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    Clinical Trial Results:
    Efficacy and safety of bumetanide oral liquid formulation in children aged from 2 to less than 7 years old with Autism Spectrum Disorder. A 6-month randomised, double-blind, placebo controlled multicentre parallel group study to evaluate efficacy and safety of bumetanide 0.5mg twice a day followed by an open label active 6-month treatment period with bumetanide (0.5mg twice a day) and a 6 weeks discontinuation period after treatment stop.

    Summary
    EudraCT number
    		 2017-004420-30
    Trial protocol
    		 GB   FR   ES   NL   HU   PT   PL   IE   CZ   SK   IT  
    Global end of trial date
    26 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 May 2022
    First version publication date
    11 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-95008-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03715153
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratorios Servier SL
    Sponsor organisation address
    Avenida de los Madroños, 33, Madrid, Spain, 28043
    Public contact
    Dpto. Investigación y Desarrollo, Laboratorios Servier SL, +34 917489662, itziar.martinezmelchor@servier.com
    Scientific contact
    Dpto. Investigación y Desarrollo, Laboratorios Servier SL, +34 917489662, itziar.martinezmelchor@servier.com
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Therapeutic Area in Neurology, Institut de Recherches Internationales Servier, +33 01 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Area in Neurology, Institut de Recherches Internationales Servier, +33 01 55 72 43 66, clinicaltrials@servier.com
    Sponsor organisation name
    Servier Research & Development Ltd
    Sponsor organisation address
    Sefton House, Sefton Park, Bells Hill, Stoke Poges, Berkshire, United Kingdom, SL2 4JS
    Public contact
    Therapeutic Area in Neurology, Servier Research & Development Ltd, +33 01 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Area in Neurology, Servier Research & Development Ltd, +33 01 55 72 43 66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001303-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of bumetanide (0.5mg BID) oral liquid formulation compared to placebo in the improvement of ASD core symptoms after 6 months of treatment in ASD children aged from 2 to less than 7 years old
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Oct 2018
    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
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 30
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    211
    EEA total number of subjects
    152
    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)
    211
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male and female patients from 2 to less than 7 years old. Primary diagnosis of ASD as per Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , confirmed by Autism Diagnostic Observation Schedule-Generic (ADOS-2) and Autism Diagnosis Interview Revised, Clinical Global Impression Severity (CGI-S) Score ≥ 4, CARS2 total raw score ≥ 34.

    Period 1
    Period 1 title
    Double-blind period (From W000 to W026)
    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
    		 S95008 - Double-blind period
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95008
    Investigational medicinal product code
    S95008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The IMP dispensed was an oral solution of 0.5 mg/mL of S95008 (bumetanide). All the patients took orally the study treatment twice a day: - in the morning at wake up. - in the afternoon, 3 hours before going to bed at the latest. The volume of the oral solution was adapted according to a body-weight basis for patients with a weight lower than 25 kg.

    Arm title
    		 Placebo - Double-blind period
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The IMP dispensed was an oral solution. All the patients took orally the study treatment twice a day: - in the morning at wake up. - in the afternoon, 3 hours before going to bed at the latest. The volume of the oral solution was adapted according to a body-weight basis for patients with a weight lower than 25 kg.

    Number of subjects in period 1
    		S95008 - Double-blind period Placebo - Double-blind period
    Started
    107
    104
    Completed
    90
    95
    Not completed
    17
    9
         Non medical reason
    8
    2
         Adverse event, non-fatal
    8
    6
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Open-label period (From W026 to W052)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo/S95008 - Open-label period
    Arm description
    		 Patients assigned to Placebo group at W0 and treated by S95008 in the open-label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95008
    Investigational medicinal product code
    S95008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    All patients received bumetanide b.i.d. between month 6 (W026) and month 12 (W052). This was followed by a period from W052 to WEND. During this follow-up period, the patients were not treated with IMP.

    Arm title
    		 S95008/S95008 - Open label period
    Arm description
    		 Patients assigned to S95008 group at W0 and treated by S95008 in the open-label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95008
    Investigational medicinal product code
    S95008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    All patients received bumetanide b.i.d. between month 6 (W026) and month 12 (W052). This was followed by a period from W052 to WEND. During this follow-up period, the patients were not treated with IMP.

    Number of subjects in period 2
    		Placebo/S95008 - Open-label period S95008/S95008 - Open label period
    Started
    92
    86
    Completed
    50
    46
    Not completed
    42
    40
         Non medical reason
    38
    31
         Adverse event, non-fatal
    3
    8
         Protocol deviation
    1
    1
    Period 3
    Period 3 title
    Combined period (From W000 to W052)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 S95008/S95008 - Combined period
    Arm description
    		 For the Combined period (Double-blind + Open label periods), treatment group was defined as S95008/S95008 arm: patients assigned to S95008 group at W0 and treated with S95008 in the open label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95008
    Investigational medicinal product code
    S95008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    All patients received bumetanide b.i.d. between W000 and month 12 (W052). This was followed by a period from W052 to WEND. During this follow-up period, the patients were not treated with IMP.

    Number of subjects in period 3
    		S95008/S95008 - Combined period
    Started
    86
    Completed
    46
    Not completed
    40
         Non medical reason
    31
         Adverse event, non-fatal
    8
         Protocol deviation
    1
    Period 4
    Period 4 title
    Extension period (From M000 to M006)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 S95008 - Extension period
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95008
    Investigational medicinal product code
    S95008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    During the 6-month extension period in open label (from M000 to M006), all patients were treated by bumetanide as done in the open label treatment period.

    Number of subjects in period 4 [1]
    		S95008 - Extension period
    Started
    6
    Completed
    5
    Not completed
    1
         Non medical reason
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The extension period was not mandatory.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S95008 - Double-blind period
    Reporting group description
    		 -

    Reporting group title
    Placebo - Double-blind period
    Reporting group description
    		 -

    Reporting group values
    		 S95008 - Double-blind period Placebo - Double-blind period Total
    Number of subjects
    		 107 104 211
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 107 104 211
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.4 ( 1.2 ) 4.6 ( 1.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 17 35
        Male
    		 89 87 176

    End points

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    End points reporting groups
    Reporting group title
    S95008 - Double-blind period
    Reporting group description
    		 -

    Reporting group title
    Placebo - Double-blind period
    Reporting group description
    		 -
    Reporting group title
    Placebo/S95008 - Open-label period
    Reporting group description
    		 Patients assigned to Placebo group at W0 and treated by S95008 in the open-label period.

    Reporting group title
    S95008/S95008 - Open label period
    Reporting group description
    		 Patients assigned to S95008 group at W0 and treated by S95008 in the open-label period.
    Reporting group title
    S95008/S95008 - Combined period
    Reporting group description
    		 For the Combined period (Double-blind + Open label periods), treatment group was defined as S95008/S95008 arm: patients assigned to S95008 group at W0 and treated with S95008 in the open label period.
    Reporting group title
    S95008 - Extension period
    Reporting group description
    		 -

    Primary: CARS2 total raw score: change from baseline to 6 months.

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    End point title
    		 CARS2 total raw score: change from baseline to 6 months.
    End point description
    Its main expression was the change from baseline to 6 months. The primary analysis consisted in the difference between bumetanide and placebo using a general linear model with baseline CARS2 total raw score and stratification factors as covariates.
    End point type
    Primary
    End point timeframe
    CARS2 was completed by an independent rater, who performed a mandatory training before his/her involvement in the study, at W000, W004, W012, W026.
    End point values
    		 S95008 - Double-blind period Placebo - Double-blind period
    Number of subjects analysed
    89
    94
    Units: No unit
        arithmetic mean (standard deviation)
    -3.66 ( 4.52 )
    -3.88 ( 5.06 )
    Statistical analysis title
    		 S95008 minus Placebo
    Statistical analysis description
    Bumetanide was compared to placebo on the primary efficacy endpoint (change from baseline to W026 of the CARS2 total score) in the RS, using a General Linear Model including the fixed, categorical effect of treatment, gender and country as well as the continuous fixed covariate of baseline value. The Estimate of the adjusted difference was based on 211 patients (Missing data were imputed).
    Comparison groups
    S95008 - Double-blind period v Placebo - Double-blind period
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.617
    Method
    		 Two-sided 95% CI of the Estimate
    Parameter type
    		 Estimate of the adjusted difference
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.04
         upper limit
    		 1.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.71

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events which occurred or worsen or became serious according to the investigator, or upgraded by the Sponsor, between the first IMP intake date (included) and the last IMP intake date + 2 days of the considered period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    S95008 - Double-blind period
    Reporting group description
    		 -

    Reporting group title
    Placebo - Double-blind period
    Reporting group description
    		 -

    Reporting group title
    Placebo/S95008 - Open-label period
    Reporting group description
    		 -

    Reporting group title
    S95008/S95008 - Combined period
    Reporting group description
    		 -

    Reporting group title
    S95008 - Extension period
    Reporting group description
    		 -

    Serious adverse events
    		 S95008 - Double-blind period Placebo - Double-blind period Placebo/S95008 - Open-label period S95008/S95008 - Combined period S95008 - Extension period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 107 (6.54%)
    3 / 104 (2.88%)
    2 / 92 (2.17%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multisystem inflammatory syndrome in children
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Atonic seizures
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hyperacusis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 104 (0.96%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyuria
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    1 / 92 (1.09%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 S95008 - Double-blind period Placebo - Double-blind period Placebo/S95008 - Open-label period S95008/S95008 - Combined period S95008 - Extension period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 107 (96.26%)
    96 / 104 (92.31%)
    81 / 92 (88.04%)
    84 / 84 (100.00%)
    4 / 6 (66.67%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 104 (2.88%)
    5 / 92 (5.43%)
    11 / 84 (13.10%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    5
    11
    0
    Blood uric acid increased
         subjects affected / exposed
    5 / 107 (4.67%)
    0 / 104 (0.00%)
    2 / 92 (2.17%)
    5 / 84 (5.95%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    2
    6
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    2 / 107 (1.87%)
    4 / 104 (3.85%)
    5 / 92 (5.43%)
    10 / 84 (11.90%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    5
    10
    0
    Creatinine urine decreased
         subjects affected / exposed
    4 / 107 (3.74%)
    0 / 104 (0.00%)
    2 / 92 (2.17%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    2
    7
    0
    Weight decreased
         subjects affected / exposed
    13 / 107 (12.15%)
    2 / 104 (1.92%)
    10 / 92 (10.87%)
    12 / 84 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    13
    2
    10
    13
    0
    Urine calcium increased
         subjects affected / exposed
    4 / 107 (3.74%)
    1 / 104 (0.96%)
    6 / 92 (6.52%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    6
    6
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    8 / 107 (7.48%)
    4 / 104 (3.85%)
    4 / 92 (4.35%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    8
    5
    4
    7
    0
    Headache
         subjects affected / exposed
    0 / 107 (0.00%)
    6 / 104 (5.77%)
    2 / 92 (2.17%)
    2 / 84 (2.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    10
    2
    2
    0
    General disorders and administration site conditions
    Thirst
         subjects affected / exposed
    62 / 107 (57.94%)
    36 / 104 (34.62%)
    30 / 92 (32.61%)
    50 / 84 (59.52%)
    0 / 6 (0.00%)
         occurrences all number
    76
    40
    36
    66
    0
    Fatigue
         subjects affected / exposed
    10 / 107 (9.35%)
    2 / 104 (1.92%)
    4 / 92 (4.35%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    11
    2
    4
    8
    0
    Pyrexia
         subjects affected / exposed
    10 / 107 (9.35%)
    8 / 104 (7.69%)
    12 / 92 (13.04%)
    13 / 84 (15.48%)
    0 / 6 (0.00%)
         occurrences all number
    11
    13
    13
    19
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 107 (9.35%)
    5 / 104 (4.81%)
    4 / 92 (4.35%)
    15 / 84 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    13
    5
    4
    18
    0
    Abdominal pain
         subjects affected / exposed
    8 / 107 (7.48%)
    5 / 104 (4.81%)
    3 / 92 (3.26%)
    8 / 84 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    9
    5
    3
    11
    0
    Diarrhoea
         subjects affected / exposed
    9 / 107 (8.41%)
    11 / 104 (10.58%)
    10 / 92 (10.87%)
    11 / 84 (13.10%)
    0 / 6 (0.00%)
         occurrences all number
    9
    16
    10
    14
    0
    Dry mouth
         subjects affected / exposed
    20 / 107 (18.69%)
    11 / 104 (10.58%)
    9 / 92 (9.78%)
    19 / 84 (22.62%)
    0 / 6 (0.00%)
         occurrences all number
    27
    15
    9
    29
    0
    Vomiting
         subjects affected / exposed
    16 / 107 (14.95%)
    15 / 104 (14.42%)
    9 / 92 (9.78%)
    15 / 84 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    23
    19
    11
    27
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 107 (3.74%)
    7 / 104 (6.73%)
    6 / 92 (6.52%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    8
    7
    7
    0
    Dysphonia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    0 / 92 (0.00%)
    0 / 84 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 107 (4.67%)
    2 / 104 (1.92%)
    1 / 92 (1.09%)
    5 / 84 (5.95%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    1
    5
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    7 / 107 (6.54%)
    9 / 104 (8.65%)
    7 / 92 (7.61%)
    5 / 84 (5.95%)
    0 / 6 (0.00%)
         occurrences all number
    8
    9
    7
    6
    0
    Affect lability
         subjects affected / exposed
    6 / 107 (5.61%)
    8 / 104 (7.69%)
    6 / 92 (6.52%)
    5 / 84 (5.95%)
    0 / 6 (0.00%)
         occurrences all number
    6
    11
    7
    5
    0
    Anger
         subjects affected / exposed
    7 / 107 (6.54%)
    7 / 104 (6.73%)
    4 / 92 (4.35%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    8
    9
    4
    8
    0
    Agitation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 104 (0.00%)
    5 / 92 (5.43%)
    1 / 84 (1.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    9
    1
    0
    Anxiety
         subjects affected / exposed
    5 / 107 (4.67%)
    2 / 104 (1.92%)
    5 / 92 (5.43%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    5
    3
    5
    6
    0
    Impulsive behaviour
         subjects affected / exposed
    3 / 107 (2.80%)
    9 / 104 (8.65%)
    5 / 92 (5.43%)
    3 / 84 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    3
    12
    6
    3
    0
    Initial insomnia
         subjects affected / exposed
    6 / 107 (5.61%)
    6 / 104 (5.77%)
    0 / 92 (0.00%)
    6 / 84 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    6
    6
    0
    7
    0
    Irritability
         subjects affected / exposed
    16 / 107 (14.95%)
    16 / 104 (15.38%)
    9 / 92 (9.78%)
    16 / 84 (19.05%)
    0 / 6 (0.00%)
         occurrences all number
    17
    19
    11
    19
    0
    Insomnia
         subjects affected / exposed
    9 / 107 (8.41%)
    6 / 104 (5.77%)
    3 / 92 (3.26%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    10
    6
    3
    9
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    10 / 107 (9.35%)
    5 / 104 (4.81%)
    2 / 92 (2.17%)
    9 / 84 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    10
    5
    2
    10
    0
    Polyuria
         subjects affected / exposed
    39 / 107 (36.45%)
    23 / 104 (22.12%)
    25 / 92 (27.17%)
    33 / 84 (39.29%)
    0 / 6 (0.00%)
         occurrences all number
    46
    25
    26
    43
    0
    Hypercalciuria
         subjects affected / exposed
    4 / 107 (3.74%)
    1 / 104 (0.96%)
    2 / 92 (2.17%)
    5 / 84 (5.95%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    3
    5
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 107 (2.80%)
    5 / 104 (4.81%)
    0 / 92 (0.00%)
    5 / 84 (5.95%)
    1 / 6 (16.67%)
         occurrences all number
    3
    6
    0
    5
    2
    Gastroenteritis viral
         subjects affected / exposed
    9 / 107 (8.41%)
    5 / 104 (4.81%)
    1 / 92 (1.09%)
    8 / 84 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    9
    5
    1
    8
    0
    Rhinitis
         subjects affected / exposed
    1 / 107 (0.93%)
    7 / 104 (6.73%)
    5 / 92 (5.43%)
    2 / 84 (2.38%)
    1 / 6 (16.67%)
         occurrences all number
    1
    7
    5
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 107 (5.61%)
    4 / 104 (3.85%)
    0 / 92 (0.00%)
    7 / 84 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    9
    5
    0
    10
    1
    Nasopharyngitis
         subjects affected / exposed
    12 / 107 (11.21%)
    11 / 104 (10.58%)
    10 / 92 (10.87%)
    16 / 84 (19.05%)
    1 / 6 (16.67%)
         occurrences all number
    17
    14
    13
    27
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 107 (5.61%)
    7 / 104 (6.73%)
    5 / 92 (5.43%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    7
    10
    6
    9
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 107 (15.89%)
    16 / 104 (15.38%)
    10 / 92 (10.87%)
    15 / 84 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    17
    18
    12
    18
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    6 / 104 (5.77%)
    4 / 92 (4.35%)
    2 / 84 (2.38%)
    0 / 6 (0.00%)
         occurrences all number
    3
    6
    9
    5
    0
    Hypokalaemia
         subjects affected / exposed
    16 / 107 (14.95%)
    2 / 104 (1.92%)
    21 / 92 (22.83%)
    18 / 84 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    29
    2
    35
    37
    0
    Increased appetite
         subjects affected / exposed
    14 / 107 (13.08%)
    10 / 104 (9.62%)
    3 / 92 (3.26%)
    15 / 84 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    14
    15
    3
    16
    0
    Polydipsia
         subjects affected / exposed
    8 / 107 (7.48%)
    4 / 104 (3.85%)
    2 / 92 (2.17%)
    7 / 84 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    8
    4
    2
    7
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2018
    Amendment No. 1, applicable in all countries, concerned the update of the potassium supplementation recommendations in case of hypokalaemia.
    12 Dec 2018
    Amendment No. 2, applicable in all countries, mainly aimed to increase the planned number of countries (from 10 to 12), to correct safety measurements, to clarify the investigation schedule and to update some non-selection, exclusion and withdrawal criteria.
    12 Aug 2019
    Amendment No. 3, applicable in all countries, aimed to update the exclusion and the withdrawal criteria, about abnormal urinary calcium/creatinine ratio and calciuria.
    30 Nov 2020
    ­Amendment No.8, applicable in all countries, aimed to update the definition of the end of the trial as a 6-month extension period in open-label was performed in some countries.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Sep 2021
    The superiority of bumetanide compared to placebo in ASD was not demonstrated in this phase III study. As none of the efficacy endpoints were reached and due to the identified risk of hypokalaemia and associated effects linked to the drug’s diuretic activity, the Benefit/Risk ratio of the study treatment in ASD was considered negative. Consequently, the sponsor decided to stop the S95008 development and prematurely discontinue the extension period. This decision was not related to unexpected safety concerns.
    -

    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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