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    Clinical Trial Results:
    A Phase II dose ranging study of Bumetanide solution in children and adolescents with autism spectrum disorders.

    Summary
    EudraCT number
    		 2013-003259-39
    Trial protocol
    		 ES   FR  
    Global end of trial date
    06 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2021
    First version publication date
    18 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NeuroClin02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Neurochlore
    Sponsor organisation address
    Parc Scientifique et Technologique de Luminy Bâtiment Beret Delaage Zone Luminy Biotec, Marseille, France, 13288
    Public contact
    director of drug development, Neurochlore, denis.ravel@initial-rd.fr
    Scientific contact
    director of drug development, Neurochlore , denis.ravel@initial-rd.fr
    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
    10 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the optimal dose strength of Bumetanide for the pivotal Phase III studies. Age and gender characteristics as well as type of developmental disorder were not available for the completer's subject analysis set. Approximate values have therefore been entered in order to ensure the technical validation of the file.
    Protection of trial subjects
    The Investigator was responsible for ensuring that the investigation was conducted according to the signed Investigator agreement, the protocol, good clinical practice guidelines, and applicable regulations; for protecting the rights, safety, and welfare of patients under the Investigator’s care; and for the control of investigational products under investigation. The Investigator at each study center was responsible for the management of the study, which consisted of maintaining the study file and patient records, corresponding with the IRB/IEC, and completing the electronic case report forms (eCRFs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 88
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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)
    72
    Adolescents (12-17 years)
    16
    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
    		 A total of 91 patients signed informed consent from January 2014 to July 2015. Three were found not to meet inclusion or exclusion criteria. A total of 88 subjects were included in the study at 7 clinical sites located in France. A total of 72 patients has completed the study.

    Pre-assignment
    Screening details
    		 Main inclusion criteria: male or female, children and adolescents, 2-18 years old, with ASD according to ICD-10 [F84.0 (Childhood Autism) or F84.5 (Asperger’s Syndrome)], CARS (Childhood Autism Rating Scale) score > 34, criteria for Autism on ADOS-G (Autism Diagnosis Observation Schedule-General) and ADI-R (Autism Diagnosis Interview-Revised).

    Pre-assignment period milestones
    Number of subjects started
    		 91 [1]
    Number of subjects completed
    		 88

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The pre-assignment period is considered as the screening phase. 91 patients were screened, 3 were screen failures, hence the worldwide number of patients actually enrolled in the trial is 88.
    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The study team at site including investigators, nurses and pharmacists, patients and patient’s parent[s]. They remained blinded until database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bumetanide low dose
    Arm description
    		 oral administration, liquid formulation, 0.5 mg BID for 3 months, for patients below 25 kg (0.02 mg/kg BID)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bumetanide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Double-blind placebo-controlled study: Patients received Bumetanide (0.5, 1.0 or 2.0 mg BID) for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.02, 0.04 or 0.08 mg/kg, BID).

    Arm title
    		 Bumetanide medium dose
    Arm description
    		 oral administration, liquid formulation, 1.0 mg BID for 3 months, for patients below 25 kg (0.04 mg/kg, BID)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bumetanide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Double-blind placebo-controlled study: Patients received Bumetanide (0.5, 1.0 or 2.0 mg BID) for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.02, 0.04 or 0.08 mg/kg, BID).

    Arm title
    		 Bumetanide high dose
    Arm description
    		 oral administration, liquid formulation, 2.0 mg BID for 3 months, for patients below 25 kg (0.08mg/kg,BID)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bumetanide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Double-blind placebo-controlled study: Patients received Bumetanide (0.5, 1.0 or 2.0 mg BID) for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.02, 0.04 or 0.08 mg/kg, BID).

    Arm title
    		 Placebo
    Arm description
    		 oral administration, liquid formulation, Placebo for 3 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Double-blind placebo-controlled study: Patients received placebo for 3 months.

    Number of subjects in period 1
    		Bumetanide low dose Bumetanide medium dose Bumetanide high dose Placebo
    Started
    20
    23
    22
    23
    Completed
    20
    19
    13
    20
    Not completed
    0
    4
    9
    3
         Adverse event, not serious
    -
    2
    5
    1
         Consent withdrawn by subject
    -
    -
    1
    -
         Physician decision
    -
    -
    -
    1
         Protocol violation
    -
    1
    1
    1
         Adverse event, serious non-fatal
    -
    1
    1
    -
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bumetanide low dose
    Reporting group description
    		 oral administration, liquid formulation, 0.5 mg BID for 3 months, for patients below 25 kg (0.02 mg/kg BID)

    Reporting group title
    Bumetanide medium dose
    Reporting group description
    		 oral administration, liquid formulation, 1.0 mg BID for 3 months, for patients below 25 kg (0.04 mg/kg, BID)

    Reporting group title
    Bumetanide high dose
    Reporting group description
    		 oral administration, liquid formulation, 2.0 mg BID for 3 months, for patients below 25 kg (0.08mg/kg,BID)

    Reporting group title
    Placebo
    Reporting group description
    		 oral administration, liquid formulation, Placebo for 3 months

    Reporting group values
    		 Bumetanide low dose Bumetanide medium dose Bumetanide high dose Placebo Total
    Number of subjects
    		 20 23 22 23 88
    Age categorical
    Children and adolescents (2-18 years)
    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)
    		 16 18 16 16 66
        Adolescents (12-17 years)
    		 4 5 6 7 22
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 4 1 1 4 10
        Male
    		 16 22 21 19 78
    Type of developmental disorder
    Demographic characteristics were comparable between the Bumetanide and placebo treated groups. Patients in the FAS had a mean age of 8.26 years (SD=4.53) and the majority of patients were male (78 patients, 88.6%). The majority of patients had an initial diagnosis of F84.0 (Childhood Autism), (82 patients, 93.2%). Six patients (6.8%) had an initial diagnosis of F84.5 (Asperger’s Syndrome).
    Units: Subjects
        F84.0 (Childhood Autism)
    		 18 23 21 20 82
        F84.5 (Asperger's Syndrome)
    		 2 0 1 3 6
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide low dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide medium dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide high dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Completer's analysis - Bumetanide low dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Bumetanide medium dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Bumetanide high dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis sets values
    		 Full Analysis Set (FAS) - Bumetanide low dose Full Analysis Set (FAS) - Bumetanide medium dose Full Analysis Set (FAS) - Bumetanide high dose Full Analysis Set (FAS) - Placebo Completer's analysis - Bumetanide low dose Completer's analysis - Bumetanide medium dose Completer's analysis - Bumetanide high dose Completer's analysis - Placebo
    Number of subjects
    20
    23
    22
    23
    20
    19
    13
    21
    Age categorical
    Children and adolescents (2-18 years)
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
    16
    18
    16
    16
    16
    16
    11
    15
        Adolescents (12-17 years)
    4
    5
    6
    7
    4
    3
    2
    6
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    4
    1
    1
    4
    4
    1
    1
    3
        Male
    16
    22
    21
    19
    16
    18
    12
    18
    Type of developmental disorder
    Demographic characteristics were comparable between the Bumetanide and placebo treated groups. Patients in the FAS had a mean age of 8.26 years (SD=4.53) and the majority of patients were male (78 patients, 88.6%). The majority of patients had an initial diagnosis of F84.0 (Childhood Autism), (82 patients, 93.2%). Six patients (6.8%) had an initial diagnosis of F84.5 (Asperger’s Syndrome).
    Units: Subjects
        F84.0 (Childhood Autism)
    18
    23
    21
    20
    18
    19
    12
    19
        F84.5 (Asperger's Syndrome)
    2
    0
    1
    3
    2
    0
    1
    2

    End points

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    End points reporting groups
    Reporting group title
    Bumetanide low dose
    Reporting group description
    		 oral administration, liquid formulation, 0.5 mg BID for 3 months, for patients below 25 kg (0.02 mg/kg BID)

    Reporting group title
    Bumetanide medium dose
    Reporting group description
    		 oral administration, liquid formulation, 1.0 mg BID for 3 months, for patients below 25 kg (0.04 mg/kg, BID)

    Reporting group title
    Bumetanide high dose
    Reporting group description
    		 oral administration, liquid formulation, 2.0 mg BID for 3 months, for patients below 25 kg (0.08mg/kg,BID)

    Reporting group title
    Placebo
    Reporting group description
    		 oral administration, liquid formulation, Placebo for 3 months

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide low dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide medium dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Bumetanide high dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Full Analysis Set (FAS) - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all randomised patients.

    Subject analysis set title
    Completer's analysis - Bumetanide low dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Bumetanide medium dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Bumetanide high dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Subject analysis set title
    Completer's analysis - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the FAS who completed the study with CARS evaluation at Day 90.

    Primary: Childhood Autism Rating Scale (CARS)

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    End point title
    		 Childhood Autism Rating Scale (CARS)
    End point description
    The CARS is a tool used to diagnose Autism for children and adolescents, and to measure the intensity of ASD. The scale contains 15 items. The first 14 ones represents different domains of child functioning and the last one is a global rating of Autism. Each item is a 4-point scale from 1, normal functioning to 4, severely disrupted functioning. Results of each item are summed up for a final score between 15 and 60. The CARS classification allows to distinguish several categories: autistic features, mild, moderate and severe autism. A reduction in CARS corresponds to an improvement.
    End point type
    Primary
    End point timeframe
    Change in CARS from screening to Day 90 (LOCF)
    End point values
    		 Full Analysis Set (FAS) - Bumetanide low dose Full Analysis Set (FAS) - Bumetanide medium dose Full Analysis Set (FAS) - Bumetanide high dose Full Analysis Set (FAS) - Placebo Completer's analysis - Bumetanide low dose Completer's analysis - Bumetanide medium dose Completer's analysis - Bumetanide high dose Completer's analysis - Placebo
    Number of subjects analysed
    20
    23
    22
    23
    20
    19
    13
    21
    Units: score
    arithmetic mean (standard deviation)
        Change from screening to Day 90 (LOCF)
    -4.98 ± 4.33
    -3.09 ± 3.3
    -3.16 ± 3.98
    -1.63 ± 2.34
    -4.98 ± 4.33
    -3.74 ± 3.28
    -5.35 ± 3.88
    -1.79 ± 2.39
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The primary analysis of the primary endpoint was an intent-to-treat analysis, performed using the Full Analysis Set (FAS) with imputation of no change when the result for Day 90 was missing, provided the patient received at least one dose of treatment. The treatment groups were compared using the Kruskal-Wallis test with Steel-Dwass adjusted pair-wise comparisons.
    Comparison groups
    Full Analysis Set (FAS) - Bumetanide low dose v Full Analysis Set (FAS) - Bumetanide medium dose v Full Analysis Set (FAS) - Bumetanide high dose v Full Analysis Set (FAS) - Placebo v Completer's analysis - Bumetanide low dose v Completer's analysis - Bumetanide medium dose v Completer's analysis - Bumetanide high dose v Completer's analysis - Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0689
    Method
    		 Kruskal-wallis
    Confidence interval
    Statistical analysis title
    		 Change in CARS from Screening to Day 90
    Statistical analysis description
    Full Analysis Set (FAS) The FAS was defined as all patients who are randomised. The FAS was used for all efficacy analyses.. Change in CARS from Screening to Day 90 If total CARS score was missing at Day 90 the screening score was imputed for Day 90 (Last Observation Carried Forward [LOCF] imputation). The treatment groups are compared using the Kruskal-Wallis test The analyses are repeated without the imputation as a completers analysis.
    Comparison groups
    Completer's analysis - Bumetanide low dose v Completer's analysis - Bumetanide medium dose v Completer's analysis - Bumetanide high dose v Completer's analysis - Placebo v Full Analysis Set (FAS) - Placebo v Full Analysis Set (FAS) - Bumetanide high dose v Full Analysis Set (FAS) - Bumetanide medium dose v Full Analysis Set (FAS) - Bumetanide low dose
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0689
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Social Responsiveness Scale (SRS)

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    End point title
    		 Social Responsiveness Scale (SRS)
    End point description
    SRS, a brief quantitative 65-item rating scale of autistic behaviours designed to be completed by an adult who is familiar with the child's current behaviour and developmental history was administered and scores were obtained for five treatment subscales: Social awareness, social cognition, social communication, social motivation and autistic mannerisms.
    End point type
    Secondary
    End point timeframe
    Score change from screening to Day 90
    End point values
    		 Completer's analysis - Bumetanide low dose Completer's analysis - Bumetanide medium dose Completer's analysis - Bumetanide high dose Completer's analysis - Placebo
    Number of subjects analysed
    20
    19
    13
    21
    Units: score
    arithmetic mean (standard deviation)
        Change from screening to Day 90 (LOCF)
    -12.36 ± 23.57
    -13.17 ± 20.45
    -21.83 ± 19.78
    -1.55 ± 20.38
    Statistical analysis title
    		 Secondary analysis
    Statistical analysis description
    The same analysis as the primary analysis was repeated on the completers set. The treatment groups were compared using the Kruskal-Wallis test with Steel-Dwass adjusted pair-wise comparisons.
    Comparison groups
    Completer's analysis - Bumetanide low dose v Completer's analysis - Bumetanide high dose v Completer's analysis - Placebo v Completer's analysis - Bumetanide medium dose
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0202
    Method
    		 Kruskal-wallis
    Confidence interval
    Statistical analysis title
    		 Secondary analysis
    Statistical analysis description
    The same analysis as the primary analysis was repeated on the completers set. The treatment groups were compared using the Kruskal-Wallis test with Steel-Dwass adjusted pair-wise comparisons.
    Comparison groups
    Completer's analysis - Bumetanide high dose v Completer's analysis - Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017 [1]
    Method
    		 Steel-Dwass test
    Confidence interval
    Notes
    [1] - Pair-wise comparison 2 mg Bumetanide group vs Placebo

    Secondary: Clinical Global Impression-Improvement (CGI-I)

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    End point title
    		 Clinical Global Impression-Improvement (CGI-I)
    End point description
    The child psychiatric compared the patient’s overall clinical condition to the baseline visit using a seven-point scale, ranging from very much improved (1) to very much worse (7). Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse Not assessed/missing
    End point type
    Secondary
    End point timeframe
    CGI-I improvement was assessed at baseline, at the end of the treatment phase
    End point values
    		 Full Analysis Set (FAS) - Bumetanide low dose Full Analysis Set (FAS) - Bumetanide medium dose Full Analysis Set (FAS) - Bumetanide high dose Full Analysis Set (FAS) - Placebo
    Number of subjects analysed
    20
    23
    22
    23
    Units: score
        Very much improved
    0
    0
    1
    0
        Much improved
    7
    5
    5
    1
        Minimally improved
    7
    10
    7
    10
        No change
    4
    4
    0
    9
        Minimally worse
    1
    0
    0
    1
        Much worse
    0
    0
    0
    0
        Very much worse
    0
    0
    0
    0
        Not assessed/missing
    1
    4
    9
    2
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    Full Analysis Set (FAS) - Bumetanide low dose v Full Analysis Set (FAS) - Bumetanide medium dose v Full Analysis Set (FAS) - Bumetanide high dose v Full Analysis Set (FAS) - Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0043
    Method
    		 Kruskal-wallis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time of signing informed consent to the last study visit
    Adverse event reporting additional description
    The safety population included all randomly assigned participants who received at least 1 dose of double-blind study drug. A total of 64 participants in the 3 Bumetanide groups and 22 participants in the placebo group received at least 1 dose of double-blind study medication and were included in the safety analysis set.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Lay language
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Bumetanide low dose
    Reporting group description
    		 Patients received 0.5 mg BID Bumetanide for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.02 mg/kg, BID).

    Reporting group title
    Bumetanide medium dose
    Reporting group description
    		 Patients received 1.0 mg BID Bumetanide for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.04 mg/kg, BID).

    Reporting group title
    Bumetanide high dose
    Reporting group description
    		 Patients received 2.0 mg BID Bumetanide for 3 months. Dose was calculated on a body weight basis for patients below 25 kg (0.08 mg/kg, BID).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo for 3 months.

    Serious adverse events
    		 Bumetanide low dose Bumetanide medium dose Bumetanide high dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Social circumstances
    Right broken leg
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Accidental overdose due to parent's inattentiveness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (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
    Metabolism and nutrition disorders
    Hypokalaemia
    alternative dictionary used: Lay language 1
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         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
    		 Bumetanide low dose Bumetanide medium dose Bumetanide high dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 20 (70.00%)
    22 / 23 (95.65%)
    21 / 22 (95.45%)
    4 / 23 (17.39%)
    Nervous system disorders
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    3 / 22 (13.64%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Irritability
    Additional description: irritable and anxious behavior,
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    1 / 22 (4.55%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    1
    1
    Agitation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 22 (13.64%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    3
    0
    General disorders and administration site conditions
    Diuresis, enuresis, polyuria pollakiuria
         subjects affected / exposed
    2 / 20 (10.00%)
    8 / 23 (34.78%)
    11 / 22 (50.00%)
    0 / 23 (0.00%)
         occurrences all number
    4
    12
    13
    0
    Loss of appetite, anorexia
         subjects affected / exposed
    0 / 20 (0.00%)
    7 / 23 (30.43%)
    9 / 22 (40.91%)
    0 / 23 (0.00%)
         occurrences all number
    0
    7
    9
    0
    Asthenia
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 23 (8.70%)
    3 / 22 (13.64%)
    0 / 23 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Hyperuricemia
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 23 (13.04%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Hypochloremia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    4 / 22 (18.18%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    5 / 22 (22.73%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Diarrhea
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    4
    0
    3
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Sweating
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Endocrine disorders
    Polydipsia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 23 (8.70%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    6 / 20 (30.00%)
    14 / 23 (60.87%)
    16 / 22 (72.73%)
    0 / 23 (0.00%)
         occurrences all number
    6
    20
    22
    0
    Dehydration
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 23 (13.04%)
    6 / 22 (27.27%)
    0 / 23 (0.00%)
         occurrences all number
    0
    3
    6
    0
    Weight loss
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 23 (13.04%)
    3 / 22 (13.64%)
    0 / 23 (0.00%)
         occurrences all number
    0
    3
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2015
    Amendment 01: Open label extension. A 6-month extension study of Bumetanide 0.5 mg/mL solution. The proposed continued use of Bumetanide was for compassionate purposes and was not considered within the development framework of Bumetanide in ASD patients. Participation in the extension phase was on a voluntary basis. Nineteen patients were enrolled in the extension phase. Bumetanide was given at 0.5 or 1 mg BID. The primary objective was to provide Bumetanide to patients who were enrolled in the NeuroClin02 study. The secondary objective was to collect additional safety data. No specific ASD outcomes were included. The extension was conducted in 3 clinical centres in France, 19 patients entered the extension.

    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.
    Only the drug-related adverse events have been listed in line with the information presented in the Clinical Study Report.
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