patient is in the peak “ON” state and experiencing maximal peak dose dyskinesia. 
The sum of Parts 1, 3, and 4 of the UDysRS will be calculated as the sum of Part 1 (historical disability 
of ON-dyskinesia impact), Part 3 (objective impairment) and Part 4 (objective disability). The sum scores 
will be calculated as follows: 
 Part 1: sum of UDysRS items 1-11; 0-44 points 
 Part 3: sum of UDysRS items 16-22; 0-28 points 
 Part 4: sum of UDysRS items 23-26; 0-16 points. 
For the sum scores of Parts 1, 3 and 4, the following imputation rules will be used in case of incomplete 
data: 
 Part 1: Part 1 is sum of Part 1A (item 1) and Part 1B (items 2-11) 
o If Part 1A (item 1) is missing, the Part 1 sum score will be set as missing. 
o If there is one missing item in Part 1B (items 2-11), the missing item will be replaced by the 
average of the non-missing items 2-11 from the same subject. 
o If there is more than one missing item in Part 1B (items 2-11), the Part 1 sum score will be set 
as missing. 
 Part 3:  
o If there is one missing item in Part 3 (items 16-22), the missing item will be replaced by the 
average of the non-missing items 16-22 from the same subject. 
o If there is more than one missing item in Part 3 (items 16-22), the Part 3 sum score will be set 
as missing.  
 Part 4:  
o If there is one missing item in Part 4 (items 23-26), the missing item will be replaced by the 
average of the non-missing items 23-26 from the same subject. 
o If there is more than one missing item in Part 4 (items 23-26), the Part 4 sum score will be set 
as missing.  
 Sum of Parts 1, 3 and 4: 
o The sum of Parts 1, 3 and 4 will be calculated only if sum of Part 1, sum of Part 3 and sum of 
Part 4 are all non-missing, after applying the imputation rules presented above. Otherwise, the 
sum of Parts 1, 3 and 4 will be set as missing. 
6.2 
Secondary Endpoints 
Secondary endpoints are defined as below:  
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6.2.1 ON time without troublesome dyskinesia and other endpoints based on “ON/OFF” home 
diary 
Mean actual value and mean change from Baseline (Visit 2) to all post-baseline visits in ON time without 
troublesome dyskinesia based on “ON/OFF” home diary completed by the subjects during 3 consecutive 
24 hour intervals will be evaluated as a secondary endpoint. The daily ON time without troublesome 
dyskinesia is defined as the sum of daily ON time without dyskinesia and daily ON time with non-
troublesome dyskinesia.  
This endpoint will be presented both as daily ON time without troublesome dyskinesia during waking 
hours and as total number of hours with ON time without troublesome dyskinesia, normalized to a 16-
hour waking day. 
The Baseline is defined as the home diary obtained on 3 consecutive days prior to the Baseline visit (Visit 
2). The diaries collected during the Maintenance Period, on 3 consecutive days prior to Visit 4 (Week 5/7), 
Visit 5 (Week 8/10), Visit 6 (Week 11/13) and Visit 7 (Week 14/16) will be used as response variables. 
In case of missing or non-valid diary days during the 3 consecutive days prior to the visits during the 
Maintenance Period, the last 3 recorded days between Visits 3-4 (for Visit 4), 4-5 (for Visit 5), 5-6 (for 
Visit 6) and 6-7 (for Visit 7), but no more than 7 days before the visit with non-missing and valid diary 
data will be used instead. In case of missing or non-valid diary days before Baseline, the 3 last non-missing 
and valid diary days prior to the first dose of study drug will be used regardless of time between the day 
when the diary was completed and the Baseline visit. 
The validity of the diary entries will be checked prior to including a diary day in the summary calculations. 
Only valid diary days will be included in the diary summarizations. The diary endpoints will be derived 
as defined below. 
 A day will be considered as being valid if at least 44 of the 48 half hour periods during the day have 
been completed per instructions. That is, for each half hour period, only one entry among the responses 
(Asleep, OFF, ON without dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome 
dyskinesia) has been checked. The entry will not be used if no responses are checked or more than one 
response is checked. If there are duplicate entries (i.e., multiple entries recorded with same date and 
time interval), the worst entry will be used for the date and time interval in question. The worst entry 
will be defined in the following order: OFF, ON with troublesome dyskinesia, ON with non-
troublesome dyskinesia, ON without dyskinesia, Asleep. On without troublesome dyskinesia  
 The diary data expressed as hours will be normalized to 16 waking hours per day. The daily ON time 
without troublesome dyskinesia will be extrapolated to a 16-hour period by determining the percentage 
of ON time without troublesome dyskinesia among accurately recorded entries, excluding Asleep time 
and missing/non-valid recordings, and by multiplying this percentage by 16 hours. 
 The mean daily ON time without troublesome dyskinesia prior to each visit will be calculated as mean 
value of the valid days documented in the subject’s diary prior to that visit. In case there are gaps 
within the 3 days preceding the visit, the last 3 recorded days before the visit will be used regardless 
of the gaps (as defined above). If there are more than 3 valid days, only the last 3 days will be used. If 
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there are only 2 valid days, the average of these days will be used.  In case there is only 1 valid day, 
the visit will be considered missing. 
As above the following will also be summarized: 
 ON time without any dyskinesia 
 OFF time 
6.2.2 The above analysis will be generated for the EE1 and EE2 populations. Total UDysRS score -
Sum of Parts 1 to 4 
Mean change and % change from Baseline (Visit 2) to Week 3/5 (Visit 3) and Week 8/10 (Visit 5) in the 
total UDysRS score (Parts 1 to 4) will be evaluated as a secondary endpoint. The total UDysRS score 
will be calculated as the sum of Part 1 (historical disability of ON-dyskinesia impact), Part 2 (historical 
disability of OFF-dyskinesia impact), Part 3 (objective impairment) and Part 4 (objective disability). 
The sum scores for Parts 1, 3 and 4 will be calculated similarly as for the primary endpoint. The sum score 
of Part 2 will be calculated as follows: 
 Part 2: sum of UDysRS items 12-15; 0-16 points 
For the sum scores of Parts 1, 2, 3 and 4, the following imputation rules will be used in case of incomplete 
data: 
 Part 1: see definition of the primary endpoint 
 Part 2: Part 2 is sum of Part 2A (item 12) and Part 2B (items 13-15) 
o If Part 2A (item 12) is missing, the Part 2 sum score will be set as missing. 
o If there is one missing item in Part 2B (items 13-15), the missing item will be replaced by the 
average of the non-missing items 13-15. 
o If there is more than one missing item in Part 2B (items 13-15), the Part 2 sum score will be 
set as missing. 
 Part 3: see definition of the primary endpoint 
 Part 4: see definition of the primary endpoint 
 The total UDysRS score 
o The total UDysRS score, i.e. the sum of Parts 1, 2, 3 and 4 will be calculated only if sum of 
Part 1, sum of Part 2, sum of Part 3 and sum of Part 4 are all non-missing, after applying the 
imputation rules presented above. Otherwise, the total UDysRS score will be set as missing. 
The above analyses will be presented for the EE1 and EE2 populations. 
6.2.3 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2 
Mean change and % change from Baseline (Visit 2) to each post baseline assessment in the score of 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2 will be evaluated as a secondary endpoint. The 
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Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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UPDRS Part 2 sum score will be calculated as the sum of UPDRS items 5-17 (range 0-52 points). The 
Part 2 sum score will only be calculated if all 13 items have been completed. In case of at least 1 missing 
item, the whole score will be set as missing. 
The above will be summarized for the EE1 and EE2 population. 
6.2.4 Proportion of Responders 
Proportion of responders (with improvement in dyskinesia and improvement in dyskinesia with no 
worsening in parkinsonian motor function separately) at Visits 3 and 5 will be evaluated as a secondary 
endpoint. The improvement in dyskinesia is defined as ≥30% improvement in UDysRS score (Parts 1, 3, 
and 4) from Baseline (Visit 2) and no worsening from Baseline (Visit 2) in motor function is defined as 
≤30 minutes increase in OFF time from Baseline (Visit 2).  
In addition, proportion of responders with improvements of ≥ 35%,  ≥ 25% and  ≥ 20% will also be 
summarized. 
A Fisher’s exact test will be used to compare differences between each of the active treatment group vs 
placebo. 
The UDysRS score (Parts 1, 3, and 4) will be derived as defined in Section 6.1 and the OFF time as defined 
in Section 6.2.8, represented as hours normalized to a 16-hour waking day. The percentual change in the 
UDysRS score from baseline will be calculated as the absolute change divided by the baseline value. A 
decrease in the UDysRS score indicates improvement. 
The visits with missing data in either the UDysRS score (Parts 1, 3, and 4) or in OFF time will be set as 
missing. However, a sensitivity analysis will be conducted by considering missing data as non-
improvements.  
The above will be summarized for the EE1 and EE2 population. 
6.2.5 UPDRS Part 3 as Measured Immediately Prior to the In-clinic L-DOPA Dose 
Mean change and % change Baseline (Visit 2) to each post baseline visit in the UPDRS Part 3 as measured 
immediately prior to the in-clinic L-DOPA dose will be evaluated as a secondary endpoint. The UPDRS 
Part 3 sum score will be calculated as the sum of UPDRS items 18-31 (range 0-108 points). The Part 3 
sum score will only be calculated if all 27 items have been completed. In case of at least 1 missing item, 
the whole score will be set as missing. 
The above will be summarized for the EE1 and EE2 population. 
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6.2.6 Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change 
(CGI-C) 
The proportion of subjects improving based on the Patient Global Impression of Change (PGI-C) and 
Clinician Global Impression of Change (CGI-C) will be evaluated as secondary endpoints. The PGI-C and 
CGI-C will be analyzed by categorizing the non-missing assessments as improvements (very much 
improved, much improved, minimally improved) or non-improvements (no change, minimally worse, 
much worse, very much worse). The visits with missing assessments will be set as missing. 
A Fisher’s exact test will be used to compare differences between each of the active treatment group vs 
placebo. 
PGI-C and CGI-C will be summarized for the EE1 population for each post baseline assessment. 
6.2.7 Parkinson’s Disease Questionnaire -39 (PDQ-39) 
Since PDQ-39 was removed per the amendment any available data will be included in listings and no 
analyses will be performed. 
6.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be presented in listings and may be analyzed post-hoc. 
 Parkinson’s Disease Sleep Scale (PDSS-2) overall score 
The PDSS-2 overall score will be calculated as the sum of responses to the 15 questions, each scored 
from 0 to 4 (Never = 0, Occasionally = 1, Sometimes = 2, Often = 3, Very often =4). In case of at least 
1 missing item, the overall PDSS-2 score will be set as missing. 
 Total Non-motor Symptom Scale (NMSS) score 
The NMSS includes 30 items on 9 different domains. For each item, the severity is rated on a scale 
from 0 to 3 and frequency from 1 to 4. These two ratings are multiplied to derive a final item score, 
ranging from 0 to 12. A domain score is calculated for each of the 9 domains as the sum of the item 
scores within that domain. The NMSS total score is the sum of all 30 item scores (ranging from 0 to 
360). 
6.4 
Safety and tolerability endpoints 
Following safety and tolerability endpoints will be evaluated. For more details, see section 15 (Analysis 
of safety and tolerability data). 
 Safety 
o Adverse events (AEs) occurring throughout the study. 
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o QTc parameters: absolute QTcF of >450 msec, >480 msec and ≤500 msec, and >500 msec, 
mean QTcF, changes in QTcF>30 msec and ≤60 msec, and changes in QTcF>60 msec 
throughout the study. 
o Clinical safety laboratory (Only Creatinine Clearance, Serum Creatinine, Potassium and 
Magnesium), vital signs (including assessment of orthostatic hypotension), physical and 
neurological examination, concomitant medications throughout the study. 
o Columbia-Suicide Severity Rating Scale (C-SSRS)- At baseline and Since last visit throughout 
the study.  
o Change from Baseline (Visit 2) in impulse control disorder as evaluated by the Questionnaire 
for Impulsive Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS) 
throughout the study. 
 Tolerability 
o The number (%) of subjects who complete the study drug 
o The number (%) of subjects who fail to complete the study drug due to AEs 
o The number (%) of subjects who fail to complete the study drug due to QTcF and QT stopping 
rules, seizure or convulsions. 
6.5 
PK Endpoints 
Plasma concentrations of pridopidine and its metabolite TV-45065. 
7 
Sample Size Considerations 
The sample size calculations for the study were based on  38 randomized subjects in each treatment group 
(114 randomized subjects overall) providing 80% power to detect a between-group difference of 8.5 points 
in the UDysRS score with standard deviation of 13 points using two sided significance level of 0.05. 
Assuming a drop-out rate of 15%, a total of 135 subjects were to be randomized. The sample size was 
calculated based on two sample t-test assuming equal variances in the two groups, using nQuery Advisor 
version 7.0. 
Due to COVID-19 the study was terminated early. 
8 
Statistical Hypotheses 
Each primary and secondary endpoint includes the comparison of each of the two dosages of pridopidine 
vs placebo as well as the two Pridopidine doses combined vs. placebo. 
9 
General Statistical Considerations 
All data from all subjects entered into the database will be included in subject data listings. The listings 
will be generally sorted by study drug, center and subject number (and by visit, if applicable). In addition 
to the data collected on the case report form, all other study data, including data collected electronically 
outside of the case report form and all protocol violations will be listed. 
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All applicable data will be summarized by treatment group (pridopidine 150 mg BID, pridopidine 100 mg 
BID, pridopidine 150 mg BID and 100 mg BID pooled active or placebo). Where appropriate, data will 
be summarized by visit in addition to the treatment group.  
Unless otherwise indicated unscheduled or repeat assessments will not be included in summary tables, but 
will be included in listings. For safety analyses which summarize the total number of abnormal values 
over the whole study or period, the unscheduled or repeat assessments will be used for these totals, but 
not for the visit-specific analyses.  For assessments done at the ET visit, these assessments will be used as 
data for the scheduled visit closest to the ET time point, in case the corresponding data are missing from 
this closest visit. 
Unless specific otherwise, baseline is defined as the last non-missing assessment prior to the first dose of 
the study drug. 
Continuous variables will be summarized using the number of observations (n), mean, standard deviation 
(SD), first quartile (Q1), median, third quartile (Q3), minimum, and maximum. Standard error of the mean 
(SEM) will also be provided for summaries of efficacy data, if relevant.  
Descriptive statistics for categorical data will include frequency counts and percentages. The total number 
of subjects in the treatment group overall (N) will be used as the denominator for percent calculations, 
unless stated otherwise. Missing categories will be included as appropriate. 
Significance testing will be 2-sided using α = 0.05, unless otherwise specified.  
All statistical analyses and summaries will be produced using SAS version 9.4 or higher. Deviations from 
the statistical plan will be reported in the clinical study report, including the rationale for the deviation. 
9.1 
Adjustment for Covariates 
For the analysis of efficacy endpoints, the baseline value of the endpoint in question will be included as a 
baseline covariate (for continuous endpoints) or as a stratification factor (for categorical endpoints), if 
available. As a general rule, the last assessment before the first dose of study drug at the Baseline visit 
(Visit 2) will be used as the baseline covariate. 
As no stratification factors were used in the randomization, the primary analyses will not include any 
additional covariates. 
9.2 
Handling of Drop-Outs or Missing Data 
In this study, missing or incomplete efficacy data are managed in two steps. In the first step, imputation 
methods are defined to derive endpoints from questionnaires or diaries with incomplete data within a visit 
or time point. In the second step, statistical methods are defined for analysis of incomplete longitudinal 
datasets in case data are still missing after the first step.  
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9.2.1 Imputation of Incomplete Data within a Visit or Timepoint 
 The imputation rules for the incomplete UDysRS ratings are provided in Sections 6.1 and 6.2, in order 
to derive the endpoints based on UDysRS. 
 The imputation rules for the incomplete “ON/OFF” home diaries (i.e., diaries for days with less or 
more than 24 recorded hours per day) are provided in Section 6.2.1, in order to derive the relevant 
endpoints based on the “ON/OFF” home diaries. 
 The imputation rules for the other continuous efficacy endpoints derived from questionnaires (UPDRS 
sum scores, PDQ-39 summary index and dimension scores, PDSS-2 and NMSS scores) are provided 
in Sections 6.2 and 6.3. 
9.2.2 Handling of Missing Longitudinal Data 
The following methods will be used to manage longitudinal incomplete data after the data within each 
visit has been imputed as described above.   
 For the primary efficacy analysis, likelihood-based modeling approach will be used to handle 
incomplete data. For this purpose, Mixed Model for Repeated Measures (MMRM) will be applied, see 
Section 14.1. 
 Sensitivity analyses for the primary endpoint data will be conducted using the Multiple Imputation 
(MI) approach.  For the MI approach, each missing value will be replaced with a set of plausible values 
that represent the uncertainty about the right value to impute, see Section 14.1. Imputation will only 
be done under the assumption of Missing At Random (MAR). 
Safety data will not be subject to any imputation and will be summarized on an observed case basis. 
9.3 
Interim Analyses and Data Monitoring 
No interim analyses were planned.  
Since the study was terminated prematurely before 30 subjects were enrolled no formal Drug Safety 
Monitoring Board (DSMB) meeting was conducted.  
9.4 
Multiple Comparison/Multiplicity 
Since the study was terminated early and the sample size is small no adjustment for multiplicity will be 
performed. Statistical testing and p-values will be evaluated based on totality of information in assessing 
efficacy and provided primarily for descriptive purposes. 
 
 
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10 
Subjects Disposition, Demographic and Other Baseline Characteristics 
 
The following will be summarized in the Subject Disposition table.  
 
A summary of the number of subjects in each of the analysis populations.  
 
The number and percentage of subjects who were randomized but not treated.  
 
The count and percentage of subjects who completed or discontinued from the study or treatment. 
For those who discontinued from the study or treatment, the primary reason for discontinuation from 
the study or treatment will be presented.  
Demographics and baseline characteristics will be summarized descriptively for the Safety Population, by 
treatment group and overall. For categorical endpoints, categories for missing data will be presented. 
The following variables will be summarized: 
 Demographics: age (continuous, calculated as date of informed consent minus date of birth, 
divided by 365.25), age categorized as <65 years versus ≥65 years, gender, ethnicity, race, height, 
weight, BMI (calculated as weight [kg] divided by squared height [m2]) and country. In case of 
missing day of birth, the day will be imputed as 15. In case of missing month of birth, the month 
will be imputed as 6. 
 PD history: time since diagnosis of PD, time since start of levodopa treatment and time since onset 
of levodopa-induced dyskinesia, all measured in years at time of informed consent 
 Report of direct observation of ON-time with dyskinesia during half-hour periods of the screening 
visit 
 Baseline dyskinesia status: total score on UDysRS part 4 disability scale. 
 Cognitive status: Mini–Mental State Examination (MMSE) total score (as categorical, % of 
subjects with a score of 30, 29, 28, 27, 26 or <26) 
 Distribution of Modified Hoehn and Yahr stages 
 Total daily levodopa dose (mg) and distribution of dosing frequency at Screening.  
11 
Prior and Concomitant Medications 
Prior and Concomitant medications data are coded using WHODD Global-B3-Sep 2018 and will be 
presented in listings with no summary tables. 
12 
Medical History 
Medical History data will be presented in listings with no summary tables. 
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13 
Protocol Deviations 
Protocol Deviations data will be presented in listings with no summary tables. 
14 
Analysis of Efficacy 
Each primary and secondary endpoint of this study includes the comparison of each of the two dosages 
of pridopidine vs placebo and the two pooled active doses vs placebo.  
14.1 
Primary Endpoint 
The primary endpoint of this study is the mean change from Baseline (Visit 2) to Visit 3 and Visit 5 in the 
sum of Parts 1, 3, and 4 of the UDysRS. The difference in the primary endpoint between the groups 
(pridopidine 150 mg BID versus placebo, pridopidine 100 mg BID versus placebo) will be estimated using 
a MMRM using the EE1 and EE2 populations after imputing missing data under assumption of MAR. 
The model will include the observed changes from Baseline using Visits 3, 4, 5, 6 and 7 as the response 
values. The treatment difference at each visit will be estimated using contrasts. The MMRM will include 
the treatment group (pridopidine 150 mg BID, pridopidine 100 mg BID or placebo), visit (3, 4, 5, 6 or 7) 
and the interaction between the treatment group and visit as fixed factors. The baseline value will be used 
as a covariate in the model.  
A separate analysis will compare pooled active vs placebo under same assumptions as above. 
An unstructured covariance structure will be applied for MMRM. In case the model will not converge 
with the unstructured covariance structure, heterogeneous Toeplitz structure (TOEPH), Autoregressive 
with heterogeneity (ARH (1)), Heterogeneous variances with Compound Symmetry (CSH), Toeplitz 
(TOEP), Autoregressive(1) (AR(1)) or Compound Symmetry without heterogeneous variances (CS) 
covariance structure will be used instead in this order. The denominator degrees of freedom will be 
computed using the Kenward-Roger method. 
The least square (LS) means, standard errors and LS mean differences between pridopidine 150 mg BID 
versus placebo and pridopidine 100 mg BID versus placebo at each visit along with the 95% confidence 
intervals (CIs) will be provided. The nominal p-values for the hypothesis testing will also be provided. 
Treatment difference will be assessed with a 2-sided alpha level of 0.05.   
The EE1 and EE2  populations will be used for the primary efficacy analysis.  
The above analysis will be conducted after imputation of missing data using multiple imputations (MI) 
under MAR assumption: This methodology will structure data based on missing data patterns. The method 
will be based on a missingness pattern having a monotone structure, i.e. if among the observations over 
time one data value is missing, all other values after this missing value will also be treated as missing. For 
subjects with intermittent missing values, before performing MI, a monotone missingness pattern will be 
generated. Intermittent missing values will be imputed using the Markov Chain Monte Carlo (MCMC) 
methodology which assumes a multivariate normal distribution over all variables included in the 
imputation model. The MI procedure in SAS will be used for this purpose and this first MI step is planned 
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Study: PL101-LID201                                                                       SAP Version 1.0 23 July 2020 
 
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to be repeated 100 times, creating several different datasets with a monotone missing data structure.  Seed 
value of 1995 will be used in the MI procedure. The imputation is based on the MAR assumption, i.e. the 
missing data are assumed to follow the same model as the other subjects in their respective treatment arm. 
After this, the remaining missing data will be imputed using a method for monotone missingness, also 
based on the MAR assumption. Thus, for each of the created dataset with a monotone missing data pattern, 
the MI procedure in SAS will used to impute missing values based on a sequential procedure reflecting 
the monotone missing data pattern. Subjects with the first missing value occurring at Visit 3 will have 
their missing Visit 3 value replaced by an imputed value from a regression model with treatment group 
and the baseline value as explanatory variables. In the next step, subjects with their Visit 4 value missing 
will have their missing Visit 4 value replaced by an imputed value from a regression model with treatment 
group, baseline value and the Visit 3 value as explanatory variables. In the next step, subjects with their 
Visit 5 value missing will have their missing Visit 5 value replaced by an imputed value from a regression 
model with treatment group, baseline value and the Visit 3 and Visit 4 values as explanatory variables. 
Similar procedure will be used to replace the missing values at Visit 6 and 7. 
The imputed datasets generated with the approach described above do contain only non-missing values 
and are used as input in the model for the sensitivity analysis of the primary endpoint. MMRM models 
similar as described for the primary analysis will thus be run on each of the 100 generated imputed datasets 
and the difference between the treatment groups at Visit 7 will be estimated. Finally, the MIANALYZE 
procedure in SAS will be applied to combine the results from these analyses to derive overall estimates of 
the treatment differences at Visit 7. In addition to the estimates, corresponding 95% confidence intervals 
and p-values will be calculated. 
14.2 
Secondary Endpoints 
14.2.1 Continuous Secondary Endpoints 
The secondary endpoints that will be treated as continuous (all endpoints derived from “ON/OFF” home 
diaries, UDysRS questionnaire and UPDRS questionnaire part 2 and 3) will be analyzed with MMRMs 
similar to the one used for the primary endpoint. The baseline value of the analysis variable in question 
will be used as the baseline covariate in the MMRM. The analyses will be performed in the EE1 and EE2 
set. In addition to Visit 7, data from Visits 3, 4, 5 and 6 will be analyzed as well.  
For “ON/OFF” home diaries, in addition to the secondary endpoints, also ON time with troublesome 
dyskinesia and ON time with ON time with non-troublesome dyskinesia will be analyzed as well.  
For UDysRS, all four sum scores (Part 1, Part 2, Part 3 and Part 4), Individual parts. 
15 
Analysis of Safety and Tolerability 
15.1 
Extent of Exposure 
The following information will be summarized by treatment group and overall using the Safety Population.  
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The summary include either a tabulation of number (and %) of subjects or descriptive statistics (for 
durations and total exposure). 
The number of subjects exposed to study treatment and summary statistics on duration of exposure (Mean, 
SD, etc.) by each of the 4 treatment groups (placebo, 100 mg BID, 150 mg BID, pridopidine total) – in 
titration period (all subjects, subjects with 2 weeks titration, subjects with 4 weeks titration), in 
maintenance period (all subjects, subjects with 2 weeks titration, subjects with 4 weeks titration) 
15.2 
Compliance 
Subjects will be instructed to bring with them the used and unused drug kits at Visit 3, Visit 5, Visit 6, 
Visit 7/ET, and at Visit 8/FU, in which treatment compliance will be evaluated. Treatment compliance at 
the Visit 3, Visit 5, Visit 6, Visit 7/ET, and Visit 8/FU and overall for the 14 week active treatment period 
will be calculated using the following formula: 
Compliance (%) = [Total number of administered doses/Total number of scheduled doses] × 100 
The total number of scheduled doses will be calculated based on the extent (days) of exposure of each 
subject. A range between 80% to 120% will be taken as reference limits for a satisfactory level of 
compliance. The compliance (expressed as %) will be summarized with descriptive statistics by treatment 
group. In addition, the number (and %) of subjects with compliance between 80% to 120% will be 
tabulated by treatment group. 
15.3 
Adverse Events 
All AEs will be coded using MedDRA version 21.0. Treatment-emergent adverse events (TEAEs) are 
defined as all AEs that start or increase in severity after the subject receives the first dose of study drug. 
Events with a missing start time, but with a start date equal to the date of first dose of study drug will be 
considered treatment-emergent.  If the AE start date is incomplete, it will be imputed as follows for the 
purpose of determining TEAE:  
 If the start date is completely missing, the start date will be equal to the date of the first dose of study 
drug.  However, if the stop date is not missing and is before the date of the first dose of study drug, 
then the stop date will be used instead.  
 If the start day is missing, the first day of the month will be used.  
 If the start day and month are missing, then the first day of the first month (January) will be used. 
 If the end date is completely missing, the latest end date of any other adverse event, or the date of last 
study visit for the same subject will be used, whichever occurs later. 
 If the end day is missing, the last day of the month will be used. 
 If the end day and month are missing, then the last day of the month of the last study visit for the same 
subject will be used. 
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In the AE summaries, data will be presented in four columns (pridopidine 150 mg BID, pridopidine 100 
mg BID, pridopidine total, placebo) using the Safety Population. 
The following summaries will be provided. If not stated otherwise, the tables will be sorted in alphabetic 
order by SOC, and within each SOC, in descending order according to the % of subjects reporting each 
PT in the pridopidine total group. 
 An overall summary of the number and percentage of subjects reporting TEAEs and the number of 
TEAE events, treatment-related TEAEs, severe TEAEs, TEAEs leading to death (if there are any 
subjects who died), SAEs other than death, TEAEs leading to study drug discontinuation and TEAEs 
leading to temporary withdrawal  
 The incidence (number and % of subjects) and frequency (event count) of TEAEs broken down by 
System Organ Class (SOC) and PT. 
15.4 
Laboratory Safety Parameters 
Only select clinical laboratory safety parameters will be converted to consistent units according to the 
International System of Units (SI) before summarization.  
As of development of this SAP only Creatinine Clearance and Serum Creatinine will be summarized as 
below. Any other available data will be included in listings. 
The following will be summarized: 
 Numeric laboratory parameters: In case the value of a numeric laboratory parameter is below the lower 
limit of quantification, the lower limit of quantification will be used as the response value for the 
purpose of calculating the descriptive statistics. 
 Laboratory parameters which have an upper and/or lower reference range: Number and percentage of 
subjects with 6 categories (missing, clinically significant low, not clinically significant low, normal, 
not clinically significant high, clinically significant high) values at each visit for each parameter will 
be summarized by treatment group. If a subject has both low and high abnormalities at a given visit, 
then only the worst value would be displayed in the appropriate category. 
 These values will be presented as a shift table, i.e. the distribution of the 6 response categories at each 
post-baseline visit and the worst post-baseline value across all visits will be classified by the baseline 
category. 
15.5 
Vital Signs 
Vital sign measurements include pulse rate, systolic and diastolic blood pressure (BP) and body weight. 
The BPs will be assessed in supine and standing positions and the standing minus supine values will be 
summarized in addition to the separate summaries of the supine and standing position. The mean of the 
triplicate values at baseline will be calculated, without rounding the result. These calculated means will 
constitute the analysis values for baseline. 
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Potentially clinically significant vital signs will be identified for selected parameters as defined below. 
These abnormalities will be summarized using at each visit, the last visit and by the worst post baseline 
values. 
 Systolic BP: <90 mmHg, 90-140 mmHg, >140 mmHg – 160 mmHg, >160 mmHg 
 Diastolic BP: <50 mmHg, 50-90 mmHg , >90 mmHg – 100 mmHg, >100 mmHg 
 Pulse rate: <60 beats per minute (bpm), 60-100bpm, >100 bpm 
 Standing minus supine systolic BP ≤-20 mmHg 
 Standing minus supine diastolic BP ≤-10 mmHg. 
15.6 
ECG 
At Baseline (Visit 2) and at every visit thereafter, triplicate 12-lead ECG evaluations will be assessed 
before, and 1 to 2 hours after the study drug dose administrated at the clinic. The mean of the triplicate 
ECG values will be calculated, without rounding the result. These calculated means will constitute the 
analysis values. The original values will be listed only. 
The following will be summarized by treatment group and visit: 
 Actual values and change from baseline for each ECG parameter will be summarized with descriptive 
statistics.  
The potentially clinically significant ECGs will be identified for selected parameters as defined below. 
These abnormalities will be summarized using shift tables by visit and the worst value across all visits.  
 QTcF: ≤450 msec, >450 – 480 msec, >480 – 500 msec, >500 msec. 
In addition to the shift table by visit, the highest post-baseline QTcF value during the study for each subject 
will be tabulated using the categories listed above. 
The potentially clinically significant changes from Baseline in ECGs will be identified for selected 
parameters as defined below. These abnormalities will be summarized by visit and the worst value across 
all visits. 
 QTcF: change ≤30 msec, change >30 – 60 msec, change >60 msec. 
In addition to the summary by visit, the highest post-baseline QTcF change during the study for each 
subject will be tabulated using the categories listed above. 
15.7 
Physical and Neurological Examination 
Physical exam data will be only listed with no summary tables. 
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15.8 
Other Safety Variables 
15.8.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale Screening/Baseline Version (C-SSRS-BL) will be measured 
at Baseline. 
The Columbia-Suicide Severity Rating Scale Since Last Visit Version (C-SSRS-SLV) will be assessed at 
the post-Baseline visits. 
C-SSRS data will only be included in listings and no summary tables created. 
15.8.2 Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS) 
The QUIP-RS consists of four questions which have to be answered for each disorder (gambling, sex, 
buying, eating, hobbyism, punding and PD medication use) on a 5-point Likert scale. Scoring range for 
each scale (i.e. disorder) is 0–16. The total Impulsive Control Disorder (ICD) score and the total QUIP-
RS score will be calculated and changes from baseline on these parameters.  The individual scores, total 
scores and changes from baseline in total scores will be presented in listings. 
15.9 
Tolerability 
The evaluation of tolerability is based on the following 
 The number (%) of subjects who complete the study drug. 
o This analysis includes all premature discontinuations of the study 
 The number (%) of subjects who fail to complete the study drug due to AEs 
o This analysis includes the premature discontinuations of the study, in which the primary reason 
for the premature discontinuation is defined as an AE or death (as defined on the Study 
Completion case report form page). 
16 
Analysis of PK 
Plasma concentrations of pridopidine and its metabolite TV-45065 will be summarized with descriptive 
statistics by visit and timepoint (1 hour before and 1 to 2 hours after the pridopidine dose). The relationship 
between plasma concentrations of pridopidine and TV-45065 versus the primary endpoint (and the change 
from baseline in the primary endpoint) may be explored graphically for each visit which include both the 
PK and primary efficacy assessments. Separate exploration may be conducted for the PK assessments 
conducted before and 1 to 2 hours after the pridopidine dose.  
PK analyses will be performed after the study database is locked, the study unblinded only if they are 
deemed necessary. Otherwise, PK data will only be included in listings, if there is not much data for 
analysis. 
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17 
Deviations from the Analyses Planned in the Study Protocol 
This analysis plan superseded the analyses planned in the protocol since the study was prematurely 
terminated. 
18 
Execution of Statistical Analyses 
Statistical analyses will be performed by
 and supervised by the Sponsor. 
19 
Hardware and Software 
Statistical analysis, tables and subject data listings will be performed with SAS® version 9.4 or later (SAS 
Institute Inc., Cary, NC, USA). 
20 
References 
Clinical Study Protocol: Version 1.1 (24 January, 2019), Company: Prilenia Neurotherapeutics. 
Clinical Study Protocol: Version 2 (19 November, 2019), Company: Prilenia Neurotherapeutics. 
Johnston G, So Y. Analysis of data from recurring events. In: Proceedings of the twenty-eighth annual 
SAS users group international conference. Cary: SAS Institute, Inc. Paper 273-28 (2003). 
 
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