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    Clinical Trial Results:
    A Phase 2, Dose-Finding, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study, Evaluating the Safety and Efficacy of Pridopidine 45 mg, 67.5 mg, 90 mg, and 112.5 mg Twice-Daily versus Placebo for Symptomatic Treatment in Patients with Huntington’s Disease

    Summary
    EudraCT number
    		 2013-001888-23
    Trial protocol
    		 DE   IT   NL   AT   PL   DK  
    Global end of trial date
    07 Jul 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Jun 2021
    First version publication date
    09 Mar 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Change of sponsor name and additional information

    Trial information

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    Trial identification
    Sponsor protocol code
    TV7820-CNS-20002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02006472
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor study acronym: PRIDE-HD
    Sponsors
    Sponsor organisation name
    Prilenia Neurotherapeutics
    Sponsor organisation address
    Hamenofim 10, Herzliya, Israel, 4672561
    Public contact
    Henk Schuring, Prilenia Neurotherapeutics Ltd., clinicaltrialseu@prilenia.com
    Scientific contact
    Michal Geva, Prilenia Neurotherapeutics Ltd., clinicaltrialseu@prilenia.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of pridopidine 45 to 112.5 mg twice daily (bid) on motor impairment in patients with Huntington’s Disease (HD) after 26 weeks of treatment using the Unified Huntington’s Disease Rating Scale Total Motor Score (TMS). The trial was initially designed as a 26-week study to evaluate the effect of pridopidine on motor function. Due to the recognition that the Primary target of pridopidine is S1R, suggesting a therapeutic potential beyond motor function, the ongoing trial was extended from 26 to 52 weeks in order to allow the assessment of pridopidine on total functional capacity (TFC). A minimum of 52 are needed for the placebo group to decline in TFC and allow a window to detect an effect of treatment on TFC. Approximately 19% of patients completed 26 weeks (period 1) of the study before IRB approvals for the extension and did not continue into period 2 with a duration of up to 52 weeks.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    United Kingdom: 39
    Country: Number of subjects enrolled
    Austria: 27
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    408
    EEA total number of subjects
    262
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    360
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 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.

    Period 1
    Period 1 title
    Period 1 (through Week 26)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm 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.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 45 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 67.5 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 90 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 112.5 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Number of subjects in period 1
    		Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Started
    82
    81
    82
    81
    82
    Completed
    70
    59
    65
    67
    62
    Not completed
    12
    22
    17
    14
    20
         Consent withdrawn by subject
    3
    9
    3
    -
    3
         Adverse event, non-fatal
    5
    6
    11
    11
    14
         Not specified
    1
    5
    -
    2
    3
         Non-compliance
    2
    1
    1
    -
    -
         Protocol deviation
    1
    1
    1
    1
    -
         Lack of efficacy
    -
    -
    1
    -
    -
    Period 2
    Period 2 title
    Period 2 (Week 26 through Week 52)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm 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.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 45 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 67.5 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 90 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Pridopidine 112.5 mg bid
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Number of subjects in period 2 [1]
    		Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Started
    57
    49
    54
    56
    46
    Completed
    52
    43
    44
    53
    44
    Not completed
    5
    6
    10
    3
    2
         Adverse event, serious fatal
    -
    -
    -
    1
    1
         Consent withdrawn by subject
    2
    1
    2
    -
    -
         Adverse event, non-fatal
    1
    4
    5
    -
    -
         Not specified
    -
    1
    -
    1
    -
         Non-compliance
    1
    -
    -
    -
    -
         Did not receive study drug
    -
    -
    2
    -
    -
         Sponsor decision
    -
    -
    1
    -
    -
         Lack of efficacy
    1
    -
    -
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patients who did not enter the second study period from the first study period were lost due to prolonged IRB review periods at some clinical sites.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting 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.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group description
    		 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.

    Reporting group values
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid Total
    Number of subjects
    		 82 81 82 81 82 408
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.3 ( 11.34 ) 51.9 ( 11.75 ) 51.0 ( 11.83 ) 51.3 ( 12.69 ) 47.5 ( 11.40 ) -
    Gender categorical
    Units: Subjects
        Female
    		 40 40 41 43 39 203
        Male
    		 42 41 41 38 43 205
    Race
    Units: Subjects
        White
    		 73 75 78 75 77 378
        Black
    		 0 0 1 0 0 1
        Asian
    		 1 0 0 1 0 2
        Other
    		 0 1 0 1 0 2
        Missing
    		 8 5 3 4 5 25
    Use of Neuroleptics
    Antipsychotic drugs to treat psychiatric or behavioral problems associated with HD.
    Units: Subjects
        Neuroleptics use
    		 31 31 32 31 32 157
        Neuroleptics no use
    		 51 50 50 50 50 251
    CYP2D6 Genotype
    CYP2D6 is an enzyme. An association between CYP2D6 genotypes (genetic make-up) and phenotypes (response to treatment, specifically rate of metabolism of the drug) is believed to exist.
    Units: Subjects
        Poor
    		 1 5 4 2 4 16
        Extensive
    		 72 70 70 74 69 355
        Intermediate
    		 8 5 8 5 9 35
        Ultra-rapid
    		 1 1 0 0 0 2
    Number of Cytosine-Adenosine-Guanine (CAG) Repeats
    The normal huntington protein contains multiple repeats of a sequence of three DNA bases, cytosine-adenine-guanine (CAG), which encodes the amino acid glutamine. When more than 36 repeats are present in the protein, stemming from a mutation in the huntingtin gene, an abnormal protein is produced. This mutant form of the protein is more prone to aggregation than versions of the protein with a normal number of repeats. Individuals with 36–40 CAG repeats may or may not develop symptoms of HD, while people with more than 40 repeats will develop the disorder during a normal lifetime.
    Units: repeats
        arithmetic mean (standard deviation)
    		 44.4 ( 3.23 ) 44.1 ( 4.12 ) 45.0 ( 4.73 ) 44.5 ( 4.90 ) 45.3 ( 3.66 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting 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.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group description
    		 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.
    Reporting group title
    Placebo
    Reporting 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.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group description
    		 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.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in this study were administered 3 capsules twice daily (ie, 3 capsules in the morning and 3 capsules in the afternoon). Capsules either contained pridopidine in doses of 22.5 mg or 45 mg or placebo (sized to match the two active doses to assure the blind) and were supplied by the sponsor in medication packs to support the assigned treatment. Patients in the Placebo arm were only supplied placebo capsules which were taken from Day 1 to Week 52.

    Subject analysis set title
    Pridopidine 45 mg bid
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in this study were administered 3 capsules twice daily (ie, 3 capsules in the morning and 3 capsules in the afternoon). Capsules either contained pridopidine in doses of 22.5 mg or 45 mg or placebo (sized to match the two active doses to assure the blind) and were supplied by the sponsor in medication packs to support the assigned total daily dose of 90mg. Doses were titrated during the first 4 weeks, starting at a total daily dose of 45 mg, up to the assigned total daily dose of 90 mg which was taken from Day 28 to Week 52.

    Subject analysis set title
    Pridopidine 67.5 mg bid
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in this study were administered 3 capsules twice daily (ie, 3 capsules in the morning and 3 capsules in the afternoon). Capsules either contained pridopidine in doses of 22.5 mg or 45 mg or placebo (sized to match the two active doses to assure the blind) and were supplied by the sponsor in medication packs to support the assigned total daily dose of 135 mg. Doses were titrated during the first 4 weeks, starting at a total daily dose of 45 mg, up to the assigned total daily dose of 135 mg which was taken from Day 28 to Week 52.

    Subject analysis set title
    Pridopidine 90 mg bid
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in this study were administered 3 capsules twice daily (ie, 3 capsules in the morning and 3 capsules in the afternoon). Capsules either contained pridopidine in doses of 22.5 mg or 45 mg or placebo (sized to match the two active doses to assure the blind) and were supplied by the sponsor in medication packs to support the assigned total daily dose of 180mg. Doses were titrated during the first 4 weeks, starting at a total daily dose of 45 mg, up to the assigned total daily dose of 180 mg which was taken from Day 28 to Week 52.

    Subject analysis set title
    Pridopidine 112.5 mg bid
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in this study were administered 3 capsules twice daily (ie, 3 capsules in the morning and 3 capsules in the afternoon). Capsules either contained pridopidine in doses of 22.5 mg or 45 mg or placebo (sized to match the two active doses to assure the blind) and were supplied by the sponsor in medication packs to support the assigned total daily dose of 225 mg. Doses were titrated during the first 4 weeks, starting at a total daily dose of 45 mg, up to the assigned total daily dose of 225 mg which was taken from Day 28 to Week 52.

    Primary: Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26

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    End point title
    		 Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26
    End point 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.
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Number of subjects analysed
    81 [1]
    75 [2]
    79 [3]
    81 [4]
    81 [5]
    Units: units on a scale
        least squares mean (standard error)
    -4.79 ( 0.99 )
    -3.37 ( 1.05 )
    -3.09 ( 1.02 )
    -4.13 ( 1.00 )
    -2.74 ( 1.01 )
    Notes
    [1] - Full analysis set, i.e. randomised and treated patients with at least 1 post-baseline assessment
    [2] - Full analysis set, i.e. randomised and treated patients with at least 1 post-baseline assessment
    [3] - Full analysis set, i.e. randomised and treated patients with at least 1 post-baseline assessment
    [4] - Full analysis set, i.e. randomised and treated patients with at least 1 post-baseline assessment
    [5] - Full analysis set, i.e. randomised and treated patients with at least 1 post-baseline assessment
    Statistical analysis title
    		 TMS: Pridopidine 45 mg - Placebo
    Statistical analysis description
    The change from baseline in TMS was analyzed using a Repeated Measures model (SAS® MIXED procedure with REPEATED sub-command). The model included the following fixed effects: categorical week in study by treatment interaction, country, neuroleptic use or no use, baseline TMS score, and categorical week in study by baseline TMS interaction.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3202
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 4.23
    Statistical analysis title
    		 TMS: Pridopidine 67.5 mg - Placebo
    Statistical analysis description
    The change from baseline in TMS was analyzed using a Repeated Measures model (SAS® MIXED procedure with REPEATED sub-command). The model included the following fixed effects: categorical week in study by treatment interaction, country, neuroleptic use or no use, baseline TMS score, and categorical week in study by baseline TMS interaction.
    Comparison groups
    Pridopidine 67.5 mg bid v Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2266
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 4.46
    Statistical analysis title
    		 TMS: Pridopidine 90 mg - Placebo
    Statistical analysis description
    The change from baseline in TMS was analyzed using a Repeated Measures model (SAS® MIXED procedure with REPEATED sub-command). The model included the following fixed effects: categorical week in study by treatment interaction, country, neuroleptic use or no use, baseline TMS score, and categorical week in study by baseline TMS interaction.
    Comparison groups
    Pridopidine 90 mg bid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6348
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.07
         upper limit
    		 3.39
    Statistical analysis title
    		 TMS: Pridopidine 112.5 mg - Placebo
    Statistical analysis description
    The change from baseline in TMS was analyzed using a Repeated Measures model (SAS® MIXED procedure with REPEATED sub-command). The model included the following fixed effects: categorical week in study by treatment interaction, country, neuroleptic use or no use, baseline TMS score, and categorical week in study by baseline TMS interaction.
    Comparison groups
    Pridopidine 112.5 mg bid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1447
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    2.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 4.8

    Secondary: Number of patients with Adverse Events

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    End point title
    		 Number of patients with Adverse Events
    End point description
    Number of patients with Adverse Events
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Number of subjects analysed
    82
    81
    82
    81
    82
    Units: participants
    62
    63
    69
    71
    67
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Total Functional Capacity (TFC) at Week 52

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    End point title
    		 Change From Baseline in Total Functional Capacity (TFC) at Week 52
    End point description
    End point type
    Other pre-specified
    End point timeframe
    52 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Number of subjects analysed
    81
    75
    78
    81
    81
    Units: scoreon a scale
        least squares mean (standard error)
    -0.83 ( 0.20 )
    0.04 ( 0.22 )
    -0.72 ( 0.21 )
    -0.65 ( 0.20 )
    -0.59 ( 0.22 )
    Statistical analysis title
    		 TFC: Pridopidine 45 mg - Placebo
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.45
    Statistical analysis title
    		 TFC: Pridopidine 67.5 mg - Placebo
    Comparison groups
    Placebo v Pridopidine 67.5 mg bid
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7042
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.68
    Statistical analysis title
    		 TFC: Pridopidine 90 mg - Placebo
    Comparison groups
    Placebo v Pridopidine 90 mg bid
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5099
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.75
    Statistical analysis title
    		 TFC: Pridopidine 112.5 mg - Placebo
    Comparison groups
    Placebo v Pridopidine 112.5 mg bid
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4061
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.82

    Other pre-specified: Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7)

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    End point title
    		 Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7)
    End point 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.
    End point type
    Other pre-specified
    End point timeframe
    52 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid
    Number of subjects analysed
    62
    59
    Units: score on a scale
        least squares mean (standard error)
    -1.17 ( 0.22 )
    -0.01 ( 0.23 )
    Statistical analysis title
    		 TFC, early HD responders
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    121
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.78

    Other pre-specified: Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand

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    End point title
    		 Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand
    End point 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.
    End point type
    Other pre-specified
    End point timeframe
    26 and 52 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid
    Number of subjects analysed
    55
    54
    Units: second
    least squares mean (standard error)
        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 title
    		 Week 26
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    109
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0346
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    -0.0341
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0658
         upper limit
    		 -0.0026
    Statistical analysis title
    		 Week 52
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    109
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0305
    Method
    		 Mixed models analysis
    Parameter type
    		 LSM difference
    Point estimate
    -0.0444
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0847
         upper limit
    		 -0.0042

    Other pre-specified: Total Functional Capacity Responder Rate

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    End point title
    		 Total Functional Capacity Responder Rate
    End point 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.
    End point type
    Other pre-specified
    End point timeframe
    52 weeks
    End point values
    		 Placebo Pridopidine 45 mg bid
    Number of subjects analysed
    41
    37
    Units: Patients
    20
    30
    Statistical analysis title
    		 Pridopidine 45 mg bid - placebo
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Post-hoc
    Analysis type
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    52 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting 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.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group description
    		 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.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group description
    		 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.

    Serious adverse events
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 82 (0.00%)
    8 / 81 (9.88%)
    9 / 82 (10.98%)
    9 / 81 (11.11%)
    9 / 82 (10.98%)
         number of deaths (all causes)
    0
    0
    0
    1
    1
         number of deaths resulting from adverse events
    Investigations
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 81 (4.94%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Head injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Grand mal convulsion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Akathisia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Mood disorder due to a general medical condition
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Peritonitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Pridopidine 45 mg bid Pridopidine 67.5 mg bid Pridopidine 90 mg bid Pridopidine 112.5 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 82 (54.88%)
    49 / 81 (60.49%)
    63 / 82 (76.83%)
    57 / 81 (70.37%)
    53 / 82 (64.63%)
    Investigations
    Weight decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 81 (4.94%)
    3 / 82 (3.66%)
    3 / 81 (3.70%)
    7 / 82 (8.54%)
         occurrences all number
    3
    4
    3
    3
    7
    Creatinine renal clearance decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 82 (1.22%)
    5 / 81 (6.17%)
    2 / 82 (2.44%)
    3 / 81 (3.70%)
    5 / 82 (6.10%)
         occurrences all number
    1
    6
    2
    4
    8
    Injury, poisoning and procedural complications
    Fall
    alternative assessment type: Systematic
         subjects affected / exposed
    17 / 82 (20.73%)
    16 / 81 (19.75%)
    21 / 82 (25.61%)
    13 / 81 (16.05%)
    16 / 82 (19.51%)
         occurrences all number
    31
    44
    31
    19
    42
    Contusion
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 82 (3.66%)
    6 / 81 (7.41%)
    6 / 82 (7.32%)
    0 / 81 (0.00%)
    3 / 82 (3.66%)
         occurrences all number
    3
    7
    8
    0
    4
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    5 / 81 (6.17%)
    2 / 82 (2.44%)
         occurrences all number
    1
    0
    1
    6
    2
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 82 (9.76%)
    7 / 81 (8.64%)
    7 / 82 (8.54%)
    11 / 81 (13.58%)
    8 / 82 (9.76%)
         occurrences all number
    8
    18
    11
    19
    10
    Chorea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 81 (4.94%)
    13 / 82 (15.85%)
    3 / 81 (3.70%)
    7 / 82 (8.54%)
         occurrences all number
    1
    4
    15
    3
    8
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 81 (2.47%)
    6 / 82 (7.32%)
    5 / 81 (6.17%)
    6 / 82 (7.32%)
         occurrences all number
    2
    2
    12
    5
    8
    Balance disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 82 (3.66%)
    2 / 81 (2.47%)
    5 / 82 (6.10%)
    1 / 81 (1.23%)
    3 / 82 (3.66%)
         occurrences all number
    3
    3
    6
    1
    3
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 82 (8.54%)
    3 / 81 (3.70%)
    6 / 82 (7.32%)
    7 / 81 (8.64%)
    1 / 82 (1.22%)
         occurrences all number
    10
    3
    6
    7
    1
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 82 (10.98%)
    9 / 81 (11.11%)
    11 / 82 (13.41%)
    11 / 81 (13.58%)
    10 / 82 (12.20%)
         occurrences all number
    14
    11
    14
    17
    15
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 82 (4.88%)
    5 / 81 (6.17%)
    6 / 82 (7.32%)
    5 / 81 (6.17%)
    4 / 82 (4.88%)
         occurrences all number
    6
    7
    7
    5
    4
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 82 (4.88%)
    4 / 81 (4.94%)
    7 / 82 (8.54%)
    4 / 81 (4.94%)
    3 / 82 (3.66%)
         occurrences all number
    4
    6
    10
    6
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 81 (6.17%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    5 / 82 (6.10%)
         occurrences all number
    2
    5
    2
    1
    5
    Psychiatric disorders
    Anxiety
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 82 (2.44%)
    6 / 81 (7.41%)
    6 / 82 (7.32%)
    7 / 81 (8.64%)
    5 / 82 (6.10%)
         occurrences all number
    2
    6
    6
    8
    5
    Suicidal ideation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    7 / 82 (8.54%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
         occurrences all number
    0
    2
    8
    1
    0
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 81 (6.17%)
    11 / 82 (13.41%)
    9 / 81 (11.11%)
    9 / 82 (10.98%)
         occurrences all number
    5
    6
    11
    10
    11
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 82 (8.54%)
    4 / 81 (4.94%)
    6 / 82 (7.32%)
    5 / 81 (6.17%)
    2 / 82 (2.44%)
         occurrences all number
    8
    4
    7
    5
    2
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 81 (4.94%)
    3 / 82 (3.66%)
    6 / 81 (7.41%)
    5 / 82 (6.10%)
         occurrences all number
    3
    4
    3
    9
    6
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 82 (8.54%)
    14 / 81 (17.28%)
    12 / 82 (14.63%)
    13 / 81 (16.05%)
    15 / 82 (18.29%)
         occurrences all number
    8
    21
    16
    15
    23
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 82 (4.88%)
    3 / 81 (3.70%)
    6 / 82 (7.32%)
    4 / 81 (4.94%)
    5 / 82 (6.10%)
         occurrences all number
    4
    3
    6
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2013
    Amendment 1 to the protocol (dated 24 September 2013) was issued before any patients were enrolled in the study. The following major procedural changes (not all-inclusive) were made to the protocol: - The duration of treatment with study drug was increased from 12 weeks to 26 weeks - The 45 mg dose was removed from the efficacy analyses - The timing of the DSMB meetings was changed - The opportunity to enter the open-label extension study was introduced - Rules for discontinuation of treatment groups were modified
    03 Feb 2014
    Amendment 2 to the protocol (dated 03 February 2014) was issued before any patients were enrolled in the study. Clarification that the mPPT will be used as the secondary efficacy endpoint - Increased frequency of DSMB meetings until 100 patients (20 from each treatment group) have completed two weeks of treatment on full dose - Clarification that Patients with a legal guardian should be consented according to local requirements - The EQ-5D-5L scale was added as an assessment - The possibility for patients to continue in the study after study drug discontinuation, due to safety or tolerability reasons, was introduced - Clarification regarding the number of capsules in the dispensed bottles - Change to time points at which exploratory efficacy endpoints (PBA-s, CIBIC-Plus, PDS, CGI-C, Walk-12, and TUG test) are assessed to reduce patient burden
    16 Sep 2014
    Amendment 3 to the protocol (dated 16 September 2014) was issued after 24 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: - Extension of the period between screening and baseline visit to 12 weeks, to allow a switch in concomitant drugs if deemed medically justified and for the benefit of the patient by the investigator - Revised text to reflect that the investigator can unblind the treatment code in an emergency situation without prior approval of the sponsor - The ECG on Day 56 would be optional, unless required by local regulations - Clarification regarding the ECG at Week 2 (ie, that it will be performed in triplicate before the afternoon dose of that visit) - Prolonged QTcF deleted from baseline visit as an eligibility criterion. Prolonged QT at baseline will be handled according to the discontinuation rules specified in the protocol - Inclusion criterion was revised to read “IS equal to or less than 90% at the screening visit”, to include also patients with a IS of 90% - The protocol was updated to require that all serious adverse events be reported within 24 hours of when the investigator learns of the event, regardless of whether it’s a non-working day - Instructions on how to resume study drug after temporary interruption -Prohibited medications timing also changed from 6 weeks prior to screening to 6 weeks prior to baseline (eg, QT-interval prolonging meds, CYP2D6 metabolized meds, and tetrabenazine) - Rescreening of selected patients now permitted if not originally eligible for enrollment - Clarification regarding the time frame for suicide attempts prior to screening (ie, if the attempt or acts were performed within 1 year of screening) - New text regarding required reporting of suicidality as an adverse event
    12 Jan 2015
    Amendment 4 to the protocol (dated 12 January 2015) was issued after 133 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The study was extended from 26 to 52 weeks, to allow the assessment of pridopidine on TFC. A minimum of 52 weeks are needed for placebo to decline in TFC to allow a window to detect a potential therapeutic effect of a drug on this endpoint. In addition, the following major procedural changes (not all-inclusive) were made to the protocol: - endpoints modified and/or added to reflect the study extension - days of assessments and procedures modified to reflect changes in time points - clarification to allow only 1 titration during the entire study period - new text added to define the population sets that will be used to analyze the data from the second study period
    31 Mar 2016
    Amendment 5 to the protocol (dated 31 March 2016) was issued after 408 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. - Addition of 2 telephone calls for safety evaluation (at Weeks 40 to 44 and Weeks 46 to 51) including C-SSRS and an abbreviated PBA-s assessment - Addition of suicidal ideations and suicide attempts as protocol-defined adverse events for expedited reporting - Addition of discontinuation criteria for individual patients and stopping rules for treatment groups - Clarification of study conduct - Revision of the Study Procedures and Assessments and Overall Study Schema to reflect the amended study design

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33164941
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