Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Open-Label Extension Study of Tirasemtiv for Patients with Amyotrophic Lateral Sclerosis (ALS) who Completed VITALITY-ALS (CY 4031)

    Summary
    EudraCT number
    		 2016-002629-13
    Trial protocol
    		 IE   ES   NL   BE   PT   FR   GB   IT  
    Global end of trial date
    26 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Mar 2020
    First version publication date
    05 Mar 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CY 4033
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02936635
    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 6506242929, medicalaffairs@cytokinetics.com
    Scientific contact
    Medical Affairs, Cytokinetics, Inc., +1 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
    26 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the long-term safety and tolerability of tirasemtiv in patients with ALS.
    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 guidelines, consistent with Good Clinical Practice (GCP). All patients provided informed written consent before any protocol-specific procedures were performed.
    Background therapy
    		 None
    Evidence for comparator
    		 The CY 4033 trial was an open-label extension study of CY 4031, a randomized, double-blind, controlled study of tirasemtiv versus placebo in patients with ALS. All patients in CY 4033 had completed CY 4031. Following enrollment in CY 4033, patients received tirasemtiv at a dose of 250 mg/day, which was up-titrated to 375 mg/day at Week 4 and then 500 mg/day at Week 6. No comparator arm was used in CY 4033.
    Actual start date of recruitment
    17 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 52
    Country: Number of subjects enrolled
    United States: 160
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Ireland: 8
    Worldwide total number of subjects
    280
    EEA total number of subjects
    68
    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)
    213
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in patients with amyotrophic lateral sclerosis (ALS) between 17 October 2016 (date first patient enrolled) through 26 October 2018 (date last patient completed) at 69 sites in Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, the United Kingdom, and the United States.

    Pre-assignment
    Screening details
    		 280 patients who had completed CY 4031 enrolled in CY 4033. Patients were categorized by treatment received in CY 4031. The Delayed Start treatment group (n=115) included patients who received placebo in CY 4031 and tirasemtiv in CY 4033. The Early Start treatment group (n=165) included patients who received tirasemtiv in both CY 4031 and CY 4033.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Delayed Start Treatment
    Arm description
    		 The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tirasemtiv
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tirasemtiv tablets were administered orally, twice daily.

    Arm title
    		 Early Start Treatment
    Arm description
    		 The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tirasemtiv
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tirasemtiv tablets were administered orally, twice daily.

    Number of subjects in period 1
    		Delayed Start Treatment Early Start Treatment
    Started
    115
    165
    Completed
    0
    0
    Not completed
    115
    165
         Adverse event, serious fatal
    9
    15
         Consent withdrawn by subject
    8
    15
         Physician decision
    2
    9
         Adverse event, non-fatal
    43
    25
         Various reasons
    31
    65
         Lost to follow-up
    1
    2
         Progressive disease
    10
    18
         Sponsor discretion
    10
    16
         Protocol deviation
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Delayed Start Treatment
    Reporting group description
    		 The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.

    Reporting group title
    Early Start Treatment
    Reporting group description
    		 The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.

    Reporting group values
    		 Delayed Start Treatment Early Start Treatment Total
    Number of subjects
    		 115 165 280
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 89 124 213
        From 65-84 years
    		 26 41 67
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 37 46 83
        Male
    		 78 119 197

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Delayed Start Treatment
    Reporting group description
    		 The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.

    Reporting group title
    Early Start Treatment
    Reporting group description
    		 The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.

    Primary: The long-term safety and tolerability of tirasemtiv as measured by the incidence of adverse events

    		 Close Top of page
    End point title
    		 The long-term safety and tolerability of tirasemtiv as measured by the incidence of adverse events [1]
    End point description
    End point type
    Primary
    End point timeframe
    From the first administration of tirasemtiv through 28 days after the patient's last dose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary objective of this extension study was to evaluate the long-term safety and tolerability of open-label tirasemtiv in patients who had completed participation in CY 4031. As such, no formal statistical hypothesis testing or sample size calculation was conducted. The primary endpoint of incidence of adverse events was summarized using descriptive statistics.
    End point values
    		 Delayed Start Treatment Early Start Treatment
    Number of subjects analysed
    115
    165
    Units: Percent of patients
        number (not applicable)
    97.4
    95.2
    No statistical analyses for this end point

    Secondary: Change from CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033

    		 Close Top of page
    End point title
    		 Change from CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033
    End point description
    Change from baseline in percent predicted slow vital capacity. Relative difference between groups (Early Start versus Delayed Start treatment groups).
    End point type
    Secondary
    End point timeframe
    Change from baseline in CY 4031 to Week 24 in CY 4033
    End point values
    		 Delayed Start Treatment Early Start Treatment
    Number of subjects analysed
    48 [2]
    94 [3]
    Units: Percent predicted slow vital capacity
        least squares mean (standard error)
    -28.79 ( 2.845 )
    -32.69 ( 2.285 )
    Notes
    [2] - Patients who received at least 1 dose of tirasemtiv and had a Week 24 slow vital capacity assessment
    [3] - Patients who received at least 1 dose of tirasemtiv and had a Week 24 slow vital capacity assessment
    Statistical analysis title
    		 Comparison of changes from baseline
    Statistical analysis description
    Difference of LS means (Early Start minus Delayed Start)
    Comparison groups
    Delayed Start Treatment v Early Start Treatment
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2821
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.035
         upper limit
    		 3.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.619

    Secondary: Change from CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033

    		 Close Top of page
    End point title
    		 Change from CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033
    End point description
    Change from baseline in percent predicted slow vital capacity. Relative difference between groups (Early Start versus Delayed Start treatment groups).
    End point type
    Secondary
    End point timeframe
    Change from baseline in CY 4031 to Week 48 in CY 4033
    End point values
    		 Delayed Start Treatment Early Start Treatment
    Number of subjects analysed
    28 [4]
    45 [5]
    Units: Percent predicted slow vital capacity
        least squares mean (standard error)
    -35.55 ( 3.332 )
    -40.87 ( 2.667 )
    Notes
    [4] - Patients who received at least 1 dose of tirasemtiv and had a Week 48 slow vital capacity assessment
    [5] - Patients who received at least 1 dose of tirasemtiv and had a Week 48 slow vital capacity assessment
    Statistical analysis title
    		 Comparison of changes from baseline
    Statistical analysis description
    Difference of LS means (Early Start minus Delayed Start)
    Comparison groups
    Delayed Start Treatment v Early Start Treatment
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2118
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.711
         upper limit
    		 3.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.242

    Secondary: Change from CY 4031 Baseline in ALS Functional Rating Scale – Revised (ALSFRS-R) Total Score at Week 24

    		 Close Top of page
    End point title
    		 Change from CY 4031 Baseline in ALS Functional Rating Scale – Revised (ALSFRS-R) Total Score at Week 24
    End point description
    Change from baseline in ALSFRS-R total score. Relative difference between groups (Early Start versus Delayed Start treatment groups).
    End point type
    Secondary
    End point timeframe
    Change from baseline in CY 4031 to Week 24 in CY 4033
    End point values
    		 Delayed Start Treatment Early Start Treatment
    Number of subjects analysed
    75 [6]
    120 [7]
    Units: ALSFRS-R Total Score
        least squares mean (standard error)
    -13.78 ( 0.934 )
    -14.35 ( 0.767 )
    Notes
    [6] - Patients who received at least 1 dose of tirasemtiv and had a Week 24 slow vital capacity assessment
    [7] - Patients who received at least 1 dose of tirasemtiv and had a Week 24 slow vital capacity assessment
    Statistical analysis title
    		 Comparison of changes from baseline
    Statistical analysis description
    Difference of LS means (Early Start minus Delayed Start)
    Comparison groups
    Delayed Start Treatment v Early Start Treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6354
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.946
         upper limit
    		 1.801
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.205

    Secondary: Change from CY 4031 Baseline in ALSFRS-R Total Score at Week 48

    		 Close Top of page
    End point title
    		 Change from CY 4031 Baseline in ALSFRS-R Total Score at Week 48
    End point description
    Change from baseline in ALSFRS-R total score. Relative difference between groups (Early Start versus Delayed Start treatment groups).
    End point type
    Secondary
    End point timeframe
    Change from baseline in CY 4031 to Week 48 in CY 4033
    End point values
    		 Delayed Start Treatment Early Start Treatment
    Number of subjects analysed
    38 [8]
    62 [9]
    Units: ALSFRS-R Total Score
        least squares mean (standard error)
    -17.61 ( 1.171 )
    -17.82 ( 0.956 )
    Notes
    [8] - Patients who received at least 1 dose of tirasemtiv and had a Week 48 slow vital capacity assessment
    [9] - Patients who received at least 1 dose of tirasemtiv and had a Week 48 slow vital capacity assessment
    Statistical analysis title
    		 Comparison of changes from baseline
    Statistical analysis description
    Difference of LS means (Early Start minus Delayed Start)
    Comparison groups
    Early Start Treatment v Delayed Start Treatment
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8887
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.186
         upper limit
    		 2.763
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.509

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    For each patient, adverse events were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Delayed Start Treatment
    Reporting group description
    		 The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.

    Reporting group title
    Early Start Treatment
    Reporting group description
    		 The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.

    Reporting group title
    Total
    Reporting group description
    		 All enrolled patients (those in the Delayed Start Treatment group + those in the Early Start Treatment group)

    Serious adverse events
    		 Delayed Start Treatment Early Start Treatment Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 115 (27.83%)
    53 / 165 (32.12%)
    85 / 280 (30.36%)
         number of deaths (all causes)
    16
    27
    43
         number of deaths resulting from adverse events
    16
    27
    43
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 165 (1.21%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Euthanasia
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Asthenia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Feeling abnormal
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    6 / 115 (5.22%)
    8 / 165 (4.85%)
    14 / 280 (5.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
    0 / 14
         deaths causally related to treatment / all
    0 / 6
    0 / 6
    0 / 12
    Pneumonia aspiration
         subjects affected / exposed
    2 / 115 (1.74%)
    7 / 165 (4.24%)
    9 / 280 (3.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    2 / 115 (1.74%)
    4 / 165 (2.42%)
    6 / 280 (2.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 165 (0.61%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Obstructive airways disorder
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bronchial secretion retention
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 165 (1.82%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 115 (2.61%)
    1 / 165 (0.61%)
    4 / 280 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 165 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 165 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Traumatic fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    3 / 165 (1.82%)
    4 / 280 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 165 (1.21%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Acute myocardial infarction
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         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
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    4 / 115 (3.48%)
    13 / 165 (7.88%)
    17 / 280 (6.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 14
    0 / 18
         deaths causally related to treatment / all
    0 / 4
    0 / 11
    0 / 15
    Dizziness
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 165 (1.21%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 115 (1.74%)
    3 / 165 (1.82%)
    5 / 280 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 115 (0.00%)
    9 / 165 (5.45%)
    9 / 280 (3.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Lobar pneumonia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 165 (1.21%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 165 (0.61%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 165 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 165 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 165 (0.61%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 165 (1.21%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Delayed Start Treatment Early Start Treatment Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 115 (96.52%)
    155 / 165 (93.94%)
    266 / 280 (95.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 115 (11.30%)
    9 / 165 (5.45%)
    22 / 280 (7.86%)
         occurrences all number
    15
    9
    24
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    22 / 115 (19.13%)
    23 / 165 (13.94%)
    45 / 280 (16.07%)
         occurrences all number
    44
    45
    89
    Contusion
         subjects affected / exposed
    11 / 115 (9.57%)
    13 / 165 (7.88%)
    24 / 280 (8.57%)
         occurrences all number
    17
    20
    37
    Skin abrasion
         subjects affected / exposed
    9 / 115 (7.83%)
    4 / 165 (2.42%)
    13 / 280 (4.64%)
         occurrences all number
    11
    9
    20
    Post-traumatic pain
         subjects affected / exposed
    6 / 115 (5.22%)
    4 / 165 (2.42%)
    10 / 280 (3.57%)
         occurrences all number
    9
    4
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    49 / 115 (42.61%)
    44 / 165 (26.67%)
    93 / 280 (33.21%)
         occurrences all number
    73
    63
    136
    Somnolence
         subjects affected / exposed
    28 / 115 (24.35%)
    27 / 165 (16.36%)
    55 / 280 (19.64%)
         occurrences all number
    33
    35
    68
    Headache
         subjects affected / exposed
    8 / 115 (6.96%)
    14 / 165 (8.48%)
    22 / 280 (7.86%)
         occurrences all number
    8
    17
    25
    Dysarthria
         subjects affected / exposed
    7 / 115 (6.09%)
    6 / 165 (3.64%)
    13 / 280 (4.64%)
         occurrences all number
    9
    7
    16
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    42 / 115 (36.52%)
    51 / 165 (30.91%)
    93 / 280 (33.21%)
         occurrences all number
    58
    65
    123
    Asthenia
         subjects affected / exposed
    14 / 115 (12.17%)
    8 / 165 (4.85%)
    22 / 280 (7.86%)
         occurrences all number
    17
    11
    28
    Oedema peripheral
         subjects affected / exposed
    6 / 115 (5.22%)
    6 / 165 (3.64%)
    12 / 280 (4.29%)
         occurrences all number
    8
    6
    14
    Feeling abnormal
         subjects affected / exposed
    6 / 115 (5.22%)
    4 / 165 (2.42%)
    10 / 280 (3.57%)
         occurrences all number
    7
    6
    13
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    20 / 115 (17.39%)
    33 / 165 (20.00%)
    53 / 280 (18.93%)
         occurrences all number
    26
    38
    64
    Nausea
         subjects affected / exposed
    19 / 115 (16.52%)
    22 / 165 (13.33%)
    41 / 280 (14.64%)
         occurrences all number
    21
    28
    49
    Dysphagia
         subjects affected / exposed
    12 / 115 (10.43%)
    9 / 165 (5.45%)
    21 / 280 (7.50%)
         occurrences all number
    13
    9
    22
    Salivary hypersecretion
         subjects affected / exposed
    8 / 115 (6.96%)
    10 / 165 (6.06%)
    18 / 280 (6.43%)
         occurrences all number
    9
    12
    21
    Diarrhoea
         subjects affected / exposed
    3 / 115 (2.61%)
    12 / 165 (7.27%)
    15 / 280 (5.36%)
         occurrences all number
    3
    14
    17
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 115 (5.22%)
    4 / 165 (2.42%)
    10 / 280 (3.57%)
         occurrences all number
    6
    4
    10
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    16 / 115 (13.91%)
    16 / 165 (9.70%)
    32 / 280 (11.43%)
         occurrences all number
    17
    20
    37
    Cough
         subjects affected / exposed
    7 / 115 (6.09%)
    7 / 165 (4.24%)
    14 / 280 (5.00%)
         occurrences all number
    9
    9
    18
    Choking
         subjects affected / exposed
    7 / 115 (6.09%)
    4 / 165 (2.42%)
    11 / 280 (3.93%)
         occurrences all number
    8
    5
    13
    Increased upper airway secretion
         subjects affected / exposed
    6 / 115 (5.22%)
    5 / 165 (3.03%)
    11 / 280 (3.93%)
         occurrences all number
    6
    5
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 115 (13.91%)
    14 / 165 (8.48%)
    30 / 280 (10.71%)
         occurrences all number
    16
    16
    32
    Anxiety
         subjects affected / exposed
    16 / 115 (13.91%)
    12 / 165 (7.27%)
    28 / 280 (10.00%)
         occurrences all number
    19
    13
    32
    Depression
         subjects affected / exposed
    16 / 115 (13.91%)
    10 / 165 (6.06%)
    26 / 280 (9.29%)
         occurrences all number
    19
    11
    30
    Confusional state
         subjects affected / exposed
    8 / 115 (6.96%)
    8 / 165 (4.85%)
    16 / 280 (5.71%)
         occurrences all number
    10
    8
    18
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    16 / 115 (13.91%)
    33 / 165 (20.00%)
    49 / 280 (17.50%)
         occurrences all number
    25
    45
    70
    Muscle spasms
         subjects affected / exposed
    18 / 115 (15.65%)
    10 / 165 (6.06%)
    28 / 280 (10.00%)
         occurrences all number
    20
    12
    32
    Back pain
         subjects affected / exposed
    9 / 115 (7.83%)
    7 / 165 (4.24%)
    16 / 280 (5.71%)
         occurrences all number
    9
    7
    16
    Pain in extremity
         subjects affected / exposed
    4 / 115 (3.48%)
    9 / 165 (5.45%)
    13 / 280 (4.64%)
         occurrences all number
    6
    12
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 115 (6.96%)
    18 / 165 (10.91%)
    26 / 280 (9.29%)
         occurrences all number
    10
    22
    32
    Urinary tract infection
         subjects affected / exposed
    5 / 115 (4.35%)
    10 / 165 (6.06%)
    15 / 280 (5.36%)
         occurrences all number
    6
    10
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 115 (13.91%)
    13 / 165 (7.88%)
    29 / 280 (10.36%)
         occurrences all number
    19
    15
    34

    More information

    		 Close Top of page

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sat Apr 20 05:31:46 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA