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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of MYK-491 in Patients With Stable Heart Failure With Reduced Ejection Fraction

    Summary
    EudraCT number
    		 2018-002239-11
    Trial protocol
    		 DE   GB   SE   NL   PL  
    Global end of trial date
    24 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2022
    First version publication date
    26 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MYK-491-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    03 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to establish preliminary safety and tolerability of single-and multiple-ascending oral doses of Danicamtiv in ambulatory patient
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 42
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    52
    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)
    39
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 52 participants randomized and treated

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SAD Cohort 1
    Arm description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 175mg and Danicamtiv 350mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days. Some participants received a fourth single dose of Danicamtiv ranging between 350mg-550mg in the optional open-label period D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    175mg single-dose

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    350mg single-dose

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo single-dose

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    450mg single-dose divided to 2 administrations

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    525mg single-dose

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    550mg single-dose divided to 2 administrations

    Arm title
    		 SAD Cohort 2
    Arm description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 400mg and Danicamtiv 500mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg single-dose

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg single-dose

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo single-dose

    Arm title
    		 MAD Cohort 1
    Arm description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (fasting) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75mg (fasting) BID for 7 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo BID for 2 days

    Arm title
    		 MAD Cohort 2
    Arm description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo BID for 2 days

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg (with food) BID for 7 days

    Arm title
    		 MAD Cohort 3
    Arm description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75mg (with food) BID for 7 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo BID for 2 days

    Arm title
    		 MAD Cohort 4
    Arm description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danicamtiv
    Investigational medicinal product code
    MYK-491
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg (with food) BID for 7 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo BID for 2 days

    Arm title
    		 MAD Placebo
    Arm description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.
    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 BID for 9 days

    Number of subjects in period 1
    		SAD Cohort 1 SAD Cohort 2 MAD Cohort 1 MAD Cohort 2 MAD Cohort 3 MAD Cohort 4 MAD Placebo
    Started
    8
    4
    6
    9
    9
    6
    10
    Completed Treatment Period A
    8
    4
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    Completed Treatment Period B
    8
    4
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Completed Treatment Period C
    8
    4
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    Completed Treatment Period D
    6 [16]
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    Completed
    8
    4
    6
    9
    9
    6
    9
    Not completed
    0
    0
    0
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [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: This is for the number of participants completed treatment in period D only
    [20] - 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: This is for the number of participants completed treatment in period D only
    [21] - 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: This is for the number of participants completed treatment in period D only
    [22] - 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: This is for the number of participants completed treatment in period D only

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAD Cohort 1
    Reporting group description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 175mg and Danicamtiv 350mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days. Some participants received a fourth single dose of Danicamtiv ranging between 350mg-550mg in the optional open-label period D

    Reporting group title
    SAD Cohort 2
    Reporting group description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 400mg and Danicamtiv 500mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days

    Reporting group title
    MAD Cohort 1
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (fasting) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 2
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 3
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 4
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group values
    		 SAD Cohort 1 SAD Cohort 2 MAD Cohort 1 MAD Cohort 2 MAD Cohort 3 MAD Cohort 4 MAD Placebo Total
    Number of subjects
    		 8 4 6 9 9 6 10 52
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ( 9.4 ) 57.5 ( 5.07 ) 62.7 ( 12.50 ) 63.0 ( 9.86 ) 56.8 ( 5.09 ) 58.5 ( 5.36 ) 58.6 ( 6.98 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 1 3 3 2 1 1 14
        Male
    		 5 3 3 6 7 5 9 38
    Race (NIH/OMB)
    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
    		 6 1 3 1 2 0 3 16
        White
    		 2 3 3 8 7 6 7 36
        More than one race
    		 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 0 1 1
        Not Hispanic or Latino
    		 8 4 6 9 9 6 9 51
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    SAD Cohort 1
    Reporting group description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 175mg and Danicamtiv 350mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days. Some participants received a fourth single dose of Danicamtiv ranging between 350mg-550mg in the optional open-label period D

    Reporting group title
    SAD Cohort 2
    Reporting group description
    		 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 400mg and Danicamtiv 500mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days

    Reporting group title
    MAD Cohort 1
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (fasting) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 2
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 3
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Cohort 4
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Reporting group title
    MAD Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 175mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Danicamtiv 175mg in either period A, B, or C

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 350mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Danicamtiv 350mg in either period A, B, C, or D

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 350mg Period D
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Danicamtiv 350mg in period D

    Subject analysis set title
    SAD Cohort 1 Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Placebo in either period A, B, or C

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 450mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received split dose of Danicamtiv 450mg in period D

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 525mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Danicamtiv 525mg in period D

    Subject analysis set title
    SAD Cohort 1 Danicamtiv 550mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received split dose of Danicamtiv 550mg in period D

    Subject analysis set title
    SAD Cohort 2 Danicamtiv 400mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received split dose of Danicamtiv 400mg

    Subject analysis set title
    SAD Cohort 2 Danicamtiv 500mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received split dose of Danicamtiv 500mg

    Subject analysis set title
    SAD Cohort 2 Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single dose of Placebo

    Subject analysis set title
    MAD Cohort 2 Danicamtiv 50mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Subject analysis set title
    MAD Cohort 1+3 Danicamtiv 75mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Subject analysis set title
    MAD Cohort 4 Danicamtiv 100mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Subject analysis set title
    MAD Cohorts Danicamtiv
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MAD cohorts at doses ranging from 50 mg to 100 mg

    Subject analysis set title
    MAD Cohort Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Subject analysis set title
    SAD Cohorts Danicamtiv
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    SAD cohorts at doses ranging from 175 mg to 550 mg

    Subject analysis set title
    SAD Cohorts Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    SAD cohorts with participants that received placebo

    Subject analysis set title
    SAD Cohorts
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    SAD cohorts Placebo and Danicamtiv at doses ranging from 175 mg to 550 mg

    Subject analysis set title
    MAD Cohorts
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MAD cohorts Placebo and Danicamtiv doses ranging from 50 mg to 100 mg

    Subject analysis set title
    SAD Cohorts <2000 ng/mL
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    SAD Cohorts with plasma concentration less than 2000 ng/mL

    Subject analysis set title
    SAD Cohorts ≥2000 ng/mL
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    SAD Cohorts with plasma concentration greater than or equal to 2000 ng/mL

    Subject analysis set title
    MAD Cohorts <2000 ng/mL
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MAD Cohorts with plasma concentration less than 2000 ng/mL

    Subject analysis set title
    MAD Cohorts 2000-<3500 ng/mL
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MAD Cohorts with plasma concentration between 2000 (inclusive) to 3500 (non-inclusive) ng/mL

    Subject analysis set title
    MAD Cohorts ≥3500 ng/mL
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MAD Cohorts with plasma concentration greater than or equal to 3500 ng/mL

    Primary: Number of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (Up to 2 months)
    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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg MAD Cohort Placebo
    Number of subjects analysed
    8
    8
    8
    1
    2
    2
    4
    4
    4
    9
    15
    6
    10
    Units: Participants
        TEAEs
    2
    5
    3
    0
    0
    1
    3
    0
    0
    7
    6
    4
    4
        SAEs
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Change from Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts

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    End point title
    		 Number of Participants with Change from Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts [2]
    End point description
    Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to the corresponding period.
    End point type
    Primary
    End point timeframe
    Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
    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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo
    Number of subjects analysed
    8
    8
    8
    1
    2
    2
    4
    4
    4
    Units: Participants
        Change in QTcF from Baseline > 30msec
    1
    1
    0
    0
    0
    0
    1
    1
    2
        Change in QTcF from Baseline > 60msec
    0
    0
    0
    0
    0
    0
    0
    0
    1
        Change in PR from baseline > 25%
    1
    0
    0
    0
    0
    0
    0
    0
    0
        Change in QRS from baseline > 25%
    1
    1
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Change from Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts

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    End point title
    		 Number of Participants with Change from Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts [3]
    End point description
    Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to first randomized dose.
    End point type
    Primary
    End point timeframe
    Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose
    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 summary statistics planned for this endpoint
    End point values
    		 MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg MAD Cohort Placebo
    Number of subjects analysed
    9
    15
    6
    10
    Units: Participants
        Change in QTcF from Baseline > 30msec
    2
    5
    1
    3
        Change in QTcF from Baseline > 60msec
    0
    0
    1
    1
        Change in PR from baseline > 25%
    0
    0
    0
    1
        Change in QRS from baseline > 25%
    1
    2
    0
    2
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Vital Signs Part 1 - MAD Cohorts

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    End point title
    		 Mean Change from Baseline in Vital Signs Part 1 - MAD Cohorts [4]
    End point description
    Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
    End point type
    Primary
    End point timeframe
    Baseline and at 6-hours post-dose
    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 summary statistics planned for this endpoint
    End point values
    		 MAD Cohorts Danicamtiv MAD Cohort Placebo
    Number of subjects analysed
    7
    3
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine SBP
    -4.86 ( 7.537 )
    -6.33 ( 3.215 )
        Supine DBP
    -3.57 ( 7.323 )
    -5.67 ( 3.055 )
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Vital Signs Part 2 - MAD Cohorts

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    End point title
    		 Mean Change from Baseline in Vital Signs Part 2 - MAD Cohorts [5]
    End point description
    Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
    End point type
    Primary
    End point timeframe
    Baseline and at 6-hours post-dose
    Notes
    [5] - 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 summary statistics planned for this endpoint
    End point values
    		 MAD Cohorts Danicamtiv MAD Cohort Placebo
    Number of subjects analysed
    7
    3
    Units: Beats/min
        arithmetic mean (standard deviation)
    3.71 ( 2.563 )
    3.33 ( 2.517 )
    No statistical analyses for this end point

    Primary: Number of Participants with a Troponin I Increase - SAD cohorts

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    End point title
    		 Number of Participants with a Troponin I Increase - SAD cohorts [6]
    End point description
    Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing >2×ULN for the specific assay (>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase >0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
    End point type
    Primary
    End point timeframe
    Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
    Notes
    [6] - 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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohorts Danicamtiv SAD Cohorts Placebo
    Number of subjects analysed
    12
    12
    Units: Participants
    3
    0
    No statistical analyses for this end point

    Primary: Number of Participants with a Troponin I Increase - MAD cohorts

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    End point title
    		 Number of Participants with a Troponin I Increase - MAD cohorts [7]
    End point description
    Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing >2×ULN for the specific assay (>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase >0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
    End point type
    Primary
    End point timeframe
    Baseline, pre-dose and 7hr post dose on treatment day 1, day 2, day 5 and pre-dose and at 7-, 24-, and 48-hours post final dose
    Notes
    [7] - 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 summary statistics planned for this endpoint
    End point values
    		 MAD Cohorts Danicamtiv MAD Cohort Placebo
    Number of subjects analysed
    30
    10
    Units: Participants
    7
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Laboratory Abnormalities [8]
    End point description
    Number of participants with clinically significant laboratory abnormalities.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (Up to 2 months)
    Notes
    [8] - 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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohorts MAD Cohorts
    Number of subjects analysed
    12
    40
    Units: Participants
    1
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Clinically Significant Physical Examinations Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Physical Examinations Abnormalities [9]
    End point description
    Number of participants with clinically significant physical examinations abnormalities. No clinically significant abnormal findings were observed.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (Up to 2 months)
    Notes
    [9] - 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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohorts MAD Cohorts
    Number of subjects analysed
    12
    40
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Vital Signs Part 1 - SAD Cohorts

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    End point title
    		 Mean Change from Baseline in Vital Signs Part 1 - SAD Cohorts [10]
    End point description
    Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period. 99999=Not available
    End point type
    Primary
    End point timeframe
    Baseline and at 6-hours post-dose
    Notes
    [10] - 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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo
    Number of subjects analysed
    8
    8
    8
    1
    2
    2
    4
    4
    4
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine SBP
    -10.13 ( 12.23 )
    -11.38 ( 9.90 )
    -1.38 ( 15.02 )
    16.00 ( 99999 )
    -7.00 ( 19.80 )
    -9.50 ( 2.12 )
    2.50 ( 4.359 )
    01.75 ( 15.650 )
    0.00 ( 11.633 )
        Supine DBP
    -5.50 ( 12.14 )
    9.50 ( 6.44 )
    -5.75 ( 13.04 )
    12.00 ( 99999 )
    -1.00 ( 5.66 )
    -4.00 ( 8.49 )
    4.00 ( 9.933 )
    -2.25 ( 17.270 )
    -3.00 ( 14.674 )
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Vital Signs Part 2 - SAD Cohorts

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    End point title
    		 Mean Change from Baseline in Vital Signs Part 2 - SAD Cohorts [11]
    End point description
    Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period. 99999=Not available
    End point type
    Primary
    End point timeframe
    Baseline and at 6-hours post-dose
    Notes
    [11] - 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 summary statistics planned for this endpoint
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo
    Number of subjects analysed
    8
    8
    8
    1
    2
    2
    4
    4
    4
    Units: Beats/min
        arithmetic mean (standard deviation)
    7.13 ( 6.20 )
    -1.25 ( 5.75 )
    3.00 ( 5.50 )
    5.00 ( 99999 )
    5.50 ( 0.71 )
    -1.50 ( 2.12 )
    3.75 ( 9.743 )
    -0.50 ( 5.000 )
    -6.50 ( 13.699 )
    No statistical analyses for this end point

    Secondary: Danicamtiv Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Danicamtiv Maximum Observed Plasma Concentration (Cmax)
    End point description
    Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. 99999=Not available
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Danicamtiv 350mg Period D SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    8
    1
    1
    2
    2
    4
    4
    8
    15
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1476.63 ( 99999 )
    2655.83 ( 99999 )
    3590.00 ( 99999 )
    4420.00 ( 99999 )
    2718.51 ( 99999 )
    5263.71 ( 99999 )
    5337.58 ( 99999 )
    5740.50 ( 99999 )
    792.5 ( 99999 )
    1174.3 ( 99999 )
    1452.8 ( 99999 )
    No statistical analyses for this end point

    Secondary: Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)

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    End point title
    		 Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)
    End point description
    Time of maximum observed plasma concentration (Tmax) for Danicamtiv.
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Danicamtiv 350mg Period D SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    8
    1
    1
    2
    2
    4
    4
    8
    15
    6
    Units: hours
        median (full range (min-max))
    5.14 (2.0 to 6.3)
    6.18 (3.7 to 9.1)
    4.1 (4.1 to 4.1)
    12.0 (12.0 to 12.0)
    5.74 (5.4 to 6.1)
    8.93 (7.9 to 9.9)
    9.13 (6.0 to 12.2)
    9.08 (6.0 to 10.0)
    4.983 (3.00 to 9.00)
    4.000 (1.00 to 12.05)
    3.500 (2.03 to 9.00)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve (AUC)

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUC)
    End point description
    Area under the plasma concentration-time curve (AUC) for Danicamtiv including the following time points: (AUC(0-12))=from time 0 to 12 hours; (AUC(0-24))=from time 0 to 24 hours; (AUC(0-48))=from time 0 to 48 hours; (AUClast)=from time 0 up to the last measurable concentration; (AUC(0-∞))=from time 0 to infinity. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. 99999=Not available
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Danicamtiv 350mg Period D SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    8
    1
    1
    2
    2
    4
    4
    8
    15
    6
    Units: hr x ng/mL
    geometric mean (geometric coefficient of variation)
        (AUC(0-12))
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 999999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    7169.245 ( 99999 )
    10310.794 ( 99999 )
    12728.956 ( 99999 )
        (AUC(0-24))
    26411.97 ( 99999 )
    48981.93 ( 99999 )
    70138.66 ( 99999 )
    79175.02 ( 99999 )
    54004.82 ( 99999 )
    97640.90 ( 99999 )
    86110.51 ( 99999 )
    97656.38 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        (AUC(0-48))
    40068.47 ( 99999 )
    76497.78 ( 99999 )
    89356.54 ( 99999 )
    143543.52 ( 99999 )
    89341.77 ( 99999 )
    159193.47 ( 99999 )
    135385.91 ( 99999 )
    161073.09 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        (AUC last)
    46750.66 ( 99999 )
    89216.40 ( 99999 )
    104060.46 ( 99999 )
    182804.71 ( 99999 )
    106987.30 ( 99999 )
    188544.49 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        (AUC(0-∞))
    52467.20 ( 99999 )
    99576.37 ( 99999 )
    99999 ( 99999 )
    234888.37 ( 99999 )
    126374.56 ( 99999 )
    211928.81 ( 99999 )
    187776.56 ( 99999 )
    225087.02 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Apparent First-order Terminal Elimination Half-life (t1/2)

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    End point title
    		 Apparent First-order Terminal Elimination Half-life (t1/2)
    End point description
    Apparent first-order terminal elimination half-life (t1/2). 99999=Not available
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Danicamtiv 350mg Period D SAD Cohort 1 Danicamtiv 450mg SAD Cohort 1 Danicamtiv 525mg SAD Cohort 1 Danicamtiv 550mg SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    8
    0 [12]
    1
    2
    2
    4
    4
    8
    13
    6
    Units: hours
        arithmetic mean (standard deviation)
    21.96 ( 4.40 )
    20.95 ( 3.23 )
    ( )
    30.62 ( 99999 )
    24.73 ( 10.76 )
    21.45 ( 0.30 )
    24.45 ( 11.363 )
    24.30 ( 13.987 )
    24.466 ( 5.8911 )
    20.573 ( 6.1033 )
    23.319 ( 3.5903 )
    Notes
    [12] - 0 participants analyzed
    No statistical analyses for this end point

    Secondary: Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts

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    End point title
    		 Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts
    End point description
    Accumulation ratio for maximum observed plasma concentration AR(Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. 99999=Not available
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    14
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3.451 ( 99999 )
    3.241 ( 99999 )
    3.827 ( 99999 )
    No statistical analyses for this end point

    Secondary: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve from Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts

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    End point title
    		 Accumulation Ratio for Area Under the Plasma Concentration-Time Curve from Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts
    End point description
    Accumulation ratio for area under the plasma concentration-time curve from time 0 to 12 hours AR(AUC(0-12)) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. 99999=Not available
    End point type
    Secondary
    End point timeframe
    1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
    End point values
    		 MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1+3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg
    Number of subjects analysed
    8
    14
    6
    Units: hr x ng/mL
        geometric mean (geometric coefficient of variation)
    3.983 ( 99999 )
    3.696 ( 99999 )
    4.607 ( 99999 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts
    End point description
    Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose and at 3, 6, 9, and 24 hours post dose
    End point values
    		 SAD Cohorts <2000 ng/mL SAD Cohorts ≥2000 ng/mL
    Number of subjects analysed
    7
    12
    Units: msec
        arithmetic mean (standard error)
    8.04 ( 10.03 )
    36.3 ( 8.2 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts
    End point description
    Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose and at 3, 6, 9, and 24 hours post dose
    End point values
    		 SAD Cohorts <2000 ng/mL SAD Cohorts ≥2000 ng/mL
    Number of subjects analysed
    7
    12
    Units: mL
        arithmetic mean (standard error)
    1.01 ( 3.67 )
    9.01 ( 2.99 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts
    End point description
    Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose and at 3, 6, 9, and 24 hours post dose
    End point values
    		 SAD Cohorts <2000 ng/mL SAD Cohorts ≥2000 ng/mL
    Number of subjects analysed
    7
    12
    Units: Percentage of blood pumped from LV
    arithmetic mean (standard error)
        LVEF
    4.06 ( 2.27 )
    4.44 ( 1.86 )
        LVFS
    3.14 ( 1.36 )
    2.81 ( 1.12 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts
    End point description
    Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
    End point values
    		 MAD Cohorts <2000 ng/mL MAD Cohorts 2000-<3500 ng/mL MAD Cohorts ≥3500 ng/mL
    Number of subjects analysed
    30
    26
    13
    Units: msec
        arithmetic mean (standard error)
    15.1 ( 3.51 )
    35.6 ( 3.78 )
    48.3 ( 4.68 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts
    End point description
    Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
    End point values
    		 MAD Cohorts <2000 ng/mL MAD Cohorts 2000-<3500 ng/mL MAD Cohorts ≥3500 ng/mL
    Number of subjects analysed
    30
    26
    13
    Units: mL
        arithmetic mean (standard error)
    3.126 ( 1.8348 )
    7.843 ( 1.9511 )
    5.685 ( 2.4988 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts

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    End point title
    		 Mean Change from Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts
    End point description
    Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
    End point values
    		 MAD Cohorts <2000 ng/mL MAD Cohorts 2000-<3500 ng/mL MAD Cohorts ≥3500 ng/mL
    Number of subjects analysed
    30
    26
    13
    Units: Percentage of blood pumped from LV
    arithmetic mean (standard error)
        LVEF
    -0.25 ( 0.872 )
    1.12 ( 0.928 )
    2.29 ( 1.158 )
        LVFS
    0.46 ( 0.537 )
    0.78 ( 0.574 )
    0.51 ( 0.725 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events were monitored from first dose to 30 days post last dose (Up to 2 months). Participants were assessed for All-cause mortality from their date of randomization to study completion (Up to approximately 20 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    SAD Cohort 1 Danicamtiv 175mg
    Reporting group description
    		 Participants received single dose of Danicamtiv 175mg in either period A, B, or C

    Reporting group title
    SAD Cohort 1 Danicamtiv 350mg
    Reporting group description
    		 Participants received single dose of Danicamtiv 350mg in either period A, B, C, or D

    Reporting group title
    SAD Cohort 1 Placebo
    Reporting group description
    		 Participants received single dose of Placebo in either period A, B, or C

    Reporting group title
    SAD Cohort 1 Danicamtiv Optional Period D
    Reporting group description
    		 Participants received Danicamtiv at either 450mg, 525mg or 550mg in period D

    Reporting group title
    SAD Cohort 2 Danicamtiv 400mg
    Reporting group description
    		 Participants received split dose of Danicamtiv 400mg

    Reporting group title
    SAD Cohort 2 Danicamtiv 500mg
    Reporting group description
    		 Participants received split dose of Danicamtiv 500mg

    Reporting group title
    SAD Cohort 2 Placebo
    Reporting group description
    		 Participants received single dose of Placebo

    Reporting group title
    MAD Cohort 1 Danicamtiv 75mg
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 2 Danicamtiv 50mg
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 1 Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 2 Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 3 Danicamtiv 75mg
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 4 Danicamtiv 100mg
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 3 Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Reporting group title
    MAD Cohort 4 Placebo
    Reporting group description
    		 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge

    Serious adverse events
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv Optional Period D SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo MAD Cohort 1 Danicamtiv 75mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1 Placebo MAD Cohort 2 Placebo MAD Cohort 3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg MAD Cohort 3 Placebo MAD Cohort 4 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    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
    		 SAD Cohort 1 Danicamtiv 175mg SAD Cohort 1 Danicamtiv 350mg SAD Cohort 1 Placebo SAD Cohort 1 Danicamtiv Optional Period D SAD Cohort 2 Danicamtiv 400mg SAD Cohort 2 Danicamtiv 500mg SAD Cohort 2 Placebo MAD Cohort 1 Danicamtiv 75mg MAD Cohort 2 Danicamtiv 50mg MAD Cohort 1 Placebo MAD Cohort 2 Placebo MAD Cohort 3 Danicamtiv 75mg MAD Cohort 4 Danicamtiv 100mg MAD Cohort 3 Placebo MAD Cohort 4 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 8 (62.50%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    3 / 4 (75.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    7 / 9 (77.78%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    4 / 9 (44.44%)
    4 / 6 (66.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Application site erosion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Application site irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Application site rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Infusion site discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Infusion site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Dry throat
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Troponin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Cardiac discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    2
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Gingival pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Oral contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 9 (22.22%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    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
    12 Feb 2018
    Update inclusion/exclusion criteria and study design
    11 Jul 2018
    Update inclusion/exclusion criteria and study design
    14 Dec 2018
    Update exclusion/inclusion criteria and clarify study design
    19 Mar 2019
    Update inclusion criteria

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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