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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120102 Administered Intrathecally in Patients with Huntington’s Disease

    Summary
    EudraCT number
    		 2016-005142-39
    Trial protocol
    		 GB   DK   FR   DE  
    Global end of trial date
    10 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Feb 2022
    First version publication date
    04 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WVE-HDSNP2-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03225846
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Wave Life Sciences UK Limited
    Sponsor organisation address
    1 Chamberlain Square CS, Birmingham, United Kingdom, B3 3AX
    Public contact
    Chief Medical Officer, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com
    Scientific contact
    Chief Medical Officer, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of WVE-120102 in patients with early manifest Huntington’s disease (HD).
    Protection of trial subjects
    The study was conducted according to the study protocol and standard operating procedures that meet the guidelines provided by the International Conference on Harmonisation for Good Clinical Practice in clinical studies and any other applicable local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    88
    EEA total number of subjects
    24
    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)
    86
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 1b/2a placebo-controlled study was conducted in adult patients with early manifest HD who carry a targeted single nucleotide polymorphism rs362331. Following completion of this study, eligible patients were enrolled in an open-label extension study (WVE-HDSNP2-002).

    Pre-assignment
    Screening details
    		 The study consists of prescreening period (at least 6 weeks), screening period ( up to 4 weeks), single-dose period (1 day) followed by multiple dose period (8 weeks), and follow-up period (14 weeks). A total of 88 patients received treatment in this study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pooled Placebo
    Arm description
    		 Placebo: 0.9% Sodium Chloride.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Placebo matching with WVE-120102 was administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (2 milligram [mg])
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure antisense oligonucleotide (ASO).
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 2 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (4 mg)
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure ASO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 4 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (8 mg)
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure ASO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 8 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (12 mg)
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure ASO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 12 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (16 mg)
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure ASO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 16 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Arm title
    		 WVE-120102 (32 mg)
    Arm description
    		 WVE-120102: WVE-120102 is a stereopure ASO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WVE-120102
    Investigational medicinal product code
    WVE-120102
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    WVE-120102 32 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

    Number of subjects in period 1
    		Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Started
    22
    9
    12
    15
    8
    9
    13
    Single Dose Period Only
    6 [1]
    3 [2]
    4 [3]
    7 [4]
    8
    0 [5]
    4 [6]
    Multiple Dose Period Only
    3 [7]
    0 [8]
    3 [9]
    6 [10]
    0 [11]
    0 [12]
    4 [13]
    Single Dose and Multiple Dose Periods
    13 [14]
    6 [15]
    5 [16]
    2 [17]
    0 [18]
    9
    5 [19]
    Completed
    22
    7
    11
    15
    8
    9
    6
    Not completed
    0
    2
    1
    0
    0
    0
    7
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    -
    -
         Patient decision
    -
    -
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    -
    6
         Death
    -
    1
    -
    -
    -
    -
    -
         Patient did not wish to comply with eligibility
    -
    -
    1
    -
    -
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [13] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [14] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [15] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [16] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [17] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [18] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
    [19] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Placebo: 0.9% Sodium Chloride.

    Reporting group title
    WVE-120102 (2 milligram [mg])
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure antisense oligonucleotide (ASO).

    Reporting group title
    WVE-120102 (4 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (8 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (12 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (16 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (32 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg) Total
    Number of subjects
    		 22 9 12 15 8 9 13 88
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.8 ( 10.16 ) 52.4 ( 11.59 ) 46 ( 10.63 ) 49.3 ( 10.40 ) 47.1 ( 8.48 ) 53.1 ( 8.33 ) 54.1 ( 8.88 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 7 10 4 2 6 42
        Male
    		 14 4 5 5 4 7 7 46
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 0 0 0 0 1
        Not Hispanic or Latino
    		 21 9 12 15 8 9 13 87
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0 0
        White
    		 22 9 12 15 8 9 13 88
        More than one race
    		 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0
    Region of Enrollment
    Units: Subjects
        Australia
    		 2 0 0 0 0 0 7 9
        Canada
    		 9 8 2 1 0 6 0 26
        Denmark
    		 0 0 2 3 0 0 0 5
        France
    		 0 0 0 0 0 0 1 1
        Germany
    		 1 0 0 0 0 0 4 5
        Poland
    		 4 0 4 3 0 1 1 13
        United Kingdom
    		 0 0 1 1 0 2 0 4
        United States
    		 6 1 3 7 8 0 0 25
    Diagnosis stage
    Units: Subjects
        Stage 1
    		 9 5 6 8 1 5 11 45
        Stage 2
    		 13 4 6 7 7 4 2 43
    Time since initial diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 6.1 ( 5.95 ) 9.9 ( 8.80 ) 3.8 ( 3.62 ) 5.6 ( 2.80 ) 3.9 ( 3.23 ) 3.2 ( 5.61 ) 5.6 ( 9.28 ) -
    Age at disease onset
    Units: years
        arithmetic mean (standard deviation)
    		 40.18 ( 10.527 ) 42.00 ( 16.363 ) 41.75 ( 12.129 ) 43.33 ( 9.378 ) 42.50 ( 9.289 ) 49.00 ( 6.652 ) 48.08 ( 12.796 ) -

    End points

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    End points reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Placebo: 0.9% Sodium Chloride.

    Reporting group title
    WVE-120102 (2 milligram [mg])
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure antisense oligonucleotide (ASO).

    Reporting group title
    WVE-120102 (4 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (8 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (12 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (16 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (32 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Primary: Safety: Number of Patients With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Safety: Number of Patients With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    All TEAEs reported or observed during the study, including TEAEs resulting from concurrent illnesses, reactions to concurrent medications, or progression of disease states. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo. A summary of serious and all other non-serious adverse events (AEs), regardless of causality, is located in the reported AEs module.
    End point type
    Primary
    End point timeframe
    Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    22
    9
    12
    15
    8
    9
    13
    Units: patients
    20
    8
    9
    13
    4
    8
    13
    No statistical analyses for this end point

    Primary: Safety: Number of Patients With Severe TEAEs

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    End point title
    		 Safety: Number of Patients With Severe TEAEs [2]
    End point description
    Severity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo. A summary of serious and all other non serious AEs, regardless of causality, is located in the reported AEs module.
    End point type
    Primary
    End point timeframe
    Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    22
    9
    12
    15
    8
    9
    13
    Units: patients
    2
    1
    1
    2
    0
    2
    9
    No statistical analyses for this end point

    Primary: Safety: Number of Patients With Serious TEAEs

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    End point title
    		 Safety: Number of Patients With Serious TEAEs [3]
    End point description
    A serious TEAE is defined as any event that results in death, is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect not present at prescreening. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo. A summary of serious and all other non-serious AEs, regardless of causality, is located in the reported AEs module.
    End point type
    Primary
    End point timeframe
    Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    22
    9
    12
    15
    8
    9
    13
    Units: patients
    0
    1
    2
    2
    0
    0
    9
    No statistical analyses for this end point

    Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

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    End point title
    		 Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs [4]
    End point description
    Patients withdraw from the study when serious or intolerable AE that in the Investigator’s opinion was reported. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo. A summary of serious and all other non-serious AEs, regardless of causality, is located in the reported AEs module.
    End point type
    Primary
    End point timeframe
    Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    22
    9
    12
    15
    8
    9
    13
    Units: patients
    0
    0
    0
    0
    0
    0
    6
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

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    End point title
    		 Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) [5]
    End point description
    Cmax of WVE-120102 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or cerebrospinal fluid (CSF) WVE-120102 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only reporting groups in which patients received WVE-120102 were evaluated for this PK end point. All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this PK end point.
    End point values
    		 WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    9
    12
    15
    9
    11
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1 (n= 9, 9, 9, 9, 8)
    1.35 ( 2.714 )
    8.54 ( 6.073 )
    29.87 ( 31.891 )
    31.49 ( 15.801 )
    96.21 ( 57.394 )
        Day 112 (n= 6, 8 , 8, 9, 0)
    7.46 ( 15.411 )
    15.55 ( 14.587 )
    36.16 ( 30.012 )
    59.49 ( 35.718 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: PK: Time of Occurrence of Cmax (Tmax)

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    End point title
    		 PK: Time of Occurrence of Cmax (Tmax) [6]
    End point description
    Tmax of WVE-120102 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120102 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only reporting groups in which patients received WVE-120102 were evaluated for this PK end point. All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this PK end point.
    End point values
    		 WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    9
    12
    15
    9
    11
    Units: hour
    arithmetic mean (standard deviation)
        Day 1 (n= 9, 9, 9, 9, 8)
    3.33 ( 7.742 )
    1.26 ( 1.044 )
    1.77 ( 1.101 )
    1.77 ( 1.345 )
    3.09 ( 3.752 )
        Day 112 (n= 6, 8, 8, 9, 0)
    1.22 ( 0.314 )
    1.86 ( 0.874 )
    2.06 ( 1.206 )
    1.98 ( 0.828 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

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    End point title
    		 PK: Area Under the Plasma Concentration-time Curve (AUClast) [7]
    End point description
    AUClast from time 0 to the last quantifiable concentration of WVE-120102 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120102 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only reporting groups in which patients received WVE-120102 were evaluated for this PK end point. All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this PK end point.
    End point values
    		 WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    9
    12
    15
    9
    11
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n= 2, 7, 8, 8, 8)
    24.65 ( 9.108 )
    62.05 ( 67.358 )
    132.44 ( 91.913 )
    804.92 ( 1456.786 )
    919.14 ( 271.997 )
        Day 112 (n= 2, 7, 7, 9, 0)
    23.83 ( 23.187 )
    35.47 ( 22.280 )
    107.83 ( 70.198 )
    133.22 ( 67.683 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: PK: Terminal Elimination Rate Constant

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    End point title
    		 PK: Terminal Elimination Rate Constant [8]
    End point description
    Elimination rate of WVE-120102 from plasma (t1/2). The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120102 concentration measurement. Here, 9999 = standard deviation is not applicable with an n=1.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this end point.
    End point values
    		 WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    0 [9]
    2
    1
    5
    6
    Units: hour
        arithmetic mean (standard deviation)
    ( )
    33.42 ( 30.983 )
    6.23 ( 9999 )
    13.45 ( 4.604 )
    18.17 ( 20.969 )
    Notes
    [9] - No patients were analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pharmacodynamics (PD): Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

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    End point title
    		 Pharmacodynamics (PD): Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation [10]
    End point description
    Percent change from baseline in concentration of mHTT protein in CSF was determined. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and last observation (up to Day 140 [32 mg cohort] or Day 196 [all other cohorts])
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this PD end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    16
    6
    8
    8
    9
    8
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -2.64 (-14.89 to 11.71)
    3.46 (-7.67 to 7.80)
    -3.53 (-4.20 to 2.41)
    -3.45 (-6.46 to 7.35)
    -5.82 (-12.09 to 6.44)
    -2.06 (-28.72 to 7.84)
    No statistical analyses for this end point

    Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

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    End point title
    		 Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation [11]
    End point description
    Percent change from baseline in the TFC, administered as part of the Unified Huntington's Disease Rating Scale was determined. Safety population included all patients who received at least 1 dose of WVE-120102 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and last observation (up to Day 140 [32 mg cohort] or Day 196 [all other cohorts])
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients enrolled in reporting group "WVE-120102 (12 mg)" were treated only in single dose period. Therefore, no patients were evaluated for this end point.
    End point values
    		 Pooled Placebo WVE-120102 (2 milligram [mg]) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Number of subjects analysed
    16
    6
    8
    8
    9
    9
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    0.0 (0.00 to 0.00)
    0.0 (-2.00 to 0.00)
    0.0 (0.00 to 0.00)
    -4.17 (-13.89 to 0.00)
    -8.33 (-16.67 to 0.00)
    0.0 (0.00 to 0.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to end of study (Day 182 [32 mg cohort in all regions except Canada] or Day 196 [32 mg cohort in Canada] or Day 210 [all other cohorts]).
    Adverse event reporting additional description
    Safety population included all patients who received at least 1 dose of WVE-120102 or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    8.2
    Reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Placebo: 0.9% Sodium Chloride.

    Reporting group title
    WVE-120102 (2 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (4 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (8 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (12 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (16 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Reporting group title
    WVE-120102 (32 mg)
    Reporting group description
    		 WVE-120102: WVE-120102 is a stereopure ASO.

    Serious adverse events
    		 Pooled Placebo WVE-120102 (2 mg) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    9 / 13 (69.23%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Accident at work
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Subdural hematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    4 / 13 (30.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo CNS origin
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    4 / 13 (30.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pooled Placebo WVE-120102 (2 mg) WVE-120102 (4 mg) WVE-120102 (8 mg) WVE-120102 (12 mg) WVE-120102 (16 mg) WVE-120102 (32 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 22 (90.91%)
    8 / 9 (88.89%)
    9 / 12 (75.00%)
    13 / 15 (86.67%)
    4 / 8 (50.00%)
    8 / 9 (88.89%)
    13 / 13 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Varicose vein
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    5
    0
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    5
    Influenza like illness
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Choking
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Chronic throat clearing
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Pleural effusion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Psychiatric disorders
    Abnormal behavior
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Anger
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    4
    Apathy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Disorientation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Generalized anxiety disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    Irritability
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Mood swings
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Blood creatinine phosphokinase increased
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    CSF protein increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Complement factor C3 decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Complement factor C3 increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    White blood cells urine
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Chemical burn
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    0
    0
    Fall
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 9 (55.56%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    10
    0
    2
    1
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Post lumbar puncture syndrome
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    2 / 15 (13.33%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    4
    2
    1
    0
    1
    Post procedural complication
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    0
    Post procedural discomfort
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    2
    1
    0
    0
    0
    0
    Procedural Pain
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 9 (22.22%)
    3 / 12 (25.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    3 / 9 (33.33%)
    1 / 13 (7.69%)
         occurrences all number
    4
    4
    3
    1
    0
    3
    1
    Procedural headache
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 22 (0.00%)
    5 / 9 (55.56%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    0
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Ataxia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Cerebellar ataxia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Chorea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 9 (22.22%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    3 / 9 (33.33%)
    2 / 13 (15.38%)
         occurrences all number
    5
    5
    1
    0
    0
    3
    5
    Dizziness postural
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    8 / 22 (36.36%)
    3 / 9 (33.33%)
    3 / 12 (25.00%)
    3 / 15 (20.00%)
    0 / 8 (0.00%)
    6 / 9 (66.67%)
    5 / 13 (38.46%)
         occurrences all number
    14
    9
    3
    9
    0
    22
    6
    Hyperaesthesia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    0
    Hyporeflexia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    0
    Loss of proprioception
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    7
    0
    0
    0
    1
    0
    Presyncope
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    1
    0
    0
    1
    0
    0
    Reflexes abnormal
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Speech disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Tension headache
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Hyperacusis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    1
    2
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    2 / 13 (15.38%)
         occurrences all number
    3
    2
    0
    0
    0
    3
    2
    Paraesthesia oral
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    8
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Athralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    5 / 9 (55.56%)
    2 / 13 (15.38%)
         occurrences all number
    4
    1
    0
    1
    0
    12
    2
    Muscle spasms
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    6
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Eye infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 9 (33.33%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 9 (22.22%)
    4 / 12 (33.33%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    6
    1
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2018
    • Implemented edits made in United Kingdom versions 0.1 and 0.2, and made minor clarifications and corrections in alignment with United States version 0.3. • Utilized global language wherever possible in the objectives/endpoints to account for the fact that some regions were doing a single ascending dose (SAD)/multiple ascending dose study while other were doing only an SAD study. • Allowed patients to enter directly into the multiple-dose portion of the study. A separate schedule of assessments was added for these patients. • Objective criteria for individual stopping criteria added in the multiple-dose phase per regulatory feedback. • Extended the washout required for other investigational agents to a minimum of 1 year.
    17 Sep 2019
    • Added the 32 mg cohort to the study. • Changed the washout period after a single-dose to 4 weeks (instead of 8 weeks) based on available nonclinical and clinical data to date. A new schedule of assessments specific to the 32 mg cohort was added to account for this.

    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.
    Based on the efficacy findings in this study at the time of the interim analysis, the Sponsor decided to terminate the study as the benefit-risk analysis did not warrant continued dose escalation.
    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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