A Phase 2, to Evaluating the Safety and Efficacy of Pridopidine Vs Placebo for Symptomatic Treatment in Patients With Huntington's Disease

• Sponsor: Prilenia (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02006472
• Collaborator: European Huntington's Disease Network (Other), Huntington Study Group (Other)
• Enrollment: 408
• Locations: 58
• Arms: 5
• Actual Duration (Months): 28.3
• Patients Per Site: 7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a multicenter, multinational, randomized, parallel-group, double-blind, placebo-controlled, dose range finding study to compare the efficacy and safety of different doses of pridopidine versus placebo in the treatment of motor impairment in Huntington's Disease (HD).

Condition or Disease	Intervention/Treatment	Phase
Huntington's Disease	Drug: Pridopidine; Other: Placebo	Phase 2

Detailed Description

Originally, the study was designed to assess the effect of pridopidine on motor function at 26 weeks. Due to the recognition that the primary target of pridopidine is the Sigma-1 receptor, the trial was extended from 26 to 52 weeks to evaluate the effect of pridopidine on Total Functional Capacity (TFC). A minimum of 52 weeks are needed for the placebo group to decline and allow a window to assess an effect on TFC (a prespecified endpoint). Approximately 20% of patients completed 26 weeks of the study before IRB approvals for this extension, and did not continue into the 2nd treatment period up to 52 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 408 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Dose-Finding, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study, Evaluating the Safety and Efficacy of Pridopidine 45, 67.5, 90, and 112.5 mg Twice-Daily vs Placebo for Symptomatic Treatment in Patients With Huntington's Disease
• Actual Study Start Date: Feb 28, 2014
• Actual Primary Completion Date: Dec 16, 2015
• Actual Study Completion Date: Jul 7, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pridopidine 45 mg Twice daily	Drug: Pridopidine; 22.5 mg and 45 mg capsules; Other Names: TV7820 ; Other: Placebo; Capsules matching drug
Experimental: Pridopidine 67.5 mg Twice daily	Drug: Pridopidine; 22.5 mg and 45 mg capsules; Other Names: TV7820 ; Other: Placebo; Capsules matching drug
Experimental: Pridopidine 90 mg Twice daily	Drug: Pridopidine; 22.5 mg and 45 mg capsules; Other Names: TV7820 ; Other: Placebo; Capsules matching drug
Experimental: Pridopidine 112.5 mg Twice daily	Drug: Pridopidine; 22.5 mg and 45 mg capsules; Other Names: TV7820 ; Other: Placebo; Capsules matching drug
Placebo Comparator: Placebo Twice daily	Other: Placebo; Capsules matching drug

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 [26 weeks]

   TMS was defined as the sum of all UHDRS motor domains ratings. The motor section of the UHDRS assesses motor features of Huntington's Disease (HD) with standardized ratings of oculo-motor function, dysarthria, chorea, dystonia, gait, and postural stability. Each of 15 assessments is rated on a scale of 0 (normal) to 4 (marked impairment) for a TMS range of 0-124. Negative change from baseline values indicate improvement.

Secondary Outcome Measures

1. Number of Patients With Adverse Events [52 weeks]

Other Outcome Measures

1. Change From Baseline in Total Functional Capacity (TFC) at Week 52 [52 weeks]

   The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of HD based on the presence of >/= 36 CAG repeats

• Male or female age ≥21 years, with an onset of HD after 18 years' old.

• Females of childbearing potential must be compliant in using adequate birth control throughout the duration of the study

• Body weight ≥50 kg

• Sum of >= 25 points on the UHDRS-TMS and UHDRS Independence Score <=90%

• Able and willing to provide written informed consent prior to any study related procedure.

• Willing to provide a blood sample for genetic analyses

• Willing and able to take oral medication and able to comply with the study specific procedures.

• Ambulatory, being able to travel to the study center, and judged by the investigator as likely to be able to continue to travel for the duration of the study.

• Availability and willingness of a caregiver, informant or family member to accompany the patient to the clinic at study, and the suitability of the caregiver should be judged by the Investigator.

• Other criteria apply, please contact the investigator for more information.

Exclusion Criteria:

• Patients with clinically significant heart disease at the screening visit

• Treatment with tetrabenazine within 6 weeks of study screening

• Patients with a history of epilepsy or of seizures within the last 5 years

• Have other serious medical illnesses in the opinion of the investigator may put the patient at risk when participating in the study or may influence the results of the study or affect the patient's ability to take part in the study

• Patients receiving medications (within the last 6 weeks prior to screening) that have been proven to prolong QT interval or who may require such medications during the course of the study such as but not limited to non allowed anti psychotic medications, tricyclic antidepressants and/or Class I antiarrhythmics

• Other criteria apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site 12199	La Jolla	California	United States
2	Investigational Site 12204	Los Angeles	California	United States
3	Investigational Site 12201	Englewood	Colorado	United States
4	Investigational Site 12196	Washington	District of Columbia	United States
5	Investigational Site 12207	Chicago	Illinois	United States
6	Investigational Site 12202	Baltimore	Maryland	United States
7	Investigational Site 12206	Baltimore	Maryland	United States
8	Investigational Site 12200	Manhasset	New York	United States
9	Investigational Site 12203	New York	New York	United States
10	Investigational Site 12198	Rochester	New York	United States
11	Investigational Site 12211	Winston-Salem	North Carolina	United States
12	Investigational Site 12205	Cincinnati	Ohio	United States
13	Investigational Site 12209	Pittsburgh	Pennsylvania	United States
14	Investigational Site 12208	Salt Lake City	Utah	United States
15	Investigational Site 12210	Richmond	Virginia	United States
16	Investigational Site 12197	Kirkland	Washington	United States
17	Investigational Site 78055	Caulfield South		Australia
18	Investigational Site 78056	Kew		Australia
19	Investigational Site 78058	Subiaco		Australia
20	Investigational Site 78057	Westmead		Australia
21	Investigational Site 33021	Innsbruck		Austria
22	Investigational Site 33027	Wien		Austria
23	Investigational Site 11035	Vancouver	British Columbia	Canada
24	Investigational Site 11037	Ottawa	Ontario	Canada
25	Investigational Site 11036	Toronto	Ontario	Canada
26	Investigational Site 39028	Aarhus		Denmark
27	Investigational Site 39027	Copenhagen		Denmark
28	Investigational Site 35123	Angers cedex 9		France
29	Investigational Site 35122	Creteil		France
30	Investigational Site 35125	Lille		France
31	Investigational Site 35124	Marseille Cedex 5		France
32	Investigational Site 35121	Salouel		France
33	Investigational Site 35165	Toulouse		France
34	Investigational Site 32408	Berlin		Germany
35	Investigational Site 32410	Bochum		Germany
36	Investigational Site 32409	Muenster		Germany
37	Investigational Site 32407	Ulm		Germany
38	Investigational Site 30083	Firenze		Italy
39	Investigational Site 30080	Milano		Italy
40	Investigational Site 30082	Napoli		Italy
41	Investigational Site 30081	Pozzilli		Italy
42	Investigational Site 30084	San Giovanni Rotondo		Italy
43	Investigational Site 38059	Leiden		Netherlands
44	Investigational Site 53150	Gdansk		Poland
45	Investigational Site 53149	Krakow		Poland
46	Investigational Site 53148	Poznan		Poland
47	Investigational Site 53151	Warsaw		Poland
48	Investigational Site 50215	Kazan		Russian Federation
49	Investigational Site 50213	Moscow		Russian Federation
50	Investigational Site 50214	Nizhny Novgorod		Russian Federation
51	Investigational Site 34058	Birmingham		United Kingdom
52	Investigational Site 34054	Cambridge		United Kingdom
53	Investigational Site 34059	Cardiff		United Kingdom
54	Investigational Site 34056	Headington		United Kingdom
55	Investigational Site 34060	London		United Kingdom
56	Investigational Site 34055	Manchester		United Kingdom
57	Investigational Site 34061	Newcastle-Upon-Tyne		United Kingdom
58	Investigational Site 34057	Sheffield		United Kingdom

Sponsors and Collaborators

• Prilenia
• European Huntington's Disease Network
• Huntington Study Group

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• McGarry A, Leinonen M, Kieburtz K, Geva M, Olanow CW, Hayden M. Effects of Pridopidine on Functional Capacity in Early-Stage Participants from the PRIDE-HD Study. J Huntingtons Dis. 2020;9(4):371-380. doi: 10.3233/JHD-200440.

• Responsible Party: Prilenia
• ClinicalTrials.gov Identifier: NCT02006472
• Other Study ID Numbers: TV7820-CNS-20002; 2013-001888-23
• First Posted: Dec 10, 2013
• Last Update Posted: Jul 19, 2021
• Last Verified: May 1, 2021

• Keywords provided by Prilenia: Huntington's Disease; Pridopidine; Pride-HD
• Additional relevant MeSH terms: Huntington Disease

Study Results

Participant Flow

Pre-assignment Detail	A total of 492 patients were screened; of these, 408 were randomized. The main reason for not randomizing patients was noncompliance with the eligibility criteria.

Arm/Group Title	Placebo	Pridopidine 45 mg BID	Pridopidine 67.5 mg BID	Pridopidine 90 mg BID	Pridopidine 112.5 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to the randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Period Title: Period 1 (Through Week 26)
STARTED	82	81	82	81	82
ITT	82	81	82	81	82
FAS	81	75	79	81	81
Safety Set	82	81	82	81	82
COMPLETED	70	59	65	67	62
NOT COMPLETED	12	22	17	14	20
Period Title: Period 1 (Through Week 26)
STARTED	57	49	54	56	46
Started Treatment in Period 2	57	49	52	56	46
COMPLETED	52	43	44	53	44
NOT COMPLETED	5	6	10	3	2

Baseline Characteristics

Arm/Group Title	Placebo	Pridopidine 45 mg BID	Pridopidine 67.5 mg BID	Pridopidine 90 mg BID	Pridopidine 112.5 mg BID	Total
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg or matching placebo and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Total of all reporting groups
Overall Participants	82	81	82	81	82	408
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.3 (11.34)	51.9 (11.75)	51.0 (11.83)	51.3 (12.69)	47.5 (11.40)	50.4 (11.85)
Sex: Female, Male (Count of Participants)
Female	40 48.8%	40 49.4%	41 50%	43 53.1%	39 47.6%	203 49.8%
Male	42 51.2%	41 50.6%	41 50%	38 46.9%	43 52.4%	205 50.2%
Race/Ethnicity, Customized (Count of Participants)
White	73 89%	75 92.6%	78 95.1%	75 92.6%	77 93.9%	378 92.6%
Black	0 0%	0 0%	1 1.2%	0 0%	0 0%	1 0.2%
Asian	1 1.2%	0 0%	0 0%	1 1.2%	0 0%	2 0.5%
Other	0 0%	1 1.2%	0 0%	1 1.2%	0 0%	2 0.5%
Missing	8 9.8%	5 6.2%	3 3.7%	4 4.9%	5 6.1%	25 6.1%
Use of neuroleptics (Count of Participants)
Yes	31 37.8%	31 38.3%	32 39%	31 38.3%	32 39%	157 38.5%
No	51 62.2%	50 61.7%	50 61%	50 61.7%	50 61%	251 61.5%
CYP2D6 genotype (Count of Participants)
Poor metaboliser	1 1.2%	5 6.2%	4 4.9%	2 2.5%	4 4.9%	16 3.9%
Extensive metaboliser	72 87.8%	70 86.4%	70 85.4%	74 91.4%	69 84.1%	355 87%
Intermediate metaboliser	8 9.8%	5 6.2%	8 9.8%	5 6.2%	9 11%	35 8.6%
Ultra-rapid metaboliser	1 1.2%	1 1.2%	0 0%	0 0%	0 0%	2 0.5%
Number of Cytosine-Adenosine-Guanine (CAG) Repeats (Number of CAG repeats) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of CAG repeats]	44.4 (3.23)	44.1 (4.12)	45.0 (4.73)	44.5 (4.90)	45.3 (3.66)	44.7 (4.18)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26
Description	TMS was defined as the sum of all UHDRS motor domains ratings. The motor section of the UHDRS assesses motor features of Huntington's Disease (HD) with standardized ratings of oculo-motor function, dysarthria, chorea, dystonia, gait, and postural stability. Each of 15 assessments is rated on a scale of 0 (normal) to 4 (marked impairment) for a TMS range of 0-124. Negative change from baseline values indicate improvement.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) i.e. patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment

Arm/Group Title	Placebo	Pridopidine 45 mg BID	Pridopidine 67.5 mg BID	Pridopidine 90 mg BID	Pridopidine 112.5 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	81	75	79	81	81
Mean (Standard Error) [score on a scale]	-4.79 (0.99)	-3.37 (1.05)	-3.09 (1.02)	-4.13 (1.00)	-2.74 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3202
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; -1.39 to 4.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 67.5 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2266
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; -1.06 to 4.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 90 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6348
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; -2.07 to 3.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 112.5 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1447
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	2.04
	Confidence Interval	(2-Sided) 95%; -0.71 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients With Adverse Events
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis set, i.e. patients who received at least one dose of study drug

Arm/Group Title	Placebo	Pridopidine 45 mg BID	Pridopidine 67.5 mg BID	Pridopidine 90 mg BID	Pridopidine 112.5 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of pridopidine 22.5 mg or matching placebo and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	82	81	82	81	82
Count of Participants [Participants]	62 75.6%	63 77.8%	69 84.1%	71 87.7%	67 81.7%

3. Other Pre-specified Outcome

Title	Change From Baseline in Total Functional Capacity (TFC) at Week 52
Description	The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) i.e. patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment

Arm/Group Title	Placebo	Pridopidine 45 mg BID	Pridopidine 67.5 mg BID	Pridopidine 90 mg BID	Pridopidine 112.5 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	81	75	78	81	81
Least Squares Mean (Standard Error) [score on a scale]	-0.83 (0.20)	0.04 (0.22)	-0.72 (0.21)	-0.65 (0.20)	-0.59 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 67.5 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7042
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 90 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5099
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 112.5 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4061
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Post-Hoc Outcome

Title	Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7)
Description	The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

FAS i.e. pts receiving ≥1 dose of study drug and with ≥1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7. The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.

Arm/Group Title	Placebo	Pridopidine 45 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	62	59
Least Squares Mean (Standard Error) [score on a scale]	-1.17 (0.22)	-0.01 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Post-Hoc Outcome

Title	Total Functional Capacity Responder Rate in Early HD
Description	The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Responder was defined as a TFC change to Week 52 of TFC>=0.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

FAS i.e. pts receiving ≥1 dose of study drug and with ≥1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7 who completed 52 weeks. The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.

Arm/Group Title	Placebo	Pridopidine 45 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	41	37
Count of Participants [Participants]	20 24.4%	30 37%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Chi-squared
	Comments

6. Post-Hoc Outcome

Title	Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD
Description	Q-motor assessments were based on the application of force transducers and 3-dimensional position sensors. The reported parameter is the Pro-Sup-Inter-Tap-interval-MN-Hand, measured in seconds. Positive change from baseline indicates worsening.
Time Frame	26 and 52 weeks

Outcome Measure Data

Analysis Population Description

FAS i.e. pts receiving >=1 dose of study drug and with >=1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7. The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.

Arm/Group Title	Placebo	Pridopidine 45 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of placebo matching pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.	Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52.
Measure Participants	62	59
Change from baseline to Week 26	0.0247 (0.0118)	-0.0096 (0.0110)
Change from baseline to Week 52	0.0447 (0.0142)	0.0003 (0.0150)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments	At Week 26
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0346
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.0341
	Confidence Interval	(2-Sided) 95%; -0.0658 to -0.0026
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pridopidine 45 mg BID
	Comments	At Week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0305
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.0444
	Confidence Interval	(2-Sided) 95%; -0.0847 to -0.0042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	52 weeks
Arm/Group Title	Placebo		Pridopidine 45 mg BID		Pridopidine 67.5 mg BID		Pridopidine 90 mg BID		Pridopidine 112.5 mg BID
Arm/Group Description	Pridopidine matching placebo (hard capsules) Patients received a starting dose of pridopidine 22.5 mg or matching placebo and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 26.		Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 26.		Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 26.		Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 26.		Pridopidine given as hard capsules, twice daily Patients received a starting dose of pridopidine 22.5 mg (or matching placebo) and were during the first 4 weeks of treatment titrated to their randomised dose level. The randomised dose level was then to be maintained for the remainder of the treatment period through Week 26.
All Cause Mortality
	Placebo		Pridopidine 45 mg BID		Pridopidine 67.5 mg BID		Pridopidine 90 mg BID		Pridopidine 112.5 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/82 (0%)		0/81 (0%)		0/82 (0%)		1/81 (1.2%)		1/82 (1.2%)
Serious Adverse Events
	Placebo		Pridopidine 45 mg BID		Pridopidine 67.5 mg BID		Pridopidine 90 mg BID		Pridopidine 112.5 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/82 (0%)		8/81 (9.9%)		9/82 (11%)		9/81 (11.1%)		9/82 (11%)
Cardiac disorders
Acute myocardial infarction	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Eye disorders
Optic ischaemic neuropathy	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Gastrointestinal disorders
Duodenal ulcer perforation	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Duodenitis	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Dysphagia	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	0/82 (0%)	0
Vomiting	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Abdominal pain	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Diarrhoea	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Abdominal pain upper	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Infections and infestations
Peritonitis	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Osteomyelitis	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Bronchopneumonia	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Urinary tract infection	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Injury, poisoning and procedural complications
Laceration	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Humerus fracture	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Hand fracture	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Concussion	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Skull fracture	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Fall	0/82 (0%)	0	4/81 (4.9%)	5	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Head injury	0/82 (0%)	0	2/81 (2.5%)	2	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Intentional overdose	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Face injury	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Investigations
Blood creatine phosphokinase increased	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Acute myeloid leukaemia	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0
Adenocarcinoma of the colon	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Breast cancer	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Nervous system disorders
Grand mal convulsion	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Akathisia	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Headache	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Psychomotor hyperactivity	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Psychiatric disorders
Mood disorder due to a general medical condition	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Anxiety	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Suicide attempt	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	1/81 (1.2%)	1	2/82 (2.4%)	2
Suicidal ideation	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	1/82 (1.2%)	1
Psychotic disorder	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1
Reproductive system and breast disorders
Uterine prolapse	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Prostatitis	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Urinary tetention	0/82 (0%)	0	0/81 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/82 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/82 (0%)	0
Pneumonia aspiration	0/82 (0%)	0	0/81 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	1/82 (1.2%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Pridopidine 45 mg BID		Pridopidine 67.5 mg BID		Pridopidine 90 mg BID		Pridopidine 112.5 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/82 (54.9%)		49/81 (60.5%)		63/82 (76.8%)		57/81 (70.4%)		53/82 (64.6%)
Gastrointestinal disorders
Diarrhoea	9/82 (11%)	14	9/81 (11.1%)	11	11/82 (13.4%)	14	11/81 (13.6%)	17	10/82 (12.2%)	15
Vomiting	4/82 (4.9%)	6	5/81 (6.2%)	7	6/82 (7.3%)	7	5/81 (6.2%)	5	4/82 (4.9%)	4
Nausea	4/82 (4.9%)	4	4/81 (4.9%)	6	7/82 (8.5%)	10	4/81 (4.9%)	6	3/82 (3.7%)	3
General disorders
Fatigue	7/82 (8.5%)	10	3/81 (3.7%)	3	6/82 (7.3%)	6	7/81 (8.6%)	8	5/82 (6.1%)	5
Infections and infestations
Nasopharyngitis	7/82 (8.5%)	8	14/81 (17.3%)	21	12/82 (14.6%)	16	13/81 (16%)	15	15/82 (18.3%)	23
Urinary tract infection	4/82 (4.9%)	4	3/81 (3.7%)	3	6/82 (7.3%)	6	4/81 (4.9%)	5	5/82 (6.1%)	6
Injury, poisoning and procedural complications
Fall	17/82 (20.7%)	31	16/81 (19.8%)	44	21/82 (25.6%)	31	13/81 (16%)	19	16/82 (19.5%)	42
Contusion	3/82 (3.7%)	3	6/81 (7.4%)	7	6/82 (7.3%)	8	0/81 (0%)	0	3/82 (3.7%)	4
Investigations
Weight decreased	3/82 (3.7%)	3	4/81 (4.9%)	4	3/82 (3.7%)	3	3/81 (3.7%)	3	7/82 (8.5%)	7
Creatinine renal clearance decreased	1/82 (1.2%)	1	5/81 (6.2%)	6	2/82 (2.4%)	2	3/81 (3.7%)	4	5/82 (6.1%)	8
Musculoskeletal and connective tissue disorders
Back pain	3/82 (3.7%)	3	4/81 (4.9%)	4	3/82 (3.7%)	3	6/81 (7.4%)	9	5/82 (6.1%)	6
Nervous system disorders
Headache	8/82 (9.8%)	8	7/81 (8.6%)	18	7/82 (8.5%)	11	11/81 (13.6%)	19	8/82 (9.8%)	10
Chorea	1/82 (1.2%)	1	4/81 (4.9%)	4	13/82 (15.9%)	15	3/81 (3.7%)	3	7/82 (8.5%)	8
Dizziness	2/82 (2.4%)	2	2/81 (2.5%)	2	6/82 (7.3%)	12	5/81 (6.2%)	5	6/82 (7.3%)	8
Balance disorder	3/82 (3.7%)	3	2/81 (2.5%)	3	5/82 (6.1%)	6	1/81 (1.2%)	1	3/82 (3.7%)	3
Psychiatric disorders
Anxiety	2/82 (2.4%)	2	6/81 (7.4%)	6	6/82 (7.3%)	6	7/81 (8.6%)	8	5/82 (6.1%)	5
Suicidal ideation	0/82 (0%)	0	2/81 (2.5%)	2	7/82 (8.5%)	8	1/81 (1.2%)	1	0/82 (0%)	0
Insomnia	3/82 (3.7%)	5	5/81 (6.2%)	6	11/82 (13.4%)	11	9/81 (11.1%)	10	9/82 (11%)	11
Irritability	7/82 (8.5%)	8	4/81 (4.9%)	4	6/82 (7.3%)	7	5/81 (6.2%)	5	2/82 (2.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	2/82 (2.4%)	2	5/81 (6.2%)	5	2/82 (2.4%)	2	1/81 (1.2%)	1	5/82 (6.1%)	5
Vascular disorders
Hypertension	1/82 (1.2%)	1	0/81 (0%)	0	1/82 (1.2%)	1	5/81 (6.2%)	6	2/82 (2.4%)	2

Limitations/Caveats

Analyses for Early HD population were conducted as additional analyses

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Data and results are owned by the sponsor. Results can be used by the institution for (a) internal noncommercial research, education and patient care, and (b) as required under applicable laws and regulations. Other uses require prior written consent of the sponsor.