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    Clinical Trial Results:
    A Phase 2, Multi-Center, Double-Blind, Randomized, Dose-Ranging, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of CK-2127107 In Patients with Amyotrophic Lateral Sclerosis (ALS)

    Summary
    EudraCT number
    		 2018-000586-37
    Trial protocol
    		 IE   ES   NL  
    Global end of trial date
    07 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2020
    First version publication date
    14 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CY 5022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03160898
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cytokinetics, Inc.
    Sponsor organisation address
    280 East Grand Avenue, South San Francisco, California, United States, 94080
    Public contact
    Medical Affairs, Cytokinetics, Inc., +1 650 6242929, medicalaffairs@cytokinetics.com
    Scientific contact
    Medical Affairs, Cytokinetics, Inc., +1 650 6242929, 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
    07 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of CK-2127107 (hereafter referred to as reldesemtiv) versus placebo on respiratory function in patients with ALS.
    Protection of trial subjects
    The study was conducted in accordance with the United States (US) Code of Federal Regulations (CFR) governing protection of human subjects (21 CFR 50), financial disclosure by clinical investigators (21 CFR 54), institutional review boards (IRBs; 21 CFR 56), investigational new drug applications (21 CFR 312), and applications for the US Food and Drug Administration approval to market a new drug (21 CFR 314), as appropriate. The study was also conducted in accordance with applicable International Council on Harmonisation (ICH) guidelines. Both the US regulations along with the ICH guidelines are commonly known as good clinical practices (GCPs). An independent Data Monitoring Committee (DMC) assessed patient safety in an unblinded manner periodically during the study. The DMC was chartered to make recommendations to the sponsor, as appropriate, regarding modification in study design or conduct to ensure patient safety and the integrity of the study.
    Background therapy
    		 Concomitant use of riluzole and/or edaravone was allowed during the study if patients had been taking riluzole for at least 30 days prior to screening and if patients had completed 2 cycles of edaravone by screening. Neither drug was allowed if they had not been used for at least 30 days prior to screening.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Canada: 100
    Country: Number of subjects enrolled
    United States: 284
    Worldwide total number of subjects
    457
    EEA total number of subjects
    53
    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)
    308
    From 65 to 84 years
    149
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with familial or sporadic ALS were enrolled at 65 sites in Australia, Canada, Ireland, Netherlands, Spain, and the United States. The first patient was screened on 16 August 2017 and the last patient completed on 07 March 2019.

    Pre-assignment
    Screening details
    		 Eligible patients were male or female, ≥18 to ≤80 years of age, with familial or sporadic ALS ≤24 months prior to screening. At screening, patients were to have an upright slow vial capacity (SVC) ≥60% of predicted; must have been able to swallow tablets and perform pulmonary function tests; had normal lab tests; and had a caregiver (if needed).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients in this group received placebo (to match reldesemtiv) twice daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for reldesemtiv
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomized 1:1:1:1 to receive reldesemtiv 150 mg, 300 mg, 450 mg, or placebo, twice daily for 12 weeks. Doses were to be taken approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

    Arm title
    		 Reldesemtiv 150 mg
    Arm description
    		 Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Reldesemtiv
    Investigational medicinal product code
    CK-2127107
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomized 1:1:1:1 to receive reldesemtiv 150 mg, 300 mg, 450 mg, or placebo, twice daily for 12 weeks. Doses were to be taken approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

    Arm title
    		 Reldesemtiv 300 mg
    Arm description
    		 Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Reldesemtiv 300 mg
    Investigational medicinal product code
    CK-2127107
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomized 1:1:1:1 to receive reldesemtiv 150 mg, 300 mg, 450 mg, or placebo, twice daily for 12 weeks. Doses were to be taken approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

    Arm title
    		 Reldesemtiv 450 mg
    Arm description
    		 Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Reldesemtiv
    Investigational medicinal product code
    CK-2127107
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Other use
    Dosage and administration details
    Patients were randomized 1:1:1:1 to receive reldesemtiv 150 mg, 300 mg, 450 mg, or placebo, twice daily for 12 weeks. Doses were to be taken approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

    Number of subjects in period 1
    		Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg
    Started
    115
    112
    113
    117
    Completed
    95
    100
    97
    98
    Not completed
    20
    12
    16
    19
         Adverse event, serious fatal
    1
    -
    -
    1
         Consent withdrawn by subject
    1
    2
    2
    1
         Physician decision
    1
    -
    -
    1
         Adverse event, non-fatal
    4
    8
    7
    10
         Unspecified
    2
    -
    2
    2
         Progressive disease
    4
    1
    2
    1
         Lost to follow-up
    1
    1
    1
    2
         Sponsor decision
    2
    -
    -
    -
         Difficulty traveling to clinic visits
    3
    -
    -
    1
         Protocol deviation
    1
    -
    2
    -
    Period 2
    Period 2 title
    Efficacy Analyses
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Reldesemtiv 300 mg & 450 mg (pooled)
    Arm description
    		 Patients from the reldesemtiv 300 mg and 450 mg groups were pooled for analysis purposes only.
    Arm type
    		 Pooled for analysis purposes only

    Investigational medicinal product name
    Reldesemtiv
    Investigational medicinal product code
    CK-2127107
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For analysis purposes only, patients from the reldesemtiv 300 mg and 450 mg groups were pooled to evaluate the efficacy responses of the pooled group compared with those of the placebo group.

    Number of subjects in period 2 [1]
    		Reldesemtiv 300 mg & 450 mg (pooled)
    Started
    230
    Completed
    195
    Not completed
    35
         Adverse event, serious fatal
    1
         Physician decision
    1
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    17
         Unspecified
    4
         Progressive disease
    3
         Lost to follow-up
    3
         Difficulty traveling to clinic visits
    1
         Protocol deviation
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The Reldesemtiv 300 mg & 450 mg (pooled) arm was added for efficacy analysis purposes only. A prespecified efficacy analysis was to compare this pooled group to placebo for each efficacy endpoint. All data from this arm (disposition and efficacy) derives from both the reldesemtiv 300 mg arm and the reldesemtiv 450 mg arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this group received placebo (to match reldesemtiv) twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 150 mg
    Reporting group description
    		 Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 300 mg
    Reporting group description
    		 Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 450 mg
    Reporting group description
    		 Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks.

    Reporting group values
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg Total
    Number of subjects
    		 115 112 113 117 457
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 74 81 80 73 308
        From 65-84 years
    		 41 31 33 44 149
    Gender categorical
    Units: Subjects
        Female
    		 47 41 42 50 180
        Male
    		 68 71 71 67 277

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this group received placebo (to match reldesemtiv) twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 150 mg
    Reporting group description
    		 Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 300 mg
    Reporting group description
    		 Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 450 mg
    Reporting group description
    		 Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks.
    Reporting group title
    Reldesemtiv 300 mg & 450 mg (pooled)
    Reporting group description
    		 Patients from the reldesemtiv 300 mg and 450 mg groups were pooled for analysis purposes only.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment.

    Primary: Change from Baseline to Week 12 in Percent Predicted Slow Vital Capacity

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    End point title
    		 Change from Baseline to Week 12 in Percent Predicted Slow Vital Capacity
    End point description
    Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to percent predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]).
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects analysed
    114
    112
    113
    117
    230
    Units: percent
        least squares mean (standard error)
    -6.46 ± 0.964
    -4.97 ± 0.952
    -4.62 ± 0.963
    -4.58 ± 0.927
    -4.60 ± 0.701
    Statistical analysis title
    		 Reldesemtiv 150 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 150 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 150 mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2501
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 4.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.291
    Statistical analysis title
    		 Reldesemtiv 300 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1549
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 4.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29
    Statistical analysis title
    		 Reldesemtiv 450 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 450 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 450 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1417
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 4.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.274
    Statistical analysis title
    		 Reldesemtiv 300&450 mg (pooled)-placebo comparison
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg & 450 mg (pooled) minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0964
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 4.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.115

    Secondary: Slope from Baseline to Week 12 in Muscle Strength Mega-Score

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    End point title
    		 Slope from Baseline to Week 12 in Muscle Strength Mega-Score
    End point description
    Muscle strength of 6 muscle groups (elbow flexion, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion) and hand grip strength were measured bilaterally using a hand-held dynamometer. Muscle strength was measure twice for each body location; if the variability between the first 2 measures was > 15%, a third measure was obtained. The muscle strength of each measured body location as a percent of change from baseline was determined using the equation: ([postbaseline value – baseline value] / baseline value) × 100. The mega-score was a composite score that averaged strength across muscle groups. It was calculated as the mean of the muscle strength scores among the 6 muscle groups and hand grip strength, each measured bilaterally (totaling 14 body locations).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects analysed
    114
    112
    113
    117
    230
    Units: change/day
        least squares mean (standard error)
    -0.1444 ± 0.02492
    -0.1198 ± 0.02463
    -0.1299 ± 0.02474
    -0.0956 ± 0.02421
    -0.1127 ± 0.01731
    Statistical analysis title
    		 Reldesemtiv 150 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 150 mg minus placebo
    Comparison groups
    Reldesemtiv 150 mg v Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4824
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.0246
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0442
         upper limit
    		 0.0935
    Statistical analysis title
    		 Reldesemtiv 300 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6787
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.0146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0544
         upper limit
    		 0.0835
    Statistical analysis title
    		 Reldesemtiv 450 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 450 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 450 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1604
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.0488
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0194
         upper limit
    		 0.1171
    Statistical analysis title
    		 Reldesemtiv 300&450 mg (pooled)-placebo comparison
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg & 450 mg (pooled) minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2966
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.0317
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0279
         upper limit
    		 0.0913

    Secondary: Change from Baseline to Week 12 in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score

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    End point title
    		 Change from Baseline to Week 12 in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score
    End point description
    The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48. Higher scores reflect more normal function and lower scores reflect more impaired function.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects analysed
    114
    112
    113
    117
    230
    Units: ALSFRS-R Total Score
        least squares mean (standard error)
    -3.53 ± 0.313
    -2.40 ± 0.311
    -2.62 ± 0.317
    -2.94 ± 0.307
    -2.78 ± 0.228
    Statistical analysis title
    		 Reldesemtiv 150 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 150 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 150 mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0087
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.427
    Statistical analysis title
    		 Reldesemtiv 300 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0351
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 1.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43
    Statistical analysis title
    		 Reldesemtiv 450 mg - placebo comparison of change
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 450 mg minus placebo
    Comparison groups
    Placebo v Reldesemtiv 450 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1642
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 1.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.425
    Statistical analysis title
    		 Reldesemtiv 300&450 mg (pooled)-placebo comparison
    Statistical analysis description
    Difference in LS mean changes from baseline: reldesemtiv 300 mg & 450 mg (pooled) minus placebo
    Comparison groups
    Placebo v Reldesemtiv 300 mg & 450 mg (pooled)
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0435
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 1.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.371

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from administration of the first dose of study drug through 4 weeks after the last dose of study drug
    Adverse event reporting additional description
    An AE was treatment-emergent if it started or worsened (eg, increased in severity) during or after the first dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this group received placebo (to match reldesemtiv) twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 150 mg
    Reporting group description
    		 Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 300 mg
    Reporting group description
    		 Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks.

    Reporting group title
    Reldesemtiv 450 mg
    Reporting group description
    		 Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks.

    Serious adverse events
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 115 (8.70%)
    8 / 112 (7.14%)
    8 / 113 (7.08%)
    8 / 117 (6.84%)
         number of deaths (all causes)
    2
    0
    0
    1
         number of deaths resulting from adverse events
    1
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 112 (1.79%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    1 / 113 (0.88%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 112 (0.89%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 112 (0.00%)
    1 / 113 (0.88%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 112 (0.00%)
    0 / 113 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Reldesemtiv 150 mg Reldesemtiv 300 mg Reldesemtiv 450 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 115 (82.61%)
    99 / 112 (88.39%)
    97 / 113 (85.84%)
    107 / 117 (91.45%)
    Investigations
    Cystatin C increased
         subjects affected / exposed
    2 / 115 (1.74%)
    7 / 112 (6.25%)
    9 / 113 (7.96%)
    20 / 117 (17.09%)
         occurrences all number
    2
    7
    9
    22
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 115 (0.87%)
    6 / 112 (5.36%)
    6 / 113 (5.31%)
    10 / 117 (8.55%)
         occurrences all number
    1
    6
    6
    11
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 112 (1.79%)
    5 / 113 (4.42%)
    11 / 117 (9.40%)
         occurrences all number
    1
    2
    6
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 112 (1.79%)
    3 / 113 (2.65%)
    9 / 117 (7.69%)
         occurrences all number
    1
    2
    3
    11
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    15 / 115 (13.04%)
    8 / 112 (7.14%)
    14 / 113 (12.39%)
    17 / 117 (14.53%)
         occurrences all number
    28
    15
    15
    26
    Post-traumatic pain
         subjects affected / exposed
    2 / 115 (1.74%)
    6 / 112 (5.36%)
    8 / 113 (7.08%)
    6 / 117 (5.13%)
         occurrences all number
    2
    8
    11
    6
    Skin abrasion
         subjects affected / exposed
    5 / 115 (4.35%)
    8 / 112 (7.14%)
    3 / 113 (2.65%)
    5 / 117 (4.27%)
         occurrences all number
    7
    10
    4
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 115 (13.04%)
    16 / 112 (14.29%)
    16 / 113 (14.16%)
    12 / 117 (10.26%)
         occurrences all number
    18
    18
    19
    13
    Dizziness
         subjects affected / exposed
    11 / 115 (9.57%)
    8 / 112 (7.14%)
    11 / 113 (9.73%)
    7 / 117 (5.98%)
         occurrences all number
    13
    12
    13
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 115 (10.43%)
    14 / 112 (12.50%)
    19 / 113 (16.81%)
    20 / 117 (17.09%)
         occurrences all number
    14
    14
    20
    24
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    14 / 115 (12.17%)
    10 / 112 (8.93%)
    13 / 113 (11.50%)
    22 / 117 (18.80%)
         occurrences all number
    16
    13
    14
    23
    Constipation
         subjects affected / exposed
    5 / 115 (4.35%)
    7 / 112 (6.25%)
    13 / 113 (11.50%)
    10 / 117 (8.55%)
         occurrences all number
    5
    8
    15
    10
    Diarrhoea
         subjects affected / exposed
    8 / 115 (6.96%)
    12 / 112 (10.71%)
    6 / 113 (5.31%)
    4 / 117 (3.42%)
         occurrences all number
    8
    15
    6
    4
    Dry mouth
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 112 (1.79%)
    6 / 113 (5.31%)
    1 / 117 (0.85%)
         occurrences all number
    2
    2
    6
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 112 (0.89%)
    2 / 113 (1.77%)
    6 / 117 (5.13%)
         occurrences all number
    4
    1
    3
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 115 (1.74%)
    8 / 112 (7.14%)
    4 / 113 (3.54%)
    8 / 117 (6.84%)
         occurrences all number
    2
    9
    5
    10
    Pain in extremity
         subjects affected / exposed
    5 / 115 (4.35%)
    1 / 112 (0.89%)
    3 / 113 (2.65%)
    6 / 117 (5.13%)
         occurrences all number
    6
    1
    3
    7
    Muscle spasms
         subjects affected / exposed
    1 / 115 (0.87%)
    6 / 112 (5.36%)
    2 / 113 (1.77%)
    1 / 117 (0.85%)
         occurrences all number
    1
    7
    2
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 115 (7.83%)
    6 / 112 (5.36%)
    10 / 113 (8.85%)
    9 / 117 (7.69%)
         occurrences all number
    9
    6
    10
    9
    Urinary tract infection
         subjects affected / exposed
    8 / 115 (6.96%)
    3 / 112 (2.68%)
    5 / 113 (4.42%)
    5 / 117 (4.27%)
         occurrences all number
    9
    5
    5
    7
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 115 (2.61%)
    7 / 112 (6.25%)
    1 / 113 (0.88%)
    1 / 117 (0.85%)
         occurrences all number
    4
    7
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 115 (3.48%)
    3 / 112 (2.68%)
    7 / 113 (6.19%)
    7 / 117 (5.98%)
         occurrences all number
    4
    3
    7
    8
    Dehydration
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 112 (0.89%)
    6 / 113 (5.31%)
    6 / 117 (5.13%)
         occurrences all number
    0
    1
    6
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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