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    Clinical Trial Results:
    Phase II/III, Multicenter, Randomized, Parallel Group, Double-Blind, Placebo Controlled Study to Assess Safety and Efficacy of TRO19622 in Amyotrophic Lateral Sclerosis (ALS) Patients Treated with Riluzole

    Summary
    EudraCT number
    		 2008-007320-25
    Trial protocol
    		 DE   FR   GB   BE   ES  
    Global end of trial date
    15 Sep 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Apr 2017
    First version publication date
    02 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WN29853
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00868166
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +4161 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +4161 6878333, global.trial_information@roche.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
    02 Dec 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of TRO19622 330 milligrams (mg) once daily as add-on therapy to riluzole 50 mg twice daily in the treatment of participants suffering from ALS as compared to placebo, assessed by the overall survival at 18 months.
    Protection of trial subjects
    This protocol complied with the principal laid down by the 18th World Medical Assembly (Helsinki, 1964 an following amendments) and all applicable amendments laid down by the World Medical Assemblies, as well as the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. The trial complied with the laws and regulations of the country in which the study was performed, and any applicable guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2009
    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
    France: 221
    Country: Number of subjects enrolled
    Germany: 147
    Country: Number of subjects enrolled
    Spain: 67
    Country: Number of subjects enrolled
    United Kingdom: 52
    Country: Number of subjects enrolled
    Belgium: 25
    Worldwide total number of subjects
    512
    EEA total number of subjects
    512
    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)
    378
    From 65 to 84 years
    134
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 617 participants were screened, of which, 512 participants were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to TRO19622 once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to TRO19622 was administered once daily orally for 18 months.

    Arm title
    		 TRO19622
    Arm description
    		 Participants received TRO19622 at a dose of 330 mg once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TRO19622
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    TRO19622 was administered at a dose of 330 mg once daily orally for 18 months.

    Number of subjects in period 1
    		Placebo TRO19622
    Started
    253
    259
    Completed
    139
    147
    Not completed
    114
    112
         Consent withdrawn by subject
    25
    33
         Death
    65
    58
         Major protocol deviation
    -
    1
         Adverse event
    10
    9
         Non-compliance with study drug
    1
    1
         Unspecified
    10
    9
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to TRO19622 once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Reporting group title
    TRO19622
    Reporting group description
    		 Participants received TRO19622 at a dose of 330 mg once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Reporting group values
    		 Placebo TRO19622 Total
    Number of subjects
    		 253 259 512
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0
        >18 and <65 years
    		 193 185 378
        >=65 years
    		 60 74 134
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ( 11.2 ) 57.3 ( 11.2 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 89 92 181
        Male
    		 164 167 331

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to TRO19622 once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Reporting group title
    TRO19622
    Reporting group description
    		 Participants received TRO19622 at a dose of 330 mg once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    OS was calculated as the time from the date of randomization until the date of death or last follow-up at 18 months (or 548 days). Kaplan-Meier estimate was used for analysis. Intent-to-treat (ITT) population included all randomized participants irrespective of whether study medication was administered, and regardless of eligibility status. Here, ‘99999’ represents data were not estimable as median value had not been reached in either of the treatment arms at 18 months.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to Month 18)
    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: "No statistical analysis was planned for this endpoint."
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Were Alive

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    End point title
    		 Percentage of Participants Who Were Alive
    End point description
    ITT population.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: percentage of participants
        number (confidence interval 95%)
    67.5 (61 to 73.1)
    69.4 (63 to 74.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Stratified Log-Rank test. Stratification criteria: site of onset (bulbar or spinal)

    Secondary: Time to Failure

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    End point title
    		 Time to Failure
    End point description
    Time to failure was defined as the time from randomization to the time of the occurrence at least one of the following 3 events: death, tracheostomy, or non-invasive ventilation. Non-invasive ventilation was defined as more than (>) 23 hours of non-invasive ventilation daily for 14 consecutive days. Kaplan-Meier estimate was used for analysis. ITT population. Here, ‘99999’ represents data were not estimable as median value had not been reached in either of the treatment arms at 18 months.
    End point type
    Secondary
    End point timeframe
    Baseline up to death, tracheostomy, or non-invasive ventilation, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Failure

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    End point title
    		 Percentage of Participants With Failure
    End point description
    Failure was defined as the occurrence at least one of the following 3 events: death, tracheostomy, or non-invasive ventilation. Non-invasive ventilation was defined as more than (>) 23 hours of non-invasive ventilation daily for 14 consecutive days. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to death, tracheostomy, or non-invasive ventilation, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: percentage of participants
        number (confidence interval 95%)
    65.5 (59.1 to 71.2)
    67.1 (60.5 to 72.7)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73 [3]
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - Non-stratified Log-Rank test
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Stratified Log-Rank test. Stratification criteria: site of onset (bulbar or spinal)

    Secondary: Time to Total Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALS FRS-R) Global Score Less than (<) 30 or Death

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    End point title
    		 Time to Total Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALS FRS-R) Global Score Less than (<) 30 or Death
    End point description
    ALS FRS-R scale is a validated rating instrument for monitoring the progression of disability in ALS participants. Participants were asked to rate their functions for the following 12 parameters each on the scale of 0-4 (higher score indicated normal function): speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, respiratory insufficiency. Global score was the sum of individual scores and ranged from 0-48 (higher score indicated normal function). Time to ALS FRS-R global score <30 or death was reported. Kaplan-Meier estimate was used for analysis. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to ALS FRS-R global score <30 or death, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: days
        median (confidence interval 95%)
    341 (265 to 358)
    372 (336 to 448)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Without ALS FRS-R Global Score <30 or Death

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    End point title
    		 Percentage of Participants Without ALS FRS-R Global Score <30 or Death
    End point description
    ALS FRS-R scale is a validated rating instrument for monitoring the progression of disability in ALS participants. Participants were asked to rate their functions for the following 12 parameters each on the scale of 0-4 (higher score indicated normal function): speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, respiratory insufficiency. Global score was the sum of individual scores and ranged from 0-48 (higher score indicated normal function). Percentage of participants without ALS FRS-R global score <30 or death was reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to ALS FRS-R global score <30 or death, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: percentage of participants
        number (confidence interval 95%)
    24.9 (19.2 to 30.8)
    28.2 (22.5 to 34.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - Stratified Log-Rank test. Stratification criteria: site of onset (bulbar or spinal)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2 [6]
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - Non-stratified Log-Rank Test

    Secondary: Time to Slow Vital Capacity (SVC) Predicted <70 Percent (%) or Death

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    End point title
    		 Time to Slow Vital Capacity (SVC) Predicted <70 Percent (%) or Death
    End point description
    SVC was measured using spirometer. Time to SVC predicted <70% or death was reported. Kaplan-Meier estimate was used for analysis. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to SVC predicted <70% or death, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: days
        median (confidence interval 95%)
    335 (265 to 441)
    358 (283 to 442)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Without SVC Predicted <70% or Death

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    End point title
    		 Percentage of Participants Without SVC Predicted <70% or Death
    End point description
    SVC was measured using spirometer. Percentage of Participants Without SVC predicted <70% or death was reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to SVC predicted <70% or death, whichever occurred first (up to Month 18)
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: percentage of participants
        number (confidence interval 95%)
    28.9 (23 to 35.1)
    31.9 (25.6 to 38.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56 [7]
    Method
    		 Logrank
    Confidence interval
    Notes
    [7] - Stratified Log-Rank test. Stratification criteria: site of onset (bulbar or spinal)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47 [8]
    Method
    		 Logrank
    Confidence interval
    Notes
    [8] - Non-stratified Log-Rank Test

    Secondary: Total ALS FRS-R Global Score

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    End point title
    		 Total ALS FRS-R Global Score
    End point description
    ALS FRS-R scale is a validated rating instrument for monitoring the progression of disability in ALS participants. Participants were asked to rate their functions for the following 12 parameters each on the scale of 0-4 (higher score indicated normal function): speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, respiratory insufficiency. Global score was the sum of individual scores and ranged from 0-48 (higher score indicated normal function). ITT population. 'Number of Subjects Analyzed' = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    201
    205
    Units: units on a scale
        arithmetic mean (standard deviation)
    30.4 ( 8.23 )
    32.7 ( 7.72 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0184 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 3.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.81
    Notes
    [9] - Mixed-effect repeated measures model

    Secondary: SVC (in Liters)

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    End point title
    		 SVC (in Liters)
    End point description
    SVC was measured using spirometer. ITT population. 'Number of Subjects Analyzed' = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    190
    195
    Units: liters
        arithmetic mean (standard deviation)
    2.95 ( 1.14 )
    3.04 ( 1.22 )
    No statistical analyses for this end point

    Secondary: SVC Percent Predicted

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    End point title
    		 SVC Percent Predicted
    End point description
    SVC was measured using spirometer. Percent predicted SVC was reported. ITT population. 'Number of Subjects Analyzed' = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    190
    195
    Units: %SVC
        arithmetic mean (standard deviation)
    75.5 ( 24.7 )
    77.9 ( 24.3 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3838 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.79
         upper limit
    		 7.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.55
    Notes
    [10] - Mixed-effect repeated measures model

    Secondary: McGill Quality of Life (QoL) Scale Score

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    End point title
    		 McGill Quality of Life (QoL) Scale Score
    End point description
    QoL was assessed with the McGill single item questionnaire. The questionnaire required the participant to rate on a visual analog scale of 0 (very bad) to 10 (excellent). ITT population. 'Number of Subjects Analyzed' = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    197
    202
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.25 ( 2 )
    5.3 ( 2.14 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9172 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [11] - Mixed-effect repeated measures model

    Secondary: Manual Muscle Test (MMT) Global Score

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    End point title
    		 Manual Muscle Test (MMT) Global Score
    End point description
    MMT was performed by trained experienced personnel for 30 items each on a scale of 0-5 (higher score indicated normal function). Global score was the sum of individual scores and ranged from 0-150 (higher score indicated normal function). ITT population. 'Number of Subjects Analyzed' = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    196
    200
    Units: units on a scale
        arithmetic mean (standard deviation)
    109 ( 27.1 )
    112 ( 27.1 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v TRO19622
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3699 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 8.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.86
    Notes
    [12] - Mixed-effect repeated measures model

    Secondary: Percentage of Participants With Non-Invasive Positive Pressure Ventilation (NIPPV)

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    End point title
    		 Percentage of Participants With Non-Invasive Positive Pressure Ventilation (NIPPV)
    End point description
    NIPPV was defined as >23 hours of non-invasive ventilation daily for 14 consecutive days. ITT population. 'n' = participants who were evaluable for this each category for each reporting group respectively.
    End point type
    Secondary
    End point timeframe
    Months 1, 2, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo TRO19622
    Number of subjects analysed
    253
    259
    Units: percentage of participants
    number (not applicable)
        Month 1 (n = 253, 259)
    0
    0
        Month 2 (n = 248, 248)
    0.4
    0
        Month 3 (n = 250, 256)
    0.4
    0
        Month 6 (n = 240, 248)
    0
    0.8
        Month 9 (n = 222, 227)
    0
    0
        Month 12 (n = 202, 205)
    0.5
    0
        Month 15 (n = 177, 181)
    1.1
    1.7
        Month 18 (n = 152, 164)
    0.7
    1.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 18 months
    Adverse event reporting additional description
    Safety population included all participants who had at least one intake of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    V 11.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to TRO19622 once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Reporting group title
    TRO19622
    Reporting group description
    		 Participants received TRO19622 at a dose of 330 mg once daily orally along with concurrent riluzole at a dose of 50 mg twice daily orally for 18 months.

    Serious adverse events
    		 Placebo TRO19622
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 253 (25.69%)
    68 / 259 (26.25%)
         number of deaths (all causes)
    80
    79
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial carcinoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 253 (0.79%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mechanical ventilation
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Application site inflammation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    8 / 253 (3.16%)
    14 / 259 (5.41%)
         occurrences causally related to treatment / all
    2 / 9
    2 / 14
         deaths causally related to treatment / all
    0 / 4
    1 / 6
    Pulmonary embolism
         subjects affected / exposed
    7 / 253 (2.77%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    4 / 7
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 253 (2.37%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    5 / 253 (1.98%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 253 (0.40%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchial secretion retention
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocturnal dyspnoea
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sleep disorder
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint sprain
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning deliberate
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atrial flutter
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Areflexia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnic encephalopathy
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningorrhagia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    2 / 253 (0.79%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 253 (1.98%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 253 (1.19%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fungal infection
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo TRO19622
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 253 (39.92%)
    98 / 259 (37.84%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    19 / 253 (7.51%)
    26 / 259 (10.04%)
         occurrences all number
    23
    34
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 253 (5.14%)
    7 / 259 (2.70%)
         occurrences all number
    13
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 253 (7.11%)
    19 / 259 (7.34%)
         occurrences all number
    20
    23
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 253 (5.93%)
    27 / 259 (10.42%)
         occurrences all number
    18
    31
    Nausea
         subjects affected / exposed
    16 / 253 (6.32%)
    15 / 259 (5.79%)
         occurrences all number
    19
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 253 (5.93%)
    7 / 259 (2.70%)
         occurrences all number
    16
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    15 / 253 (5.93%)
    10 / 259 (3.86%)
         occurrences all number
    18
    12
    Nasopharyngitis
         subjects affected / exposed
    36 / 253 (14.23%)
    22 / 259 (8.49%)
         occurrences all number
    45
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2010
    Introduced to implement a validated method of administering study treatments for participants with swallowing difficulties. The method involves administration via the gastrostomy tube to increase participant’s comfort and avoid complications associated with swallowing difficulties. The method was verified with treating centers and validated by a steering committee. It was not expected to influence pharmacokinetic parameters.
    22 Apr 2010
    Introduced to ensure investigators collected maximum data in the event of premature participant withdrawal for a reason other than death.
    06 Dec 2010
    A modification of the text was made to ensure agreement between the specified analysis and the analysis method used to calculate the sample size and power calculation. The term “18 month survival rate” was thus replaced with “overall survival”.

    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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