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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
    GB   DE   IT   NL   AT   PL   DK  
    Global end of trial date
    07 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Mar 2018
    First version publication date
    09 Mar 2018
    Other versions

    Trial information

    Close Top of page
    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
    Teva Branded Pharmaceutical Products R&D, Inc
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Global Head Clinical Development, Neurodegenerative Diseases, Teva Branded Pharmaceuticals Products R&D, Inc., 001 215-591-3000, info.era-clinical@teva.de
    Scientific contact
    Global Head Clinical Development, Neurodegenerative Diseases, Teva Branded Pharmaceuticals Products R&D, Inc., 001 215-591-3000, info.era-clinical@teva.de
    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
    08 Aug 2017
    Is this the analysis of the primary completion data?
    No
    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 67.5 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).
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union (EU) Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    7 Years
    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 for enrollment; 408 patients at 53 centers in Australia, Austria, Canada, Denmark, France, Germany, Italy, the Netherlands, Poland, Russia, the United Kingdom, and the US met entry criteria

    Period 1
    Period 1 title
    Treatment Period #1 (Week 26)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Randomization was performed by IRT using dynamic randomization to balance the treatment groups within centers and neuroleptics use or no use. Patients were randomly and equally assigned to the 5 treatment groups of the study (4 active treatment groups and placebo, allocation ratio of 1:1:1:1:1). All of the roles listed were blinded until the database was locked for analysis after the first 26-week study period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm 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 26 in Period 1.
    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
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Arm title
    Pridopidine 45 mg bid
    Arm 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 26 (Period 1).
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 67.5 mg bid
    Arm 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 26 (Period 1).
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 90 mg bid
    Arm 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 26 (Period 1).
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 112.5 mg bid
    Arm 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 26 (Period 1).
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    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
         Protocol deviation
    1
    1
    1
    1
    -
         Lack of efficacy
    -
    -
    1
    -
    -
         Non-compliance
    2
    1
    1
    -
    -
         Not specified
    1
    5
    -
    2
    3
         Adverse event, non-fatal
    5
    6
    11
    11
    14
         Consent withdrawn by subject
    3
    9
    3
    -
    3
    Period 2
    Period 2 title
    Treatment Period #2 (Week 52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    After the data base was cleaned and locked for the analysis of the first 26-week study period and treatment assignment were revealed, select sponsor personnel had access to treatment assignments. The sponsor study core team were only exposed to data summaries by treatments. Investigators, the patient, and any other personnel involved in patients’ assessment, monitoring, analysis and data management were blinded to patient assignment until the database was locked for analysis of week 52 data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm 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 assigned to the Placebo arm were supplied only placebo capsules which were taken from Day 1 to week 26 in Period 1, and then continued to week 52 in Period 2.
    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
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Arm title
    Pridopidine 45 mg bid
    Arm 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 26 (Period 1) and then continued to week 52 in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 67.5 mg bid
    Arm 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 26 (Period 1), and continued to Week 52 in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 90 mg bid
    Arm 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 26 (Period 1) and continued up to Week 52 in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    Arm title
    Pridopidine 112.5 mg bid
    Arm 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 26 (Period 1), continuing up to Week 52 in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as white, hard gelatin capsules matching the 22.5 mg or 45 mg pridopidine capsules but containing no active ingredient.

    Investigational medicinal product name
    pridopidine
    Investigational medicinal product code
    Other name
    pridopidine hydrochloride, TV-7820
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pridopidine was presented as white, hard gelatin capsules of 22.5 mg or 45 mg.

    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
         Lack of efficacy
    1
    -
    -
    1
    1
         Non-compliance
    1
    -
    -
    -
    -
         Adverse event, serious fatal
    -
    -
    -
    1
    1
         Not specified
    -
    1
    -
    1
    -
         Adverse event, non-fatal
    1
    4
    5
    -
    -
         Did not receive study drug
    -
    -
    2
    -
    -
         Consent withdrawn by subject
    2
    1
    2
    -
    -
         Sponsor decision
    -
    -
    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: Sixty-one participants completed treatment period 1 but did not continue into treatment period 2. These patients were lost due to prolonged IRB review periods at certain sites.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group 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 26 in Period 1.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group 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 26 (Period 1).

    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
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    71 73 76 76 75 371
        Hispanic or Latino
    3 3 3 0 2 11
        Unknown
    0 0 0 1 0 1
        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
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    72.7 ± 1.36 69.5 ± 1.55 69.9 ± 12.76 70.5 ± 11.83 70.7 ± 14.60 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    171.2 ± 9.77 170.5 ± 9.70 168.9 ± 9.77 169.8 ± 10.03 170.5 ± 9.22 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    24.9 ± 4.38 23.8 ± 3.78 24.5 ± 3.93 24.4 ± 3.63 24.2 ± 3.89 -
    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
    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 26 in Period 1.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group 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 26 (Period 1).

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group 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 26 (Period 1).
    Reporting group title
    Placebo
    Reporting group 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 assigned to the Placebo arm were supplied only placebo capsules which were taken from Day 1 to week 26 in Period 1, and then continued to week 52 in Period 2.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group 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 26 (Period 1) and then continued to week 52 in Period 2.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group 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 26 (Period 1), and continued to Week 52 in Period 2.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group 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 26 (Period 1) and continued up to Week 52 in Period 2.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group 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 26 (Period 1), continuing up to Week 52 in Period 2.

    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 Total Motor Score (TMS) at Week 26

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    End point title
    Change from Baseline in Total Motor Score (TMS) at Week 26
    End point description
    TMS was defined as the sum of all Unified Huntington's Disease Rating Scale (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 0-60. Negative change from baseline values indicate improvement. 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. Baseline was the last observation prior to the first dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0), Weeks 4, 8, 12, 16, 20, and 26 (or endpoint for the first treatment period)
    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 - those who received >= 1 dose of study drug and >=1 post-baseline efficacy.
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    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
    Pridopidine 45 mg bid v Placebo
    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: Pridopdine 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: Pridopdine 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: Pridopdine 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: Change from Baseline in Modified Physical Performance Test (mPPT) at Week 26

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    End point title
    Change from Baseline in Modified Physical Performance Test (mPPT) at Week 26
    End point description
    mPPT includes 9 physical challenges, each scored on a 0-4 scale with 0 = unable to perform and 4 = performed well for a total score of 0-36. Positive change from baseline scores indicate improvement. The change from baseline in mPPT 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 mPPT score, and categorical week in study by baseline mPPT interaction.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0), Weeks 4, 8, 12, 16, 20, and 26 (or endpoint for the first treatment period)
    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
    78 [6]
    75 [7]
    75 [8]
    80 [9]
    81 [10]
    Units: units on a scale
        least squares mean (standard error)
    0.71 ± 0.41
    0.75 ± 0.42
    0.64 ± 0.41
    0.70 ± 0.40
    1.00 ± 0.40
    Notes
    [6] - FAS
    [7] - FAS
    [8] - FAS
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    mPPT: Pridopidine 45 mg - Placebo
    Statistical analysis description
    The change from baseline in mPPT 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 mPPT score, and categorical week in study by baseline mPPT interaction.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9462
    Method
    Mixed models analysis
    Parameter type
    LSM difference
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.09
         upper limit
    1.17
    Statistical analysis title
    mPPT: Pridopidine 67.5 mg - Placebo
    Statistical analysis description
    The change from baseline in mPPT 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 mPPT score, and categorical week in study by baseline mPPT interaction.
    Comparison groups
    Pridopidine 67.5 mg bid v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8968
    Method
    Mixed models analysis
    Parameter type
    LSM difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    1.05
    Statistical analysis title
    mPPT: Pridopidine 90 mg - Placebo
    Statistical analysis description
    The change from baseline in mPPT 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 mPPT score, and categorical week in study by baseline mPPT interaction.
    Comparison groups
    Pridopidine 90 mg bid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9853
    Method
    Mixed models analysis
    Parameter type
    LSM difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    1.1
    Statistical analysis title
    mPPT: Pridopidine 112.5 mg - Placebo
    Statistical analysis description
    The change from baseline in mPPT 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 mPPT score, and categorical week in study by baseline mPPT interaction.
    Comparison groups
    Pridopidine 112.5 mg bid v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6063
    Method
    Mixed models analysis
    Parameter type
    LSM difference
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    1.4

    Secondary: Participants with Adverse Events

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    End point title
    Participants with Adverse Events
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    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 [11]
    81 [12]
    82 [13]
    81 [14]
    82 [15]
    Units: participants
        All AEs
    62
    63
    69
    71
    67
        AEs leading to discontinuation
    6
    10
    16
    12
    15
        Serious AEs
    0
    8
    9
    9
    9
        Severe AEs
    5
    7
    10
    12
    11
        AEs assessed as related to study drug
    27
    26
    40
    38
    36
    Notes
    [11] - Safety
    [12] - Safety
    [13] - Safety
    [14] - Safety
    [15] - Safety
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 52
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group 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.

    Reporting group title
    Pridopidine 45 mg bid
    Reporting group 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.

    Reporting group title
    Pridopidine 67.5 mg bid
    Reporting group 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.

    Reporting group title
    Pridopidine 90 mg bid
    Reporting group 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.

    Reporting group title
    Pridopidine 112.5 mg bid
    Reporting group 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.

    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
    Injury, poisoning and procedural complications
    Laceration
         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
         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
         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
         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
         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
         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
         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
         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
         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
    Investigations
    Blood creatine phosphokinase increased
         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
         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
         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
         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
         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
         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
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         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
         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
    Nervous system disorders
    Grand mal convulsion
         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
         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
         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
         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
         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
    Psychiatric disorders
    Mood disorder due to a general medical condition
         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
         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
         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
         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
         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
    Gastrointestinal disorders
    Duodenal ulcer perforation
         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
         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
         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
         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
         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
         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
         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
         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
         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
    Renal and urinary disorders
    Urinary retention
         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
         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
         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
         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
         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%)
    Vascular disorders
    Hypertension
         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
    Injury, poisoning and procedural complications
    Fall
         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
         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
    Investigations
    Weight decreased
         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
         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
    Respiratory, thoracic and mediastinal disorders
    Cough
         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
    Nervous system disorders
    Headache
         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
         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
         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
         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
         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
    Psychiatric disorders
    Anxiety
         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
         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
         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
         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
    Gastrointestinal disorders
    Diarrhoea
         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
         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
         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
    Musculoskeletal and connective tissue disorders
    Back pain
         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
         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
         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

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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 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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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