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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Effect of Omecamtiv Mecarbil on Exercise Capacity in Subjects with Heart Failure with Reduced Ejection Fraction and Decreased Exercise Tolerance

    Summary
    EudraCT number
    		 2018-001233-40
    Trial protocol
    		 FR   DE   HU   PL   NL   IT  
    Global end of trial date
    06 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jan 2023
    First version publication date
    21 Jan 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CY1031
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03759392
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cytokinetics, Inc.
    Sponsor organisation address
    350 Oyster Point Blvd, South San Francisco, United States, 94080
    Public contact
    Medical Affairs, Cytokinetics Inc., +1 650 624 2929, medicalaffairs@cytokinetics.com
    Scientific contact
    Medical Affairs, Cytokinetics Inc., +1 650 624 2929, 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
    31 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on exercise capacity as determined by CPET following 20 weeks of treatment with omecamtiv mecarbil or placebo
    Protection of trial subjects
    The protocol and consent form were submitted by each investigator to an institutional review board (IRB), an ethics committee (EC), or a research ethics board (REB) for review and approval before study initiation. All amendments to the protocol or revisions to the consent form (if applicable) after initial IRB/EC/REB approval were submitted by the investigator to the IRB/EC/REB for review and approval before implementation. This study was conducted in accordance with the United States Code of Federal Regulations and applicable International Council on Harmonisation (ICH) guidelines, consistent with Good Clinical Practice (GCP). All patients provided informed written consent before any protocol-specific procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Apr 2019
    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
    Netherlands: 41
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    United States: 155
    Country: Number of subjects enrolled
    Canada: 19
    Worldwide total number of subjects
    276
    EEA total number of subjects
    102
    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)
    140
    From 65 to 84 years
    134
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in subjects between 09-April-2019 (date first subject enrolled) through 06-January-2022 (date last subject completed) at 63 sites in Canada, France, Germany, Hungary, Italy, Netherlands, Poland, Sweden, and United States.

    Pre-assignment
    Screening details
    		 A total of 474 subjects were screened for the study; 198 failed screening, primarily due to not satisfying eligibility criteria. Of 474 subjects, 276 subjects were enrolled and randomised in the study in 2:1 ratio i.e., 185 and 91 subjects received omecamtiv mecarbil and placebo, respectively.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects self-administered placebo (matched to omecamtiv mecarbil) at doses 25 milligrams (mg), 37.5 mg, or 50 mg tablets orally, twice a day (BID) from Day 1 up to Week 20.
    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
    Subjects self-administered placebo (matched to omecamtiv mecarbil) tablets orally BID.

    Arm title
    		 Omecamtiv Mecarbil
    Arm description
    		 Subjects Self-administered omecamtiv mecarbil oral tablets at doses 25 mg, 37.5 mg, or 50 mg, BID from Day 1 up to Week 20. All subjects started at a dose of 25 mg BID and the omecamtiv mecarbil dose was adjusted at Week 4 and Week 8 based on predose omecamtiv mecarbil plasma concentrations from blood collected at Week 2 and Week 6, respectively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered film-coated, white to off-white, oval, modified-release tablets in doses of 25 mg, 37.5 mg, or 50 mg, orally BID.

    Number of subjects in period 1
    		Placebo Omecamtiv Mecarbil
    Started
    91
    185
    Completed
    85
    164
    Not completed
    6
    21
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    4
    12
         Death
    1
    2
         Other-unspecified
    -
    3
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects self-administered placebo (matched to omecamtiv mecarbil) at doses 25 milligrams (mg), 37.5 mg, or 50 mg tablets orally, twice a day (BID) from Day 1 up to Week 20.

    Reporting group title
    Omecamtiv Mecarbil
    Reporting group description
    		 Subjects Self-administered omecamtiv mecarbil oral tablets at doses 25 mg, 37.5 mg, or 50 mg, BID from Day 1 up to Week 20. All subjects started at a dose of 25 mg BID and the omecamtiv mecarbil dose was adjusted at Week 4 and Week 8 based on predose omecamtiv mecarbil plasma concentrations from blood collected at Week 2 and Week 6, respectively.

    Reporting group values
    		 Placebo Omecamtiv Mecarbil Total
    Number of subjects
    		 91 185 276
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 42 98 140
        From 65-84 years
    		 48 86 134
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ( 11.41 ) 63.3 ( 9.64 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 27 42
        Male
    		 76 158 234
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 2 3 5
        Black or African American
    		 6 16 22
        White
    		 82 163 245
        Other
    		 1 2 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 12 20
        Not Hispanic or Latino
    		 81 167 248
        Unknown
    		 2 6 8

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects self-administered placebo (matched to omecamtiv mecarbil) at doses 25 milligrams (mg), 37.5 mg, or 50 mg tablets orally, twice a day (BID) from Day 1 up to Week 20.

    Reporting group title
    Omecamtiv Mecarbil
    Reporting group description
    		 Subjects Self-administered omecamtiv mecarbil oral tablets at doses 25 mg, 37.5 mg, or 50 mg, BID from Day 1 up to Week 20. All subjects started at a dose of 25 mg BID and the omecamtiv mecarbil dose was adjusted at Week 4 and Week 8 based on predose omecamtiv mecarbil plasma concentrations from blood collected at Week 2 and Week 6, respectively.

    Primary: Change in Peak Oxygen Uptake (pVO2) on Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)

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    End point title
    		 Change in Peak Oxygen Uptake (pVO2) on Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)
    End point description
    The change in pVO2 from baseline to Week 20 was analysed using an analysis of covariance (ANCOVA) model which included terms of treatment, Baseline respiratory exchange ratio (RER) randomisation strata (less than [<] 1.15, greater than equal to [≥] 1.15), persistent atrial fibrillation (yes/no), age, sex, baseline pVO2, Baseline hemoglobin level, and Baseline body weight. pVO2 assessed effect of treatment on exercise capacity by assessing total workload and ventilatory efficiency during CPET by evaluating CPET with gas-exchange analysis. Analysis was performed on full analysis set (FAS) population that included all randomised subjects who had received at least 1 dose of randomised investigational product (IP). Here, "Subjects analysed" signifies number of subjects with available data at the specified timepoint for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 20
    End point values
    		 Placebo Omecamtiv Mecarbil
    Number of subjects analysed
    81
    162
    Units: millilitre per minute per kilogram
        least squares mean (standard error)
    0.207 ( 0.2412 )
    -0.239 ( 0.1718 )
    Statistical analysis title
    		 Omecamtiv Mecarbil versus Placebo
    Statistical analysis description
    Each completed dataset was analysed using ANCOVA with fixed effects of treatment, RER (<1.15,≥1.15), persistent atrial fibrillation (Y/N) at randomisation, age, sex, baseline pVO2, hemoglobin (Hb), and weight. Missing Week 20 pVO2 were imputed using regression multiple imputation including estimated glomerular filtration rate (eGFR), Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS), NYHA and average daily activity units along with parameters mentioned for complete dataset.
    Comparison groups
    Omecamtiv Mecarbil v Placebo
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.447
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.024
         upper limit
    		 0.131
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2931
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Change in Total Workload During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)

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    End point title
    		 Change in Total Workload During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)
    End point description
    The change in total workload during CPET from Baseline to Week 20 using an ANCOVA model which included terms of treatment, baseline RER randomisation strata (<1.15, ≥1.15), persistent atrial fibrillation (yes/no), age, sex, baseline workload, Baseline hemoglobin level, and Baseline body weight. The pVO2 assessed effect of treatment on exercise capacity by assessing total workload and ventilatory efficiency during CPET by evaluating CPET with gas-exchange analysis. Analysis was performed on FAS population. Here, "Subjects analysed" signifies number of subjects with available data at the specified timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 20
    End point values
    		 Placebo Omecamtiv Mecarbil
    Number of subjects analysed
    81
    162
    Units: Watts
        least squares mean (standard error)
    1.590 ( 1.9477 )
    -3.798 ( 1.3352 )
    Statistical analysis title
    		 Omecamtiv Mecarbil versus Placebo
    Statistical analysis description
    Each completed dataset was analysed using ANCOVA with fixed effects of treatment, RER (<1.15, ≥1.15), persistent atrial fibrillation (Yes/No) at randomisation, age, sex, baseline workload, Hb, and weight. Missing Week 20 workload were imputed using regression multiple imputation including eGFR, KCCQ TSS, NYHA and average daily activity units along with parameters mentioned for complete dataset.
    Comparison groups
    Omecamtiv Mecarbil v Placebo
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -5.388
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.108
         upper limit
    		 -0.668
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3937
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Change in Ventilatory Efficiency, as Measured by the slope of Change in Ventilation (VE) divided by the change in Carbon Dioxide Output (VCO2), During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)

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    End point title
    		 Change in Ventilatory Efficiency, as Measured by the slope of Change in Ventilation (VE) divided by the change in Carbon Dioxide Output (VCO2), During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 20 (Multiple Imputation)
    End point description
    The change in ventilatory efficiency during CPET from Baseline to Week 20 was analyzed using an ANCOVA model which included terms of treatment, baseline RER randomisation strata (<1.15, ≥1.15), persistent atrial fibrillation (yes/no), age, sex, baseline ventilatory efficiency, Baseline hemoglobin level, and Baseline body weight. Analysis was performed on FAS population. Here, "Subjects analysed" signifies number of subjects with available data at the specified timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 20
    End point values
    		 Placebo Omecamtiv Mecarbil
    Number of subjects analysed
    81
    162
    Units: VE/VCO2 slope
        least squares mean (standard error)
    -0.138 ( 0.5065 )
    0.277 ( 0.3616 )
    Statistical analysis title
    		 Omecamtiv Mecarbil versus Placebo
    Statistical analysis description
    Each completed dataset was analysed using ANCOVA with fixed effects of treatment, RER (<1.15, ≥1.15), persistent atrial fibrillation (Yes/No) at randomisation, age, sex, baseline ventilatory efficiency, Hb, and weight. Missing Week 20 ventilatory efficiency were imputed using regression multiple imputation including eGFR, KCCQ TSS, NYHA and average daily activity units along with parameters mentioned for complete dataset.
    Comparison groups
    Omecamtiv Mecarbil v Placebo
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Least Sqaure Mean Difference
    Point estimate
    0.414
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 1.639
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6215
    Notes
    [3] - Threshold for significance at 0.05 level.

    Secondary: Change in the Average Daily Activity Units From Baseline (Week -2 to Day 1) to Weeks 18 to 20 (≥7 Days of Wear ≥10 hours During Awake Time)

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    End point title
    		 Change in the Average Daily Activity Units From Baseline (Week -2 to Day 1) to Weeks 18 to 20 (≥7 Days of Wear ≥10 hours During Awake Time)
    End point description
    The change in the average daily activity units measured over a 2-week period from baseline (Week −2 to Day 1) to Week 18-20 was analysed using a repeated measures mixed model with terms such as treatment, baseline value, visit, RER randomization strata (<1.15, ≥1.15), and persistent atrial fibrillation (yes/no) as well as interaction terms of treatment-by-visit and baseline-by-visit with an unstructured covariance matrix. Analysis was performed on FAS population. Here, "Subjects analysed" signifies number of subjects with available data at the specified timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -2 to Day 1), Weeks 18 to 20
    End point values
    		 Placebo Omecamtiv Mecarbil
    Number of subjects analysed
    77
    147
    Units: Activity Units (10^5)
        least squares mean (standard error)
    -0.5 ( 0.38 )
    -0.2 ( 0.30 )
    Statistical analysis title
    		 Omecamtiv Mecarbil versus Placebo
    Statistical analysis description
    Change from baseline in average daily activity units use a mixed model repeated measures model with fixed effect of treatment, visit, baseline average daily activity units, baseline RER (<1.15, >=1.15) and persistent atrial fibrillation (Yes/No) at randomization and interaction terms of treatment-by-visit, and baseline-by-visit.
    Comparison groups
    Omecamtiv Mecarbil v Placebo
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54 [4]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Sqaure Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [4] - Threshold for significance at 0.05 level.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to 4 weeks following the last visit (Week 24) regardless of seriousness or relationship to IP.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs that developed/worsened during 'on-treatment period' (time form first dose of study drug up to end of study [i.e., 4 weeks following last visit [Week 24]). Safety population included all randomised subjects who had received at least 1 dose of IP. 1 of 4 deaths occurred after end of treatment (Week 20).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects self-administered placebo (matched to omecamtiv mecarbil) at doses 25 milligrams (mg), 37.5 mg, or 50 mg tablets orally, twice a day (BID) from Day 1 up to Week 20.

    Reporting group title
    Omecamtiv Mecarbil
    Reporting group description
    		 Subjects Self-administered omecamtiv mecarbil oral tablets at doses 25 mg, 37.5 mg, or 50 mg, BID from Day 1 up to Week 20. All subjects started at a dose of 25 mg BID and the omecamtiv mecarbil dose was adjusted at Week 4 and Week 8 based on predose omecamtiv mecarbil plasma concentrations from blood collected at Week 2 and Week 6, respectively.

    Serious adverse events
    		 Placebo Omecamtiv Mecarbil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 91 (14.29%)
    30 / 185 (16.22%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Complications of transplanted heart
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    3 / 91 (3.30%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 91 (1.10%)
    7 / 185 (3.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 91 (2.20%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 91 (2.20%)
    5 / 185 (2.70%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Heart transplant
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Omecamtiv Mecarbil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 91 (59.34%)
    121 / 185 (65.41%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 91 (3.30%)
    3 / 185 (1.62%)
         occurrences all number
    3
    4
    Hypotension
         subjects affected / exposed
    1 / 91 (1.10%)
    4 / 185 (2.16%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 91 (4.40%)
    9 / 185 (4.86%)
         occurrences all number
    4
    9
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 91 (3.30%)
    4 / 185 (2.16%)
         occurrences all number
    4
    4
    Asthenia
         subjects affected / exposed
    0 / 91 (0.00%)
    4 / 185 (2.16%)
         occurrences all number
    0
    5
    Chest discomfort
         subjects affected / exposed
    0 / 91 (0.00%)
    4 / 185 (2.16%)
         occurrences all number
    0
    4
    Oedema peripheral
         subjects affected / exposed
    0 / 91 (0.00%)
    4 / 185 (2.16%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 91 (8.79%)
    5 / 185 (2.70%)
         occurrences all number
    9
    5
    Cough
         subjects affected / exposed
    1 / 91 (1.10%)
    5 / 185 (2.70%)
         occurrences all number
    1
    5
    Dyspnoea exertional
         subjects affected / exposed
    0 / 91 (0.00%)
    4 / 185 (2.16%)
         occurrences all number
    0
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 91 (1.10%)
    5 / 185 (2.70%)
         occurrences all number
    1
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 91 (1.10%)
    7 / 185 (3.78%)
         occurrences all number
    1
    8
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 91 (3.30%)
    4 / 185 (2.16%)
         occurrences all number
    4
    28
    Atrial fibrillation
         subjects affected / exposed
    3 / 91 (3.30%)
    4 / 185 (2.16%)
         occurrences all number
    3
    4
    Cardiac failure
         subjects affected / exposed
    2 / 91 (2.20%)
    5 / 185 (2.70%)
         occurrences all number
    2
    6
    Palpitations
         subjects affected / exposed
    2 / 91 (2.20%)
    1 / 185 (0.54%)
         occurrences all number
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 91 (5.49%)
    9 / 185 (4.86%)
         occurrences all number
    6
    10
    Headache
         subjects affected / exposed
    3 / 91 (3.30%)
    4 / 185 (2.16%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 91 (4.40%)
    7 / 185 (3.78%)
         occurrences all number
    4
    7
    Nausea
         subjects affected / exposed
    3 / 91 (3.30%)
    3 / 185 (1.62%)
         occurrences all number
    3
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 91 (1.10%)
    4 / 185 (2.16%)
         occurrences all number
    1
    4
    Rash
         subjects affected / exposed
    4 / 91 (4.40%)
    0 / 185 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 91 (1.10%)
    4 / 185 (2.16%)
         occurrences all number
    1
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 91 (4.40%)
    5 / 185 (2.70%)
         occurrences all number
    4
    5
    Arthralgia
         subjects affected / exposed
    0 / 91 (0.00%)
    6 / 185 (3.24%)
         occurrences all number
    0
    7
    Myalgia
         subjects affected / exposed
    1 / 91 (1.10%)
    5 / 185 (2.70%)
         occurrences all number
    1
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 91 (2.20%)
    2 / 185 (1.08%)
         occurrences all number
    2
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 91 (2.20%)
    1 / 185 (0.54%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    3 / 91 (3.30%)
    4 / 185 (2.16%)
         occurrences all number
    3
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2019
    Amendment 1: • Modified inclusion criteria to specify that screening assessments were to be completed prior to randomisation • Modified exclusion criteria to: − Qualify that a subject would be excluded if they had paroxysmal atrial fibrillation or flutter that required treatment − Lower the screening CPET for chronotropic incompetence from 60% to <55% of maximum predicted heart rate • Specified permanent discontinuation of IP if a subject had an acute ST-segment elevation myocardial infarction • Specified permanent discontinuation of IP and treatment unblinding if the omecamtiv mecarbil plasma concentration was ≥1000 nanograms per millilitre (ng/mL) at an unscheduled visit • Added electrocardiogram (ECG) assessments at Weeks −2, 2, and 6 • Added iron testing (iron, ferritin, total iron binding capacity) to laboratory assessments • For interim analysis, reduced the conditional power to 0.1
    31 Jul 2020
    Amendment 2: Revised the time between screening CPET and randomization to not more than 3 weeks to harmonize timing between subjects who had 2 screening visits and those having a combined screening visit • Clarified that if the Week 2 or Week 6 PK assessment was missed, the subjects randomised to omecamtiv mecarbil would be titrated to, or maintained at a dose of 25 mg to ensure omecamtiv mecarbil plasma concentrations remained <1000 ng/mL • Reduced the number of in-person study visits to reduce potential COVID-19 exposure, with the following specific changes: − Changed Week 14 clinic visit to a telephone visit − Removed the omecamtiv mecarbil concentration assessment, vital signs assessment, and IP tablet count at Week 14 • Provided additional flexibility in the conduct of the study because of the COVID-19 pandemic, with the following specific changes: − Added the ability to extend the treatment duration when the Week 20 CPET was delayed − Extended the potential study duration − Added the option of a second rescreening if a prior screen failure was due to the COVID-19 pandemic − Added the ability to use an alternative IP dispensing method − Added the option to complete the KCCQ over the telephone − Added unscheduled visits to perform the Week 20 CPET, if it could not be performed in the planned Week 20 window − Added the ability to increase sample size (to overcome the loss of information due to possible important protocol deviations due to COVID-19 • Added statistical analyses to assess the impact of the COVID-19 pandemic • Added the ability to perform remote source data verification (to overcome possible on-site or travel restrictions due to COVID-19)
    30 Jun 2021
    Amendment 3: Updated the study sponsor from Amgen to Cytokinetics • Updated data from GALACTIC-HF study • Made administrative changes to align with the change in sponsor, including updates of contact personnel and safety reporting procedures

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Apr 2020
    The new screening within the study was temporarily suspended due to COVID-19. On 04-Jun-2020, the decision to re-open screening on site by site basis was made.
    04 Jun 2020

    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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