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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Arm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in Patients with Early Stage of Huntington Disease

    Summary
    EudraCT number
    		 2020-002822-10
    Trial protocol
    		 DE   AT   FR   CZ   NL   IT  
    Global end of trial date
    21 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2024
    First version publication date
    30 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PL101-HD301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04556656
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prilenia Therapeutics B.V.
    Sponsor organisation address
    Gooimeer 2, DC Naarden, Netherlands, 1411
    Public contact
    Prilenia medical information, Prilenia Therapeutics B.V., medinfo@prilenia.com
    Scientific contact
    Prilenia medical information, Prilenia Therapeutics B.V., medinfo@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
    Interim
    Date of interim/final analysis
    25 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of pridopidine on functional capacity in participants with stage 1-2 HD. Note: The primary and key secondary endpoints showed no beneficial effect of pridopidine compared to placebo in the full study population. Importantly, however, this population consisted of both patients on ADMs and patients off ADMs. Concomitant use of these drugs may have masked or interfered with clinically meaningful effects of pridopidine. Indeed, in the group of patients who did not use ADMs at any point in the study, pridopidine demonstrated robust benefits over placebo. The observed benefit are considered clinically meaningful.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and according to the ethical principles derived from the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), and applicable laws and regulations. Participants were informed that their participation is voluntary. Participants were required to sign a statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study center. During the double-blind treatment period of the Main Study, an independent, unblinded Safety Monitoring Committee assessed the safety and if requested efficacy.
    Background therapy
    		 For allowed antipsychotic, antidepressant, antiarrhythmic, or other medication, the dosing had to be stable for at least 4 weeks before the baseline visit (Amiodarone was not allowed within 6 weeks of baseline visit) and had to be kept constant during the study. Prohibited medication included medications that prolong QT interval such as non-allowed antipsychotic medications, tricyclic antidepressants, and/or Class I antiarrhythmics, use of pridopidine within 12 months before the baseline visit, gene therapy at any time, and prior participation in studies with tominersen at any time.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    16 Oct 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United States: 201
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Italy: 58
    Worldwide total number of subjects
    499
    EEA total number of subjects
    254
    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)
    420
    From 65 to 84 years
    78
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 480 participants were planned to be enrolled (240 per arm) at approximately 60 sites in North America and Europe. A total of 499 patients with Huntington Disease were randomized and received at least one dose of study treatment.

    Pre-assignment
    Screening details
    		 Screening period of up to 6 weeks.

    Period 1
    Period 1 title
    Main Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    All participants, site staff, Sponsor, contract research organization (CRO) and vendors involved with the study remained blinded to treatment assignments until the database was locked and the study unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pridopidine 45 mg bid
    Arm description
    		 During the titration period, all participants self-administered 1 capsule of study drug orally (PO), once daily, in the morning for 2 weeks. Thereafter, the study drug was taken PO, bid in the morning and in the afternoon (7-10 hours apart).
    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
    Administered orally at a dose of 45 mg bid

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

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

    Number of subjects in period 1
    		Pridopidine 45 mg bid Placebo
    Started
    250
    249
    Completed
    222
    227
    Not completed
    28
    22
         Consent withdrawn by subject
    14
    12
         Physician decision
    1
    -
         Adverse event, non-fatal
    4
    7
         Death
    4
    -
         Other
    2
    1
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 During the titration period, all participants self-administered 1 capsule of study drug orally (PO), once daily, in the morning for 2 weeks. Thereafter, the study drug was taken PO, bid in the morning and in the afternoon (7-10 hours apart).

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Pridopidine 45 mg bid Placebo Total
    Number of subjects
    		 250 249 499
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 207 213 420
        From 65-84 years
    		 42 36 78
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ( 11.93 ) 52.7 ( 11.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 132 127 259
        Male
    		 118 122 240
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all randomized participants. Treatment was assigned based on the treatment to which participants were randomized. The ITT population was the main analysis population of the primary endpoint for EMA region.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent to treat (mITT) population was a subset of the ITT population and included all participants in the ITT population who received at least one dose of study drug and had valid in-clinic TFC scores both at baseline and at least one post-baseline timepoint. The mITT population was analyzed according to the treatment to which the participant was randomized. The mITT population was the main analysis population for the primary endpoint in non-EMA regions. For all other efficacy analyses, the mITT population was the main analysis population in both EMA and non-EMA regions.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (SP) included all randomized participants who received at least one dose of study drug. Treatment was assigned based upon the treatment participants actually received.

    Subject analysis sets values
    		 ITT mITT Safety
    Number of subjects
    499
    490
    499
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    420
    414
    420
        From 65-84 years
    78
    75
    78
        85 years and over
    1
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.5 ( 11.66 )
    52.5 ( 11.63 )
    52.5 ( 11.66 )
    Gender categorical
    Units: Subjects
        Female
    259
    256
    259
        Male
    240
    234
    240

    End points

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    End points reporting groups
    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 During the titration period, all participants self-administered 1 capsule of study drug orally (PO), once daily, in the morning for 2 weeks. Thereafter, the study drug was taken PO, bid in the morning and in the afternoon (7-10 hours apart).

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all randomized participants. Treatment was assigned based on the treatment to which participants were randomized. The ITT population was the main analysis population of the primary endpoint for EMA region.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent to treat (mITT) population was a subset of the ITT population and included all participants in the ITT population who received at least one dose of study drug and had valid in-clinic TFC scores both at baseline and at least one post-baseline timepoint. The mITT population was analyzed according to the treatment to which the participant was randomized. The mITT population was the main analysis population for the primary endpoint in non-EMA regions. For all other efficacy analyses, the mITT population was the main analysis population in both EMA and non-EMA regions.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (SP) included all randomized participants who received at least one dose of study drug. Treatment was assigned based upon the treatment participants actually received.

    Primary: Change from baseline to Week 65 in the Unified Huntington Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) score (ITT)

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    End point title
    		 Change from baseline to Week 65 in the Unified Huntington Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) score (ITT)
    End point description
    The primary efficacy endpoint for this study was the change from baseline to Week 65 in the TFC (defined as the sum of all TFC 5-items ratings [domestic chores, activities of daily living, finances, care level, and occupation]). The TFC is the standard and well-accepted clinical scale for staging and tracking the progression of HD using functional capacity. Scores range from 0 to 13, with 13 as the least affected and 0 as complete incapacity. In Europe, the ITT set was used for the primary endpoint analysis.
    End point type
    Primary
    End point timeframe
    From baseline to Week 65
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    250
    249
    Units: Score on a scale
        least squares mean (standard error)
    -1.17 ( 0.120 )
    -0.94 ( 0.120 )
    Statistical analysis title
    		 Mixed model for repeated measures (MMRM)
    Statistical analysis description
    In the MMRM, change from baseline in TFC score is the dependent variable, and independent variables include treatment arm, baseline TFC, region, neuroleptic use or no use, baseline HD stage (HD1 and HD2), categorical week, and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. The unstructured covariance matrix is used for repeated measurements at patient level.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1598
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.162

    Primary: Change from baseline to Week 65 in the UHDRS TFC score (mITT)

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    End point title
    		 Change from baseline to Week 65 in the UHDRS TFC score (mITT)
    End point description
    The primary efficacy endpoint for this study was the change from baseline to Week 65 in the TFC (defined as the sum of all TFC 5-items ratings [domestic chores, activities of daily living, finances, care level, and occupation]). The TFC is the standard and well-accepted clinical scale for staging and tracking the progression of HD using functional capacity. Scores range from 0 to 13, with 13 as the least affected and 0 as complete incapacity. In non-EMA regions, the mITT set was used for the primary endpoint analysis.
    End point type
    Primary
    End point timeframe
    From baseline to Week 65.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    243
    247
    Units: Score on a scale
        least squares mean (standard error)
    -1.18 ( 0.119 )
    -0.95 ( 0.119 )
    Statistical analysis title
    		 Mxed model for repeated measures (MMRM)
    Statistical analysis description
    In the MMRM, change in TFC score from baseline was the dependent variable, and independent variables included treatment arm, baseline TFC, region, neuroleptic use or no use, baseline HD stage (HD1 and HD2), categorical week, and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.167
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.162

    Secondary: Change from baseline to Week 65 in composite UHDRS (cUHDRS) total score (mITT)

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    End point title
    		 Change from baseline to Week 65 in composite UHDRS (cUHDRS) total score (mITT)
    End point description
    The composite Unified Huntington Disease Rating Scale (cUHDRS) is a composite measure of motor (Total Motor Score [TMS]), cognitive (Stroop Word Reading [SWR] and Symbol Digit Modalities Test [SDMT]), and global functional decline (Total Functional Capacity [TFC]).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 65.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    243
    247
    Units: Score on a scale
        least squares mean (standard error)
    -0.99 ( 0.109 )
    -0.88 ( 0.108 )
    Statistical analysis title
    		 Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM, change in cUHDRS score from baseline was the dependent variable, while independent variables included treatment arm, baseline cUHDRS, region, neuroleptic use or no use, baseline HD stage (HD1 and HD2), categorical week, and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. The unstructured covariance matrix was used for repeated measurements at patient level. No imputation was performed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4544
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.148

    Other pre-specified: Change from baseline in cUHDRS total score - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in cUHDRS total score - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Time course from baseline to Week 78
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: Score on a scale
    least squares mean (standard error)
        Week 26
    0.15 ( 0.114 )
    -0.31 ( 0.108 )
        Week 39
    0.10 ( 0.130 )
    -0.34 ( 0.125 )
        Week 52
    -0.07 ( 0.140 )
    -0.48 ( 0.135 )
        Week 65
    -0.26 ( 0.143 )
    -0.53 ( 0.137 )
        Week 78
    -0.40 ( 0.159 )
    -0.54 ( 0.158 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM model, change in cUHDRS score from baseline was the dependent variable and independent variables included treatment group, baseline cUHDRS, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, concomitant use of select medications and Treatment x Concomitant use of select medications, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.156
    Notes
    [1] - P-value for Week 26.
    Statistical analysis title
    		 Week 39 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0135 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.179
    Notes
    [2] - P-value for Week 39.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0351 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.193
    Notes
    [3] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1683 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.197
    Notes
    [4] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5315 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.223
    Notes
    [5] - P-value for Week 78.

    Other pre-specified: Change from baseline in Q-Motor Finger Tapping Inter-Onset Interval (IOI) Mean - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in Q-Motor Finger Tapping Inter-Onset Interval (IOI) Mean - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes. Note that negative changes represent improvements.
    End point type
    Other pre-specified
    End point timeframe
    Time course from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: milliseconds
    least squares mean (standard error)
        Week 26
    -14.85 ( 6.846 )
    6.30 ( 6.449 )
        Week 52
    -2.37 ( 7.135 )
    11.95 ( 6.792 )
        Week 65
    -0.79 ( 7.365 )
    23.93 ( 7.028 )
        Week 78
    1.46 ( 7.444 )
    24.36 ( 7.230 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In thMMRM model, change in Q-Motor Finger Tapping IOI Mean from baseline was the dependent variable and independent variables included treatment group, baseline Q-Motor Finger Tapping IOI Mean, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, concomitant use of select medications and Treatment x Concomitant use of select medications, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0253 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -21.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.66
         upper limit
    		 -2.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.406
    Notes
    [6] - P-value for Week 26.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1474 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.71
         upper limit
    		 5.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.853
    Notes
    [7] - P-value for Week 52
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0159 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.76
         upper limit
    		 -4.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.185
    Notes
    [8] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0283 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.34
         upper limit
    		 -2.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.38
    Notes
    [9] - P-value for Week 78.

    Other pre-specified: Change from baseline in Q-Motor Pronation/Supination Inter-Tap Interval Mean - Patients Off ADMs (mITT)

    		 Close Top of page
    End point title
    		 Change from baseline in Q-Motor Pronation/Supination Inter-Tap Interval Mean - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Time course from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: milliseconds
    least squares mean (standard error)
        Week 26
    -17.63 ( 8.029 )
    20.43 ( 7.448 )
        Week 52
    -0.15 ( 9.124 )
    20.07 ( 8.555 )
        Week 65
    4.64 ( 8.380 )
    28.55 ( 7.867 )
        Week 78
    12.73 ( 9.740 )
    34.97 ( 9.412 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM model, change in Q-Motor Pronation/Supination ITI Mean from baseline was the dependent variable and independent variables included treatment group, baseline Q-Motor Pronation/Supination ITI Mean, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -38.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.74
         upper limit
    		 -16.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.999
    Notes
    [10] - P-value at Week 26.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1087 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.95
         upper limit
    		 4.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.547
    Notes
    [11] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0395 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -23.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.68
         upper limit
    		 -1.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.541
    Notes
    [12] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1038 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.08
         upper limit
    		 4.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.587
    Notes
    [13] - P-value for Week 78.

    Other pre-specified: Change from baseline in Q-Motor Pronation/Supination IOI Mean - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in Q-Motor Pronation/Supination IOI Mean - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Time course from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: milliseconds
    least squares mean (standard error)
        Week 26
    -16.70 ( 9.399 )
    13.68 ( 8.829 )
        Week 52
    7.40 ( 10.978 )
    24.23 ( 10.467 )
        Week 65
    7.34 ( 10.730 )
    30.13 ( 10.232 )
        Week 78
    19.21 ( 12.702 )
    41.93 ( 12.435 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In MMRM model, change in Q-Motor Pronation/Supination IOI Mean from baseline was the dependent variable and independent variables included treatment group, baseline Q-Motor Pronation/Supination IOI Mean, region, categorical week, baseline HD stage (HD1 and HD2), treatment by categorical week interaction, concomitant use of select medications and Treatment x Concomitant use of select medications, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0193 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -30.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.78
         upper limit
    		 -4.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.902
    Notes
    [14] - P-value for Week 26.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.268 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.69
         upper limit
    		 13.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.17
    Notes
    [15] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1255 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.97
         upper limit
    		 6.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.829
    Notes
    [16] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2024 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.72
         upper limit
    		 12.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.777
    Notes
    [17] - P-value for Week 78.

    Other pre-specified: Change from baseline in the UHDRS TFC score - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in the UHDRS TFC score - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Timecourse from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: Score on a scale
    least squares mean (standard error)
        Week 26
    -0.01 ( 0.131 )
    -0.23 ( 0.124 )
        Week 39
    -0.11 ( 0.137 )
    -0.31 ( 0.131 )
        Week 52
    -0.19 ( 0.149 )
    -0.45 ( 0.143 )
        Week 65
    -0.49 ( 0.156 )
    -0.54 ( 0.150 )
        Week 78
    -0.42 ( 0.166 )
    -0.54 ( 0.163 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM model, change in UHDRS-TFC score from baseline was the dependent variable and independent variables included treatment group, baseline UHDRS-TFC, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, concomitant use of select medications and Treatment x Concomitant use of select medications, with Kenward-Roger approximation for degrees of freedom. No imputation wasperformed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2088 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.179
    Notes
    [18] - P-value for Week 26.
    Statistical analysis title
    		 Week 39 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2991 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.188
    Notes
    [19] - P-value for Week 39.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2116 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.205
    Notes
    [20] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8242 [21]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.215
    Notes
    [21] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5918 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.231
    Notes
    [22] - P-value for Week 78.

    Other pre-specified: Change from baseline in Stroop Word Reading (SWR) - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in Stroop Word Reading (SWR) - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Timecourse from baseline to Week 78
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: Score on a scale
    least squares mean (standard error)
        Week 26
    2.34 ( 0.964 )
    -0.82 ( 0.916 )
        Week 39
    2.85 ( 1.100 )
    -0.04 ( 1.051 )
        Week 52
    2.73 ( 1.078 )
    -0.32 ( 1.039 )
        Week 65
    1.39 ( 1.243 )
    -0.94 ( 1.193 )
        Week 78
    0.91 ( 1.261 )
    -1.08 ( 1.249 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In MMRM model, change in SWR score from baseline was the dependent variable and independent variables included treatment group, baseline SWR, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, concomitant use of select medications and Treatment x Concomitant use of select medications, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0178 [23]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 5.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.326
    Notes
    [23] - P-value for Week 26.
    Statistical analysis title
    		 Week 39 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0576 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 5.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.518
    Notes
    [24] - P-value for Week 39.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0418 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 5.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.493
    Notes
    [25] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1775 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 5.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.719
    Notes
    [26] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2627 [27]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 5.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.772
    Notes
    [27] - P-value for Week 78.

    Other pre-specified: Change from baseline in Symbol Digit Modalities Test (SDMT) - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in Symbol Digit Modalities Test (SDMT) - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Timecourse from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: Score on a scale
    least squares mean (standard error)
        Week 26
    0.54 ( 0.521 )
    -0.47 ( 0.484 )
        Week 39
    0.82 ( 0.512 )
    -0.06 ( 0.478 )
        Week 52
    -0.42 ( 0.578 )
    -0.33 ( 0.543 )
        Week 65
    0.35 ( 0.616 )
    0.07 ( 0.576 )
        Week 78
    0.07 ( 0.617 )
    -0.36 ( 0.598 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM model, change in SDMT score from baseline was the dependent variable and independent variables included treatment group, baseline SDMT, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1586 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.712
    Notes
    [28] - P-value for Week 26.
    Statistical analysis title
    		 Week 39 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2144 [29]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 2.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.701
    Notes
    [29] - P-value for Week 39.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9119 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 1.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.793
    Notes
    [30] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7339 [31]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.38
         upper limit
    		 1.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.844
    Notes
    [31] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6213 [32]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 2.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.859
    Notes
    [32] - P-vlaue for Week 78.

    Other pre-specified: Change from baseline in Total Motor Score (TMS) - Patients Off ADMs (mITT)

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    End point title
    		 Change from baseline in Total Motor Score (TMS) - Patients Off ADMs (mITT)
    End point description
    In addition to the main efficacy analyses, sensitivity analyses were performed in a sub-group of patients who were off neuroleptics AND off vesicular monoamine transporter-2 (VMAT2) inhibitors (together called antidopaminergics, or ADMs) at any time during the study. In this population (“off ADMs”), pridopidine demonstrated robust benefits, with consistent and clinically meaningful effect sizes.
    End point type
    Other pre-specified
    End point timeframe
    Timecourse from baseline to Week 78.
    End point values
    		 Pridopidine 45 mg bid Placebo
    Number of subjects analysed
    97
    112
    Units: Score on a scale
    least squares mean (standard error)
        Week 26
    -0.21 ( 0.568 )
    -0.03 ( 0.530 )
        Week 39
    0.06 ( 0.780 )
    0.96 ( 0.729 )
        Week 52
    0.47 ( 0.766 )
    0.80 ( 0.720 )
        Week 65
    0.92 ( 0.847 )
    1.28 ( 0.790 )
        Week 78
    2.19 ( 0.954 )
    1.63 ( 0.916 )
    Statistical analysis title
    		 Week 26 - Mixed Model for Repeated Measures (MMRM)
    Statistical analysis description
    In the MMRM model, change in TMS score from baseline was the dependent variable and independent variables included treatment group, baseline TMS, region, categorical week, baseline HD stage (HD1 and HD2), and treatment by categorical week interaction, with Kenward-Roger approximation for degrees of freedom. No imputation was performed on missing data.
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8205 [33]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 1.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.777
    Notes
    [33] - P-value for Week 26.
    Statistical analysis title
    		 Week 39 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4028 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.067
    Notes
    [34] - P-value for Week 39.
    Statistical analysis title
    		 Week 52 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7577 [35]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 1.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.051
    Notes
    [35] - P-value for Week 52.
    Statistical analysis title
    		 Week 65 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Pridopidine 45 mg bid v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7605 [36]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 1.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.158
    Notes
    [36] - P-value for Week 65.
    Statistical analysis title
    		 Week 78 - Mixed Model for Repeated Measures (MMRM)
    Comparison groups
    Placebo v Pridopidine 45 mg bid
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6694 [37]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.05
         upper limit
    		 3.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.323
    Notes
    [37] - P-value for Week 78.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening until 2 weeks after End of Study/End of Treatment visit (unless a patient continued in the open-label extension part of the study).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Pridopidine 45 mg bid
    Reporting group description
    		 During the titration period, all participants self-administered 1 capsule of study drug orally (PO), once daily, in the morning for 2 weeks. Thereafter, the study drug was taken PO, bid in the morning and in the afternoon (7-10 hours apart).

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Pridopidine 45 mg bid Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 250 (13.60%)
    21 / 249 (8.43%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    3
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    2 / 250 (0.80%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 250 (0.40%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 250 (1.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 250 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accident
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Head injury
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal cord injury cervical
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 250 (0.00%)
    3 / 249 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 250 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chorea
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pridopidine 45 mg bid Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    204 / 250 (81.60%)
    212 / 249 (85.14%)
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 250 (5.20%)
    7 / 249 (2.81%)
         occurrences all number
    13
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    55 / 250 (22.00%)
    57 / 249 (22.89%)
         occurrences all number
    114
    111
    Contusion
         subjects affected / exposed
    12 / 250 (4.80%)
    14 / 249 (5.62%)
         occurrences all number
    20
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 250 (6.40%)
    25 / 249 (10.04%)
         occurrences all number
    18
    34
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 250 (8.40%)
    22 / 249 (8.84%)
         occurrences all number
    27
    32
    Psychiatric disorders
    Depression
         subjects affected / exposed
    26 / 250 (10.40%)
    12 / 249 (4.82%)
         occurrences all number
    27
    12
    Anxiety
         subjects affected / exposed
    19 / 250 (7.60%)
    16 / 249 (6.43%)
         occurrences all number
    22
    20
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 250 (4.80%)
    14 / 249 (5.62%)
         occurrences all number
    13
    16
    Infections and infestations
    COVID-19
         subjects affected / exposed
    59 / 250 (23.60%)
    57 / 249 (22.89%)
         occurrences all number
    62
    66
    Nasopharyngitis
         subjects affected / exposed
    19 / 250 (7.60%)
    18 / 249 (7.23%)
         occurrences all number
    22
    20
    Urinary tract infection
         subjects affected / exposed
    11 / 250 (4.40%)
    17 / 249 (6.83%)
         occurrences all number
    12
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2020
    Updated secondary and exploratory endpoints, clarified OLE duration, removed blood draws for coagulation test.
    29 Sep 2020
    Updated exclusion criteria, specified OLE duration, updated frequencies of assessments, added exploratory endpoints.
    25 Oct 2020
    Added text for handling of intercurrent events, added that separate analyses of the primary endpoint would be performed for EMA and Non EMA regions
    13 May 2021
    Added objectives and endpoints for OLE, updated inclusion and exclusion criteria, expanded post Week 4 (V3) in-clinic visit windows, updated permitted medications.
    27 Jan 2022
    Added Q-Motor to efficacy endpoints, updated assessments and visits during OLE, clarified virtual phone visits vs in-clinic visits.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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