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    Clinical Trial Results:
    A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults with Symptomatic Hypertrophic Cardiomyopathy

    Summary
    EudraCT number
    		 2019-002785-12
    Trial protocol
    		 ES   GB   NL   IT  
    Global end of trial date
    28 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2024
    First version publication date
    31 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CY 6021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04219826
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cytokinetics, Inc.
    Sponsor organisation address
    350 Oyster Point Blvd, South San Francisco, United States, CA 94080
    Public contact
    Medical Affairs, Cytokinetics Inc, +1 8336332986, medicalaffairs@cytokinetics.com
    Scientific contact
    Medical Affairs, Cytokinetics Inc, +1 8336332986, medicalaffairs@cytokinetics.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
    28 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to determine the safety and tolerability of aficamten in participants with symptomatic hypertrophic cardiomyopathy (HCM).
    Protection of trial subjects
    This study was conducted in accordance with the protocol, consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation guidelines for Good Clinical Practices, and all applicable laws and regulations.
    Background therapy
    		 Cohorts 1 and 2: participants with symptomatic obstructive HCM (oHCM) continued taking background medications. Cohort 3: participants with symptomatic oHCM were receiving disopyramide as a background therapy in addition to beta-blockers and/or calcium channel blockers. Cohort 4: participants with symptomatic non-obstructive HCM (nHCM) continued taking standard of care background medications. Disopyramide as background therapy was excluded in Cohorts 1, 2, and 4.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2020
    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
    Spain: 6
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    96
    EEA total number of subjects
    9
    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)
    65
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 96 participants were enrolled at 19 study centers in Italy, Spain, and the United States between January 2020 and February 2023. One participant in the placebo group was discontinued from the study prior to receiving treatment and is represented within the pre-assignment period.

    Pre-assignment
    Screening details
    		 All participants had a 4-week screening period, after which, eligible participants were randomized to once daily aficamten or matching placebo in a 2:1 ratio for Cohorts 1 and 2 or given once daily aficamten in Cohorts 3 and 4.

    Pre-assignment period milestones
    Number of subjects started
    		 96
    Number of subjects completed
    		 95

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 1
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Aficamten (oHCM)
    Arm description
    		 Participants with symptomatic obstructive HCM (oHCM) receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aficamten
    Investigational medicinal product code
    CK-3773274
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aficamten tablets administered orally.

    Arm title
    		 Cohort 1: Placebo (oHCM)
    Arm description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets administered orally.

    Arm title
    		 Cohort 2: Aficamten (oHCM)
    Arm description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aficamten
    Investigational medicinal product code
    CK-3773274
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aficamten tablets administered orally.

    Arm title
    		 Cohort 2: Placebo (oHCM)
    Arm description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets administered orally.

    Arm title
    		 Cohort 3: Aficamten and Background Disopyramide (oHCM)
    Arm description
    		 Participants with symptomatic oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg) based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aficamten
    Investigational medicinal product code
    CK-3773274
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aficamten tablets administered orally.

    Arm title
    		 Cohort 4: Aficamten (nHCM)
    Arm description
    		 Participants with symptomatic nHCM whose standard of care background therapy included beta-blockers and/or calcium channel blockers. Participants receiving disopyramide were excluded from Cohort 4. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg), titrated based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aficamten
    Investigational medicinal product code
    CK-3773274
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aficamten tablets administered orally.

    Number of subjects in period 1 [1]
    		Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM)
    Started
    14
    7
    14
    6
    13
    41
    Completed
    14
    6
    14
    6
    13
    39
    Not completed
    0
    1
    0
    0
    0
    2
         Death
    -
    -
    -
    -
    -
    1
         Withdrawal by participant
    -
    -
    -
    -
    -
    1
         Protocol deviation
    -
    1
    -
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One participant in the placebo group was discontinued from the study prior to receiving treatment due to a protocol deviation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic obstructive HCM (oHCM) receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 1: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 3: Aficamten and Background Disopyramide (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg) based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 4: Aficamten (nHCM)
    Reporting group description
    		 Participants with symptomatic nHCM whose standard of care background therapy included beta-blockers and/or calcium channel blockers. Participants receiving disopyramide were excluded from Cohort 4. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg), titrated based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group values
    		 Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM) Total
    Number of subjects
    		 14 7 14 6 13 41 95
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.3 ± 13.69 61.4 ± 6.40 58.9 ± 13.65 52.3 ± 10.78 59.4 ± 14.43 55.9 ± 15.76 -
    Gender categorical
    Units: Subjects
        Female
    		 4 6 11 2 7 24 54
        Male
    		 10 1 3 4 6 17 41
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 1 1
        Asian
    		 0 0 0 0 1 2 3
        Black or African American
    		 0 0 0 1 1 8 10
        White
    		 14 7 14 5 11 27 78
        Other
    		 0 0 0 0 0 3 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 1 2 3
        Not Hispanic or Latino
    		 14 7 14 6 12 39 92

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic obstructive HCM (oHCM) receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 1: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 3: Aficamten and Background Disopyramide (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg) based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 4: Aficamten (nHCM)
    Reporting group description
    		 Participants with symptomatic nHCM whose standard of care background therapy included beta-blockers and/or calcium channel blockers. Participants receiving disopyramide were excluded from Cohort 4. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg), titrated based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Primary: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE) [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. The AE did not necessarily have a causal relationship with the study treatment. A serious AE was defined as an AE that met at least one of the following regulatory criteria: • fatal • immediately life-threatening • requires hospitalization or prolongation of existing hospitalization • results in persistent disability/incapacity • congenital anomaly/birth defect • other medically important serious event. TEAEs were defined as the AEs which were not present prior to the first dose of study treatment and start thereafter, or were present prior to the first dose of study treatment and increased in severity, frequency, or outcome thereafter. Only TEAEs and treatment-emergent serious AEs (TESAEs) are summarized. Safety Analysis Set: included all participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 14 weeks
    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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM)
    Number of subjects analysed
    14
    7
    14
    6
    13
    41
    Units: participants
        ≥ 1 TEAE
    10
    7
    11
    4
    9
    28
        ≥ 1 TESAE
    1
    1
    1
    0
    0
    4
    No statistical analyses for this end point

    Primary: Number of Participants who Experienced Left Ventricular Ejection Fraction (LVEF) < 50%

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    End point title
    		 Number of Participants who Experienced Left Ventricular Ejection Fraction (LVEF) < 50% [2]
    End point description
    LVEF < 50% was assessed per core laboratory assessment of echocardiography. Safety Analysis Set: included all participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 12 weeks
    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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM)
    Number of subjects analysed
    14
    7
    14
    6
    13
    41
    Units: participants
    0
    0
    2
    0
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 14 weeks
    Adverse event reporting additional description
    Safety Analysis Set: included all participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 1: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 1: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Aficamten (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 2: Placebo (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM receiving background therapy (not including disopyramide) were randomized 2:1 to active or matching placebo treatment and received up to 3 escalating doses of aficamten (10, 20, and 30 mg) or matching placebo based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 3: Aficamten and Background Disopyramide (oHCM)
    Reporting group description
    		 Participants with symptomatic oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg) based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Reporting group title
    Cohort 4: Aficamten (nHCM)
    Reporting group description
    		 Participants with symptomatic nHCM whose standard of care background therapy included beta-blockers and/or calcium channel blockers. Participants receiving disopyramide were excluded from Cohort 4. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg), titrated based on echocardiographic guidance. Treatment duration was 10 weeks with a 4-week follow-up period after the last dose.

    Serious adverse events
    		 Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    4 / 41 (9.76%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Atrial fibrillation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    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
    Cardiac arrest
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    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 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Myasthenia gravis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Cohort 1: Aficamten (oHCM) Cohort 1: Placebo (oHCM) Cohort 2: Aficamten (oHCM) Cohort 2: Placebo (oHCM) Cohort 3: Aficamten and Background Disopyramide (oHCM) Cohort 4: Aficamten (nHCM)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 14 (71.43%)
    7 / 7 (100.00%)
    11 / 14 (78.57%)
    4 / 6 (66.67%)
    9 / 13 (69.23%)
    26 / 41 (63.41%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    7 / 41 (17.07%)
         occurrences all number
    1
    1
    0
    0
    1
    9
    Chest discomfort
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Complication associated with device
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    2 / 41 (4.88%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
    2 / 41 (4.88%)
         occurrences all number
    1
    0
    2
    0
    2
    2
    Nasal congestion
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pleurisy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Orthopnoea
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pulmonary mass
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Electrocardiogram PR prolongation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Scratch
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    Tachycardia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Angina pectoris
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Bradycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 7 (42.86%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
    1 / 41 (2.44%)
         occurrences all number
    3
    4
    0
    1
    2
    1
    Dizziness
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    3
    2
    3
    0
    0
    4
    Paraesthesia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    1
    0
    0
    0
    2
    Bowel movement irregularity
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
    3 / 41 (7.32%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 41 (2.44%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Defaecation urgency
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bursitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Joint swelling
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pertussis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    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
    09 Aug 2019
    Exclusion criteria revised to disallow use of disopyramide and other antiarrhythmic drugs.
    13 Jul 2020
    Requirements for screening echocardiograms and dose titration/withdrawal for scheduled and unscheduled visits clarified, exclusion criteria regarding CYP2D6 removed, and option for re-testing laboratory assessments during screening added.
    17 Feb 2021
    Study design updated for addition of Cohort 3.
    09 Nov 2021
    Study design updated for addition of Cohort 4.

    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
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    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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