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    Clinical Trial Results:
    A Phase IIb, multi-national, double-blind, randomised, placebo-controlled study to evaluate the safety, tolerability and efficacy of CK-2017357 in patients with amyotrophic lateral sclerosis (ALS)

    Summary
    EudraCT number
    		 2012-004987-23
    Trial protocol
    		 IE   GB   DE   NL   ES  
    Global end of trial date
    21 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Feb 2020
    First version publication date
    19 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CY 4026
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01709149
    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., 001 6506242929, medicalaffairs@cytokinetics.com
    Scientific contact
    Medical Affairs, Cytokinetics, Inc., 001 6506242929, 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
    21 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of CK-2017357 (hereafter referred to as tirasemtiv) versus placebo on the ALS Functional Rating Scale-Revised (ALSFRS-R) total score when administered twice daily at each patient's maximum tolerated dose, up to a maximum of 500 mg daily.
    Protection of trial subjects
    The study was conducted in accordance with the Code of Federal Regulations (CFR) governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical Investigators (21 CFR 54), Institutional Review Boards (21 CFR 56), Investigational New Drug Applications (21 CFR 312), and Applications for Food and Drug Administration Approval to Market a New Drug (21 CFR 314), as appropriate. These sections of United States Title 21 CFR, along with the applicable International Conference on Harmonization (ICH) Guidelines, are commonly known as Good Clinical Practices (GCP), which are consistent with the Declaration of Helsinki, 1996.
    Background therapy
    		 During the open-label portion of the study, patients taking riluzole prior to study entry continued riluzole from their personal supply at a dose of 50 mg once daily (in the morning). Patients not taking riluzole prior to the study did not receive riluzole during the study. During the double-blind portion of the study, patients taking riluzole prior to study entry continued riluzole treatment during the 12-week double-blind portion of the study as follows: patients randomized to placebo took riluzole 50 mg from their personal supply once daily (in the morning) and over-encapsulated riluzole 50 mg, supplied by the sponsor, once daily (in the evening); patients randomized to tirasemtiv took riluzole 50 mg from their personal supply once daily (in the morning) and placebo to match over-encapsulated riluzole, supplied by the sponsor, once daily (in the evening). Patients not taking riluzole prior to the study did not receive riluzole during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2012
    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
    United States: 409
    Country: Number of subjects enrolled
    Canada: 104
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    France: 60
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Ireland: 13
    Worldwide total number of subjects
    711
    EEA total number of subjects
    198
    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)
    511
    From 65 to 84 years
    197
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with familial or sporadic ALS were enrolled at 73 sites in Canada, France, Germany, Ireland, Netherlands, Spain, the United Kingdom, and the United States. The first patient was screened on 23 October 2012 and the last subject completed on 21 March 2014.

    Pre-assignment
    Screening details
    		 A total of 711 patients were enrolled in the study and began treatment with open-label tirasemtiv during the 7-day lead-in phase of the study. Patients who completed this phase were randomized (1:1) to receive either placebo (N=295) or tirasemtiv (N=301) in the double-blind treatment period.

    Period 1
    Period 1 title
    Open-label Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label lead-in treatment: Tirasemtiv
    Arm description
    		 During the open-label phase, all 711 enrolled patients initiated treatment with tirasemtiv immediate release 125 mg tablets, administered orally twice daily (for a total daily dose of 250 mg) for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tirasemtiv
    Investigational medicinal product code
    CK-2017357
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tirasemtiv immediate release 125 mg tablets were administered orally twice daily (for a total daily dose of 250 mg) for 7 days.

    Number of subjects in period 1
    		Open-label lead-in treatment: Tirasemtiv
    Started
    711
    Completed
    596
    Not completed
    115
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    109
         Protocol deviation
    3
    Period 2
    Period 2 title
    Double-blind Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-blind treatment: Tirasemtiv
    Arm description
    		 Patients started at a dose of 125 mg twice daily, then up-titrated, over 3 to 4 weeks, to a dose of 250 mg twice daily (for a total daily dose of 500 mg), depending on tolerability. Patients remained at their last tolerated dose for the remainder of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tirasemtiv
    Investigational medicinal product code
    CK-2017357
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated for a total of 12 weeks with a dose-titration phase lasting approximately 3 to 4 weeks, followed by a maximum tolerated dose phase lasting for the remainder of the study. During the first week of the dose-titration phase, patients took 1 tirasemtiv tablet (125 mg) twice daily (for a total daily dose of 250 mg) for 7 days depending on tolerability. During the second week of dose-titration, the tirasemtiv dose was increased to 1 tablet (125 mg) in the morning and 2 tablets (250 mg) in the evening (for a total daily dose of 375 mg) for 7 days depending on tolerability. During the third week of dose-titration, the dose was increased to 2 tablets (250 mg) twice daily (for a total daily dose of 500 mg) for 7 days depending on tolerability. The start of the fourth week represented the end of the dose-titration phase and the start of the maximum tolerated dose phase. Patients remained on their maximum tolerated dose for the remainder of the study.

    Arm title
    		 Double-blind treatment: Placebo
    Arm description
    		 Patients started taking 1 placebo table twice daily, then up-titrated, over 3 to 4 weeks, to 2 placebo tablets twice daily. Patients remained at their last tolerated dose for the remainder of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for tirasemtiv
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated for a total of 12 weeks with a dose-titration phase lasting approximately 3 to 4 weeks, followed by a maximum tolerated dose phase lasting for the remainder of the study. During the first week of the dose-titration phase, patients took 1 placebo tablet twice daily for 7 days. During the second week of dose-titration, patients took 1 placebo tablet in the morning and 2 placebo tablets in the evening for 7 days. During the third week of dose-titration, patients took 2 placebo tablets twice daily for 7 days. The start of the fourth week represented the end of the dose-titration phase and the start of the maximum tolerated dose phase. Patients remained on their maximum tolerated dose for the remainder of the study.

    Number of subjects in period 2
    		Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Started
    301
    295
    Completed
    204
    269
    Not completed
    97
    26
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    12
    7
         Adverse event, non-fatal
    78
    12
         Investigator Judgment
    5
    2
         Unspecified
    2
    1
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label Phase
    Reporting group description
    		 All 711 enrolled patients started in the open-label phase and initiated open-label tirasemtiv treatment.

    Reporting group values
    		 Open-label Phase Total
    Number of subjects
    		 711 711
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 511 511
        From 65-84 years
    		 197 197
        85 years and over
    		 3 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 10.98 ) -
    Gender categorical
    Units: Subjects
        Female
    		 226 226
        Male
    		 485 485

    End points

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    End points reporting groups
    Reporting group title
    Open-label lead-in treatment: Tirasemtiv
    Reporting group description
    		 During the open-label phase, all 711 enrolled patients initiated treatment with tirasemtiv immediate release 125 mg tablets, administered orally twice daily (for a total daily dose of 250 mg) for 7 days.
    Reporting group title
    Double-blind treatment: Tirasemtiv
    Reporting group description
    		 Patients started at a dose of 125 mg twice daily, then up-titrated, over 3 to 4 weeks, to a dose of 250 mg twice daily (for a total daily dose of 500 mg), depending on tolerability. Patients remained at their last tolerated dose for the remainder of the study.

    Reporting group title
    Double-blind treatment: Placebo
    Reporting group description
    		 Patients started taking 1 placebo table twice daily, then up-titrated, over 3 to 4 weeks, to 2 placebo tablets twice daily. Patients remained at their last tolerated dose for the remainder of the study.

    Primary: Change from Baseline in ALSFRS-R Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in ALSFRS-R Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is score from 0 (indicating incapable or dependent) to 4 (normal). The total score ranged from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function. For analysis of the primary endpoint, changes from baseline in ALSFRS-R total score at Visits 6 (Week 8) and 7 (Week 12) were averaged.
    End point type
    Primary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: score on a scale
        least squares mean (standard error)
    -2.98 ( 0.277 )
    -2.4 ( 0.246 )
    Statistical analysis title
    		 Analysis of Change from Baseline in ALSFRS-R Score
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.114
    Method
    		 Repeated-measures mixed model
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.366
    Notes
    [1] - The analysis was performed using a repeated-measures mixed model which included terms of treatment, baseline, pooled site, visit, and riluzole use/non-use, as well as interaction terms of treatment-by-visit and baseline-by-visit with an unstructured covariance matrix.

    Secondary: Change from Baseline in the Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in the Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    MVV was measured as the volume of air (in liters) that could be exhaled during 12 seconds of rapid deep breathing. For analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).
    End point type
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: Litres per (/) minute
        least squares mean (standard error)
    -3.79 ( 1.497 )
    -4.27 ( 1.332 )
    Statistical analysis title
    		 Analysis of Change from Baseline in MVV
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8083
    Method
    		 Repeated measures model
    Confidence interval

    Secondary: Change from Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    SNIP was measured at functional residual capacity (the bottom of the tidal breathing cycle) through one plugged nostril while the other remained open. A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.
    End point type
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: centimetres H2O
        least squares mean (standard error)
    -4.29 ( 1.243 )
    -0.89 ( 1.103 )
    Statistical analysis title
    		 Analysis of Change from Baseline in SNIP
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0372
    Method
    		 Repeated measures model
    Confidence interval

    Secondary: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    SVC 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
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: percent
        least squares mean (standard error)
    -2.98 ( 0.78 )
    -7.24 ( 0.691 )
    Statistical analysis title
    		 Analysis of Change from Baseline in SVC
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Confidence interval

    Secondary: Change from Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    Maximum handgrip strength was measured using an electronic hand dynamometer. Patients were asked to squeeze the device with the maximum possible force. Maximum handgrip strength was recorded for both the right and left hand: the greater of two attempts for each hand was used. Data presented are for the qualifying weaker hand.
    End point type
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: pound
        least squares mean (standard error)
    -2.78 ( 0.714 )
    -3.54 ( 0.64 )
    Statistical analysis title
    		 Analysis of Change in Maximum Handgrip Strength
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4328
    Method
    		 Repeated measures model
    Confidence interval

    Secondary: Change from Baseline in Muscle Strength Mega-Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in Muscle Strength Mega-Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    A hand held dynamometer (HHD) was used to measure muscle strength. The following muscle groups were assessed: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). A muscle strength mega-score was calculated as the average of responses to all tested muscles as well as handgrip strength.
    End point type
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: percent
        least squares mean (standard error)
    -9.1 ( 2.425 )
    -10.71 ( 2.108 )
    Statistical analysis title
    		 Analysis of Muscle Strength Mega-Score
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6166
    Method
    		 Repeated measures model
    Confidence interval

    Secondary: Change from Baseline in Handgrip Fatigability (at 60% of Target in Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment

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    End point title
    		 Change from Baseline in Handgrip Fatigability (at 60% of Target in Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    End of Weeks 8 and 12
    End point values
    		 Double-blind treatment: Tirasemtiv Double-blind treatment: Placebo
    Number of subjects analysed
    178
    210
    Units: seconds
        least squares mean (standard error)
    2.01 ( 3.331 )
    1.76 ( 2.863 )
    Statistical analysis title
    		 Analysis of Handgrip Fatigability
    Comparison groups
    Double-blind treatment: Tirasemtiv v Double-blind treatment: Placebo
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9546
    Method
    		 Repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 8.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.399

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier.
    Adverse event reporting additional description
    An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (during either open-label or double-blind treatment). If an AE started in the open-label phase and continued into the double-blind phase for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Open-label lead-in treatment: Tirasemtiv
    Reporting group description
    		 Tirasemtiv immediate release 125 mg tablets administered orally twice daily (for a total daily dose of 250 mg) for 7 days.

    Reporting group title
    Double-blind treatment: Placebo
    Reporting group description
    		 Patients started taking 1 placebo tablet twice daily, then up-titrated, over 3 to 4 weeks, to 2 placebo tablets twice daily. Patients remained at their last tolerated dose for the remainder of the study.

    Reporting group title
    Double-blind treatment: Tirasemtiv
    Reporting group description
    		 Patients started at a dose of 125 mg twice daily, then up-titrated, over 3 to 4 weeks, to a dose of 250 mg twice daily (for a total daily dose of 500 mg), depending on tolerability. Patients remained at their last tolerated dose for the remainder of the study.

    Serious adverse events
    		 Open-label lead-in treatment: Tirasemtiv Double-blind treatment: Placebo Double-blind treatment: Tirasemtiv
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 711 (1.83%)
    16 / 295 (5.42%)
    27 / 301 (8.97%)
         number of deaths (all causes)
    2
    3
    2
         number of deaths resulting from adverse events
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 711 (0.14%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 711 (0.14%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 711 (0.14%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 711 (0.14%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 711 (0.14%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal haematoma
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypercapnia
         subjects affected / exposed
    1 / 711 (0.14%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 711 (0.14%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 711 (0.28%)
    1 / 295 (0.34%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 711 (0.00%)
    3 / 295 (1.02%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 711 (0.28%)
    0 / 295 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 711 (0.28%)
    0 / 295 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal column stenosis
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 711 (0.14%)
    1 / 295 (0.34%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Kidney infection
         subjects affected / exposed
    0 / 711 (0.00%)
    0 / 295 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 711 (0.00%)
    1 / 295 (0.34%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open-label lead-in treatment: Tirasemtiv Double-blind treatment: Placebo Double-blind treatment: Tirasemtiv
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    523 / 711 (73.56%)
    257 / 295 (87.12%)
    290 / 301 (96.35%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 711 (0.84%)
    25 / 295 (8.47%)
    22 / 301 (7.31%)
         occurrences all number
    6
    45
    32
    Excoriation
         subjects affected / exposed
    2 / 711 (0.28%)
    15 / 295 (5.08%)
    17 / 301 (5.65%)
         occurrences all number
    2
    21
    21
    Laceration
         subjects affected / exposed
    6 / 711 (0.84%)
    11 / 295 (3.73%)
    18 / 301 (5.98%)
         occurrences all number
    6
    12
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    291 / 711 (40.93%)
    58 / 295 (19.66%)
    153 / 301 (50.83%)
         occurrences all number
    337
    65
    266
    Headache
         subjects affected / exposed
    30 / 711 (4.22%)
    33 / 295 (11.19%)
    54 / 301 (17.94%)
         occurrences all number
    30
    47
    68
    Dysarthria
         subjects affected / exposed
    13 / 711 (1.83%)
    7 / 295 (2.37%)
    23 / 301 (7.64%)
         occurrences all number
    13
    7
    30
    Muscle contractions involuntary
         subjects affected / exposed
    15 / 711 (2.11%)
    8 / 295 (2.71%)
    16 / 301 (5.32%)
         occurrences all number
    17
    8
    17
    Somnolence
         subjects affected / exposed
    50 / 711 (7.03%)
    11 / 295 (3.73%)
    39 / 301 (12.96%)
         occurrences all number
    54
    12
    46
    Tremor
         subjects affected / exposed
    8 / 711 (1.13%)
    7 / 295 (2.37%)
    16 / 301 (5.32%)
         occurrences all number
    8
    10
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 711 (5.63%)
    37 / 295 (12.54%)
    48 / 301 (15.95%)
         occurrences all number
    41
    39
    60
    Fatigue
         subjects affected / exposed
    111 / 711 (15.61%)
    42 / 295 (14.24%)
    100 / 301 (33.22%)
         occurrences all number
    116
    44
    126
    Oedema peripheral
         subjects affected / exposed
    5 / 711 (0.70%)
    17 / 295 (5.76%)
    18 / 301 (5.98%)
         occurrences all number
    5
    19
    20
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 711 (1.55%)
    17 / 295 (5.76%)
    19 / 301 (6.31%)
         occurrences all number
    11
    19
    21
    Diarrhoea
         subjects affected / exposed
    10 / 711 (1.41%)
    17 / 295 (5.76%)
    22 / 301 (7.31%)
         occurrences all number
    10
    18
    26
    Nausea
         subjects affected / exposed
    77 / 711 (10.83%)
    23 / 295 (7.80%)
    66 / 301 (21.93%)
         occurrences all number
    86
    28
    91
    Dysphagia
         subjects affected / exposed
    6 / 711 (0.84%)
    10 / 295 (3.39%)
    15 / 301 (4.98%)
         occurrences all number
    6
    11
    15
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 711 (0.14%)
    14 / 295 (4.75%)
    18 / 301 (5.98%)
         occurrences all number
    1
    14
    18
    Dyspnoea
         subjects affected / exposed
    11 / 711 (1.55%)
    8 / 295 (2.71%)
    25 / 301 (8.31%)
         occurrences all number
    15
    8
    32
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 711 (0.42%)
    3 / 295 (1.02%)
    17 / 301 (5.65%)
         occurrences all number
    3
    3
    21
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 711 (2.11%)
    13 / 295 (4.41%)
    20 / 301 (6.64%)
         occurrences all number
    16
    13
    22
    Confusional state
         subjects affected / exposed
    17 / 711 (2.39%)
    3 / 295 (1.02%)
    32 / 301 (10.63%)
         occurrences all number
    20
    4
    36
    Depression
         subjects affected / exposed
    8 / 711 (1.13%)
    10 / 295 (3.39%)
    16 / 301 (5.32%)
         occurrences all number
    8
    10
    18
    Insomnia
         subjects affected / exposed
    16 / 711 (2.25%)
    12 / 295 (4.07%)
    31 / 301 (10.30%)
         occurrences all number
    18
    12
    32
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 711 (1.27%)
    20 / 295 (6.78%)
    15 / 301 (4.98%)
         occurrences all number
    9
    20
    17
    Muscle spasms
         subjects affected / exposed
    30 / 711 (4.22%)
    16 / 295 (5.42%)
    45 / 301 (14.95%)
         occurrences all number
    33
    23
    57
    Muscular weakness
         subjects affected / exposed
    21 / 711 (2.95%)
    20 / 295 (6.78%)
    34 / 301 (11.30%)
         occurrences all number
    22
    23
    43
    Musculoskeletal pain
         subjects affected / exposed
    6 / 711 (0.84%)
    17 / 295 (5.76%)
    9 / 301 (2.99%)
         occurrences all number
    7
    19
    12
    Pain in extremity
         subjects affected / exposed
    8 / 711 (1.13%)
    17 / 295 (5.76%)
    14 / 301 (4.65%)
         occurrences all number
    8
    21
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 711 (0.98%)
    19 / 295 (6.44%)
    19 / 301 (6.31%)
         occurrences all number
    7
    22
    20
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 711 (0.42%)
    15 / 295 (5.08%)
    9 / 301 (2.99%)
         occurrences all number
    3
    16
    11
    Urinary tract infection
         subjects affected / exposed
    5 / 711 (0.70%)
    14 / 295 (4.75%)
    17 / 301 (5.65%)
         occurrences all number
    5
    17
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 711 (3.23%)
    9 / 295 (3.05%)
    30 / 301 (9.97%)
         occurrences all number
    25
    10
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2013
    The major protocol changes were as follows: to increase enrollment up to 500 patients; to amend the inclusion criterion regarding SVC to >50% of predicted for age, height, and sex; to amend the inclusion criterion regarding maximum grip strength to allow up to 50 pounds for females and up to 70 pounds for males; to amend the exclusion criterion to add tizanidine as an exclusionary medication; to amend the exclusion criterion regarding bronchodilator medications to exclude patients requiring frequent use; to add an appendix listing the substrates, inhibitors, and inducers of CYP1A2 and the rationale for including them.
    19 Jul 2013
    The major protocol changes were as follows: to increase enrollment to approximately 680 patients (the increased enrollment was intended to reduce the impact of an error in study drug assignment that affected 58 patients initially randomized to and treated with tirasemtiv who were erroneously switched to placebo at Visits 5 and 6); to add an exclusion criterion for patients judged by the Investigator as actively suicidal and a suicide risk; to add a suicidality assessment at each study visit; to update the Statistical Methods section to describe the handling of the 58 affected patients in the statistical analyses and to add the suicidality assessments.

    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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