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    Clinical Trial Results:
    MS-SMART: A Multi-Arm Phase IIb Randomised, Double Blind Placebo-Controlled Clinical Trial Comparing The Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis

    Summary
    EudraCT number
    		 2012-005394-31
    Trial protocol
    		 GB  
    Global end of trial date
    04 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    12/0219
    Additional study identifiers
    ISRCTN number
    		 ISRCTN28440672
    US NCT number
    		 NCT01910259
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CinicalTrials.gov: NCT01910259
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, UCL Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Professor Jeremy Chataway , University College London , +44 203 448 3051, jeremy.chataway@uclh.nhs.uk
    Scientific contact
    Professor Jeremy Chataway , University College London , +44 203 448 3051, jeremy.chataway@uclh.nhs.uk
    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
    13 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective - To establish whether a drug, from a panel of 3 leading candidate neuroprotective drugs, slows the rate of brain volume loss in SPMS over 96 weeks using MRI-derived percentage brain volume change (PBVC). Secondary Progressive Multiple Sclerosis (SPMS) results from progressive nerve death or neuro-degeneration that causes accumulating and irreversible disability characterised by a range of devastating problems affecting walking, balance, vision, cognition, pain control, bladder and bowel function. MS-SMART will test 3 leading drugs to determine if any are effective at slowing the rate of brain shrinkage compared to placebo. Brain volume loss will be measured using MRI brain scans, which will also advance our understanding of how the drugs are providing neuroprotection in SPMS patients.
    Protection of trial subjects
    All 3 drugs used in the trial are in human use and have a good safety record. The participants were instructed to report any side effects/adverse events so that adequate treatment could be provided. The risks were explained in the Participant Information Leaflets. Three MRI scans were needed and these can cause some discomfort or claustrophobia. Participants unable to tolerate MRIs were excluded from the study. MRI is unsafe with persons who have permanent metal inplants such as pacemakers or permanent hearing aids and therefore, such patients were also excluded. MRI should not be done on pregnant women, therefore, prior to each MRI, women of child bearing potential had a urine pregnancy test to check that they were not pregnant. At one site participants were invited to take part in a biomarker substudy which involved an injection into the lower part of their back to remove a small amount of cerebrospinal fluid (CSF) for testing. This procedure has the small risk that a leak of cerebrospinal fluid (CSF) may develop after the procedure. Symptoms of this problem may include a persistent headache that does not go away after 1 to 2 days. A CSF leak can be treated with a blood “patch,” in which the person’s own blood is injected into the area where the leak is occurring in order for it clot and seal the leak. To minimise this risk atraumatic needles were used. This information was explained in the patient information leaflets.
    Background therapy
    		 NA
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    18 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 445
    Worldwide total number of subjects
    445
    EEA total number of subjects
    445
    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)
    435
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 445 patients were randomised between January 2015 and June 2016.

    Pre-assignment
    Screening details
    		 Before invitation to clinic for a full screening and consent visit, research staff checked the eligibility criteria that could be easily established, such as age and medications taken. This saved many people the inconvenience of a hospital visit and potential disappointment that they attended a clinic visit only to find out they were not eligible.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo –1 capsule twice per day for 2 years (1 capsule once per day for first 4 weeks). Identical placebo to match the 3 active drugs was manufactured by the same manufacturer over-encapsulating the IMPs. An equivalent amount of inert excipient was used in place of the active ingredients. The placebo was packaged for the trial by a MIA IMP holder third party manufacturer in UK.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    NA
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo twice per day for 2 years (1 capsule a day for first 4 weeks)

    Arm title
    		 Amiloride
    Arm description
    		 Amiloride HCL 5 mg twice per day for 2 years (5 mg once per day for first 4 weeks). For the purpose of the trial commercial Amiloride was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amiloride
    Investigational medicinal product code
    Other name
    Amiloride HCL
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Amiloride HCL 5 mg twice per day for 2 years (5 mg once per day for first 4 weeks).

    Arm title
    		 Riluzole
    Arm description
    		 Riluzole 50 mg twice per day for 2 years (50 mg once per day for first 4 weeks). For the purpose of the trial commercial Rilutek was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riluzole
    Investigational medicinal product code
    Other name
    Rilutek
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Riluzole 50 mg twice per day for 2 years (50 mg once per day for first 4 weeks).

    Arm title
    		 Fluoxetine
    Arm description
    		 Fluoxetine 20 mg twice per day for 2 years (20 mg once per day for first 4 weeks). Fluoxetine 20mg capsules was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluoxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Fluoxetine 20 mg twice per day for 2 years (20 mg once per day for first 4 weeks).

    Number of subjects in period 1
    		Placebo Amiloride Riluzole Fluoxetine
    Started
    112
    111
    111
    111
    Completed
    105
    105
    101
    102
    Not completed
    7
    6
    10
    9
         Adverse event, serious fatal
    -
    1
    1
    1
         Consent withdrawn by subject
    3
    2
    6
    4
         Physician decision
    -
    -
    1
    -
         Lost to follow-up
    4
    3
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo –1 capsule twice per day for 2 years (1 capsule once per day for first 4 weeks). Identical placebo to match the 3 active drugs was manufactured by the same manufacturer over-encapsulating the IMPs. An equivalent amount of inert excipient was used in place of the active ingredients. The placebo was packaged for the trial by a MIA IMP holder third party manufacturer in UK.

    Reporting group title
    Amiloride
    Reporting group description
    		 Amiloride HCL 5 mg twice per day for 2 years (5 mg once per day for first 4 weeks). For the purpose of the trial commercial Amiloride was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Reporting group title
    Riluzole
    Reporting group description
    		 Riluzole 50 mg twice per day for 2 years (50 mg once per day for first 4 weeks). For the purpose of the trial commercial Rilutek was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Reporting group title
    Fluoxetine
    Reporting group description
    		 Fluoxetine 20 mg twice per day for 2 years (20 mg once per day for first 4 weeks). Fluoxetine 20mg capsules was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Reporting group values
    		 Placebo Amiloride Riluzole Fluoxetine Total
    Number of subjects
    		 112 111 111 111 445
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 111 110 109 105 435
        From 65-84 years
    		 1 1 2 6 10
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.89 ( 7.16 ) 54.36 ( 7.18 ) 54.10 ( 6.75 ) 54.83 ( 7.11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 75 75 74 74 298
        Male
    		 37 36 37 37 147
    EDSS score
    EDSS score at randomisation
    Units: EDSS Score
        median (inter-quartile range (Q1-Q3))
    		 6 (5.5 to 6.5) 6 (5.5 to 6.5) 6 (5.5 to 6.5) 6 (5.5 to 6.5) -
    Number of years since first symptoms
    The approximate number of years since the patient experienced the first symptoms of the condition.
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 19 (13 to 29) 20 (13 to 30) 21 (16 to 26) 21 (16 to 29) -
    Number of years since progression
    The approximate number of years since disease progression
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 5 (3 to 10) 6 (4 to 11) 6 (4 to 10) 5 (3 to 10) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo –1 capsule twice per day for 2 years (1 capsule once per day for first 4 weeks). Identical placebo to match the 3 active drugs was manufactured by the same manufacturer over-encapsulating the IMPs. An equivalent amount of inert excipient was used in place of the active ingredients. The placebo was packaged for the trial by a MIA IMP holder third party manufacturer in UK.

    Reporting group title
    Amiloride
    Reporting group description
    		 Amiloride HCL 5 mg twice per day for 2 years (5 mg once per day for first 4 weeks). For the purpose of the trial commercial Amiloride was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Reporting group title
    Riluzole
    Reporting group description
    		 Riluzole 50 mg twice per day for 2 years (50 mg once per day for first 4 weeks). For the purpose of the trial commercial Rilutek was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Reporting group title
    Fluoxetine
    Reporting group description
    		 Fluoxetine 20 mg twice per day for 2 years (20 mg once per day for first 4 weeks). Fluoxetine 20mg capsules was over-encapsulated by a third party manufacturer holding a MIA IMP in conformance with EU cGMP, in order to achieve the blinding.

    Primary: Percentage Brain Volume Change

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    End point title
    		 Percentage Brain Volume Change
    End point description
    The primary endpoint was the percentage brain volume change (PBVC) between baseline and 96 weeks, as measured by the Structural Image Evaluation using Normalization of Atrophy (SIENA) method.
    End point type
    Primary
    End point timeframe
    From baseline to 96 weeks
    End point values
    		 Placebo Amiloride Riluzole Fluoxetine
    Number of subjects analysed
    99
    99
    99
    96
    Units: Percentage
        arithmetic mean (standard deviation)
    -1.3 ( 1.1 )
    -1.3 ( 1.0 )
    -1.4 ( 1.5 )
    -1.4 ( 1.5 )
    Statistical analysis title
    		 Comparison of Fluoxetine versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the PBVC outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), baseline normalised brain volume, and the minimisation variables: age, gender, treatment centre and EDSS at randomisation. Dunnett-adjusted p-values and simultaneous 95% confidence intervals were computed.
    Comparison groups
    Placebo v Fluoxetine
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.863 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.3
    Notes
    [1] - Note that the results were derived from a single model covering all 393 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 393.
    [2] - Dunnett-adjusted p-value to account for multiple testing.
    Statistical analysis title
    		 Comparison of Amiloride versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the PBVC outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), baseline normalised brain volume, and the minimisation variables: age, gender, treatment centre and EDSS at randomisation. Dunnett-adjusted p-values and simultaneous 95% confidence intervals were computed.
    Comparison groups
    Placebo v Amiloride
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.995 [4]
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.5
    Notes
    [3] - Note that the results were derived from a single model covering all 393 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 393.
    [4] - Dunnett-adjusted p-value to account for multiple testing.
    Statistical analysis title
    		 Comparison of Riluzole versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the PBVC outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), baseline normalised brain volume, and the minimisation variables: age, gender, treatment centre and EDSS at randomisation. Dunnett-adjusted p-values and simultaneous 95% confidence intervals were computed.
    Comparison groups
    Riluzole v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.771 [6]
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.3
    Notes
    [5] - Note that the results were derived from a single model covering all 393 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 393.
    [6] - Dunnett-adjusted p-value to account for multiple testing.

    Secondary: Number of new or enlarging T2 lesions

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    End point title
    		 Number of new or enlarging T2 lesions
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 96 weeks.
    End point values
    		 Placebo Amiloride Riluzole Fluoxetine
    Number of subjects analysed
    100
    101
    100
    99
    Units: Number per patient
        arithmetic mean (standard deviation)
    3.0 ( 6.9 )
    3.7 ( 8.1 )
    2.8 ( 5.7 )
    1.8 ( 5.3 )
    Statistical analysis title
    		 Comparison of Amiloride versus Placebo
    Statistical analysis description
    An over-dispersed Poisson regression model was fitted to the number of new or enlarging T2 lesions at 96 weeks; with trial arm, baseline T2 lesion volume, and the minimisation factors (age, gender, treatment centre and EDSS at randomisation) included as explanatory variables.
    Comparison groups
    Placebo v Amiloride
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.291
    Method
    		 Over-dispersed Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.83
    Notes
    [7] - Note that the results were derived from a single model covering all 400 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 400.
    Statistical analysis title
    		 Comparison of Fluoxetine versus Placebo
    Statistical analysis description
    An over-dispersed Poisson regression model was fitted to the number of new or enlarging T2 lesions at 96 weeks; with trial arm, baseline T2 lesion volume, and the minimisation factors (age, gender, treatment centre and EDSS at randomisation) included as explanatory variables.
    Comparison groups
    Placebo v Fluoxetine
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.012
    Method
    		 Over-dispersed Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.87
    Notes
    [8] - Note that the results were derived from a single model covering all 400 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 400.
    Statistical analysis title
    		 Comparison of Riluzole versus Placebo
    Statistical analysis description
    An over-dispersed Poisson regression model was fitted to the number of new or enlarging T2 lesions at 96 weeks; with trial arm, baseline T2 lesion volume, and the minimisation factors (age, gender, treatment centre and EDSS at randomisation) included as explanatory variables.
    Comparison groups
    Placebo v Riluzole
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.814
    Method
    		 Over-dispersed Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.45
    Notes
    [9] - Note that the results were derived from a single model covering all 400 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 400.

    Secondary: EDSS score

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    End point title
    		 EDSS score
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 96 weeks
    End point values
    		 Placebo Amiloride Riluzole Fluoxetine
    Number of subjects analysed
    96
    100
    92
    95
    Units: EDSS score
        arithmetic mean (standard deviation)
    6.0 ( 1.0 )
    6.0 ( 1.0 )
    6.0 ( 1.1 )
    5.9 ( 1.2 )
    Statistical analysis title
    		 Comparison of Fluoxetine versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the EDSS score outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), and the minimisation variables: age, gender, treatment centre and EDSS at randomisation.
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.535
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.2
    Notes
    [10] - Note that the results were derived from a single model covering all 383 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 383.
    Statistical analysis title
    		 Comparison of Riluzole versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the EDSS score outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), and the minimisation variables: age, gender, treatment centre and EDSS at randomisation.
    Comparison groups
    Placebo v Riluzole
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.628
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.2
    Notes
    [11] - Note that the results were derived from a single model covering all 383 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 383.
    Statistical analysis title
    		 Comparison of Amiloride versus Placebo
    Statistical analysis description
    A multiple linear regression model was fitted to the EDSS score outcome, including trial arm as an explanatory factor variable (with placebo as the reference category), and the minimisation variables: age, gender, treatment centre and EDSS at randomisation.
    Comparison groups
    Placebo v Amiloride
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.609
    Method
    		 Regression, Linear
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.2
    Notes
    [12] - Note that the results were derived from a single model covering all 383 participants in the analysis set. Therefore the actual number of subjects included in the analysis was 383.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    January 2015 to July 2018
    Adverse event reporting additional description
    Relapses or expected progressive changes due to SPMS were not reported as AEs. Two of the patients randomised to the riluzole treatment arm were prescribed fluoxetine by their GP during follow-up (these were protocol deviations). These two patients experienced a total of 5 adverse events and no serious adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Amiloride
    Reporting group description
    		 -

    Reporting group title
    Fluoxetine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Riluzole
    Reporting group description
    		 -

    Serious adverse events
    		 Amiloride Fluoxetine Placebo Riluzole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 111 (9.01%)
    7 / 111 (6.31%)
    13 / 112 (11.61%)
    12 / 111 (10.81%)
         number of deaths (all causes)
    1
    1
    0
    1
         number of deaths resulting from adverse events
    1
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastic lung cancer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Intracranial bleed
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder tumour
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent procedure (Chest pain)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hyperthemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Swelling of hand
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    major depressive disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    panic attack
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Deranged LFTs
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Broken Right Arm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cut on scalp due to fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug toxicity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured right wist
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured vertebrae
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury with 24 hour amnesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury with haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic left intra-capsular fracture of neck of femur
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    soft tissue damage due to fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Fast Atrial Fibrillation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation with Bradycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic heart disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Generalised seizure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasovagal syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small bowel obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gall stones
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder stone
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic Syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Low back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chest infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 111 (0.90%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    E-Coli Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure due to pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right broken hip
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 112 (0.89%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    post-operative wound infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 112 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amiloride Fluoxetine Placebo Riluzole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 111 (88.29%)
    105 / 111 (94.59%)
    100 / 112 (89.29%)
    101 / 111 (90.99%)
    Injury, poisoning and procedural complications
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 111 (7.21%)
    18 / 111 (16.22%)
    7 / 112 (6.25%)
    4 / 111 (3.60%)
         occurrences all number
    14
    63
    10
    9
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 111 (9.01%)
    9 / 111 (8.11%)
    4 / 112 (3.57%)
    10 / 111 (9.01%)
         occurrences all number
    10
    9
    4
    12
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 111 (19.82%)
    22 / 111 (19.82%)
    20 / 112 (17.86%)
    22 / 111 (19.82%)
         occurrences all number
    28
    32
    25
    30
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 111 (9.01%)
    9 / 111 (8.11%)
    9 / 112 (8.04%)
    10 / 111 (9.01%)
         occurrences all number
    10
    11
    10
    11
    Gastrointestinal disorders
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 111 (4.50%)
    12 / 111 (10.81%)
    5 / 112 (4.46%)
    7 / 111 (6.31%)
         occurrences all number
    5
    14
    5
    8
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 111 (11.71%)
    16 / 111 (14.41%)
    17 / 112 (15.18%)
    16 / 111 (14.41%)
         occurrences all number
    18
    27
    21
    18
    Dry mouth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 111 (5.41%)
    13 / 111 (11.71%)
    0 / 112 (0.00%)
    5 / 111 (4.50%)
         occurrences all number
    8
    13
    0
    6
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 111 (9.01%)
    20 / 111 (18.02%)
    9 / 112 (8.04%)
    22 / 111 (19.82%)
         occurrences all number
    15
    21
    11
    29
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 111 (4.50%)
    12 / 111 (10.81%)
    3 / 112 (2.68%)
    1 / 111 (0.90%)
         occurrences all number
    5
    16
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 111 (6.31%)
    11 / 111 (9.91%)
    3 / 112 (2.68%)
    2 / 111 (1.80%)
         occurrences all number
    7
    12
    3
    2
    Sore throat
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 111 (3.60%)
    6 / 111 (5.41%)
    5 / 112 (4.46%)
    1 / 111 (0.90%)
         occurrences all number
    4
    10
    6
    1
    Infections and infestations
    Chest infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 111 (6.31%)
    6 / 111 (5.41%)
    3 / 112 (2.68%)
    4 / 111 (3.60%)
         occurrences all number
    7
    8
    3
    6
    Common cold
    alternative assessment type: Non-systematic
         subjects affected / exposed
    25 / 111 (22.52%)
    26 / 111 (23.42%)
    29 / 112 (25.89%)
    22 / 111 (19.82%)
         occurrences all number
    32
    31
    48
    32
    UTI
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 111 (16.22%)
    12 / 111 (10.81%)
    14 / 112 (12.50%)
    18 / 111 (16.22%)
         occurrences all number
    44
    15
    25
    37

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2013
    Substantial Amendment 1 - Addition of new sites.
    08 Sep 2014
    Substantial Amendment 3* *Note there is no Sub Amendment 2. The CTA application was made using version 2 of the protocol. Protocol version 2 was not circulated to sites as it was known that following the CTA application changes would be require to the protocol, i.e. protocol V3.
    13 Oct 2015
    Substantial Amendment 4 - Eligibility criteria amended to exclude pts on high dose simvastatin, procedural change to CSF sub study and clarification in main PIL about side effects of fluoxetine.
    16 May 2017
    Substantial amendment 5 - Protocol updated to reflect changes to fluoxetine Summary of Product Characteristics.
    22 Feb 2018
    Substantial amendment 6 - To change site Principal Investigator.

    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.
    NA
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