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Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder

Primary Purpose

Autism Spectrum Disorder (ASD)

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Bumetanide Oral Solution
Placebo
Sponsored by
Institut de Recherches Internationales Servier
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autism Spectrum Disorder (ASD)

Eligibility Criteria

7 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female patients from 7 to less than 18 years
  • Out patients
  • Primary diagnosis of ASD as per Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria
  • Criteria met for ASD on Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnosis Interview Revised (ADI-R)
  • CGI (Clinical Global Impression) - Severity rating Score ≥ 4
  • Childhood Autism Rating Scale second edition (CARS2-ST or HF) total raw score ≥ 34
  • Social responsiveness Scale second edition total score (SRS-2 T-Score) ≥ 66
  • Absence of known monogenic syndrome (Fragile X, Rett syndrome ...)
  • Absence of any clinically significant abnormality likely to interfere with the conduct of the study according to the judgment of the investigator

Exclusion Criteria:

  • Patients not able to follow the study assessments defined by the protocol, with the exception of self-rating questionnaires which will be assessed by parent/legal representative/caregiver for those patients unable to complete them
  • Patients having a high suicidal risk according to the investigator judgement
  • Chronic renal dysfunction
  • Chronic cardiac dysfunction
  • Patient with unstable psychotherapy, behavioural, cognitive or cognitive-behavioural therapy
  • Severe electrolyte imbalance that is likely to interfere with the study conduct or evaluation

Sites / Locations

  • Trial Tech em Pesquisas com Medicamentos Ltda
  • Hospital Universitário Walter Cantídio - Universidade Federal do Ceará
  • Hospital São Vicente de Paulo
  • Universidade Federal de São Paulo, Escola Paulista de Medicina
  • Faculdade de Medicina da Universidade de São Paulo - Departamento de Psiquiatria
  • GSC CHU-LENVAL Centre ressource autisme
  • Hôpitaux Universitaires de Strasbourg Service de Psychiatrie de l'Enfant et de l'Adolescent
  • Centre d'Investigation Clinique de Lyon
  • Hôpital Le Vinatier CRA Rhône-Alpes, Bat 211
  • Hôpital Robert Debré Service de Psychiatrie de l'enfant et de l'adolescent
  • CHU Rouen
  • Centre Hospitalier du Rouvray Centre de Ressources pour l'Autisme
  • Hôpital des Enfants-Pellegrin
  • Centre Hospitalier Charles Perrens CRA Aquitaine
  • Universitätsklinikum Freiburg, Zentrum für Psychische Erkrankungen, Klinik für Psychiatrie, Psychotherapie und Psychosomatik im Kindes- und Jugendalter
  • Klinik für Psychiatrie und Psychotherapie des Kindes- und Jugendalters am Zentralinstitut für Seelische Gesundheit
  • Universitätsklinikum Carl Gustav Carus an der TU Dresden, Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und
  • Vadaskert Korhaz es Szakambulancia
  • Servus Salvus Kft.
  • Bekes Megyei Kozponti Korhaz Gyermek es ifjusagpszichiatriai osztaly
  • Szegedi Tudományegyetem Szent-Gyorgy Albert Klinikai Kozpont Gyermekgyógyászati Klinika Gyermek es Ifjusagpszichiátriai o
  • Unità Semplice di Psichiatria Infantile Policlinico Universitario di Napoli - Università Federico II
  • Neuro Riabilitazione/Psicopatologia dell'età evolutiva Istituto Scientifico Medea - Bosisio Parini
  • U.O. di Neuropsichiatria Infantile Fondazione Istituto Neurologico Nazionale Casimiro Mondino Istituto di Ricovero e Cura a Carattere Scientifico
  • Clinica di Neuropsichiatria dell'Infanzia e dell'Adolescenza Ospedale Pediatrico-Microcitemico
  • Programma Interdipartimentale "Autismo 0-90" A.O.U. Policlinico "Gaetano Martino"
  • U.O.C. Psichiatria dello Sviluppo IRCCS Fondazione Stella Maris
  • U.O. di Neuropsichiatria Infantile Azienda Ospedaliera Universitaria Senese
  • Accare Groningen
  • NAVICULA Centrum Diagnozy i Terapii Autyzmu w Łodzi
  • Samodzielny Publiczny Dziecięcy Szpital Kliniczny w Warszawie Oddział Kliniczny Psychiatrii Wieku Rozwojowego
  • Niepubliczny Zakład Opieki Zdrowotnej Gdańskie Centrum Zdrowia Sp. z o.o.
  • Centrum Badań Klinicznych PI-House sp. z o.o
  • Fundacja SYNAPSIS ul.
  • Centro Hospitalar e Universitario de Coimbra Hospital Pediatrico
  • Hospita Mutua de Terrassa
  • Policlinica Guipuzcoa
  • Hospital Puerta de Hierro
  • Hospital General Universitario de Alicante
  • Hospital Clinic de Barcelona
  • Hospital Niño Jesus
  • Hospital Universitario Gregorio Marañon
  • Forward Thinking Birmingham_Birmingham Women's and Children's NHS Foundation Trust
  • ReCognition Health
  • The Winnicott Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bumetanide/S95008

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Childhood Autism Rating Scale, Second Edition (CARS2) total raw score
Efficacy criterion The CARS2 is a 15 item rated instrument. The rating values given for the 15 areas are summed to produce a Total score.

Secondary Outcome Measures

Social Responsiveness Scale, Second Edition (SRS-2) total raw score
Efficacy criterion 65 items scale measuring symptoms associated with autism
Clinical Global Impression - Global Improvement (CGI-I) score
Efficacy criterion Scale which assesses the severity of the illness and the global improvement of the patient under study treatment
Vineland Adaptative Behaviour Sales, Second Edition (VABS II) subscores
Efficacy criterion Scale designated to measure adaptative behaviour
Adverse events and Paediatric Adverse Event Rating Scale (PAERS)
Safety criterion Inventory report used to identify signs/symptoms experienced by the patient since the study treatment initiation.
Abnormalities in 12-leads electrocardiogram (ECG) parameters
Safety criterion
Renal ultrasound
Safety criterion Assessment of the renal function
the Columbia Suicide Severity Rating Scale Children's version (C-SSRS-C)
Scale which assesses suicidal ideation and suicidal behaviour
Tanner stage
Safety criterion Assessment of Pubertal development
Acceptability and palatability questionnaire
Acceptability and palatability criterion Assessment of the ease of use to use the dosing device
Paediatric Quality of Life Inventory (PedsQL) questionnaire
Quality of Life criterion Assessment of parent/legal representative perception of patient health related quality of life

Full Information

First Posted
October 12, 2018
Last Updated
March 11, 2022
Sponsor
Institut de Recherches Internationales Servier
Collaborators
ADIR, a Servier Group company
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1. Study Identification

Unique Protocol Identification Number
NCT03715166
Brief Title
Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
The 6-month efficacy analysis did not show any significant difference between bumetanide versus placebo in the treatment of ASD in the overall studied population. No unexpected safety concerns were identified.
Study Start Date
September 24, 2018 (Actual)
Primary Completion Date
September 13, 2021 (Actual)
Study Completion Date
September 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut de Recherches Internationales Servier
Collaborators
ADIR, a Servier Group company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study was to evaluate the efficacy and the safety of bumetanide/S95008 in the improvement of Autism Spectrum Disorder core symptoms.
Detailed Description
The present study (CL3-95008-001) was performed in children and adolescents from 7 to less than 18 years old presenting with ASD. A 6-month double-blind treatment period was performed in which efficacy and safety of bumetanide 0.5mg BID were assessed versus placebo. This double-blind period was followed by a 6-month open label treatment period of bumetanide 0.5mg BID in which long term safety was evaluated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autism Spectrum Disorder (ASD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
6-month, randomized, double-blind, placebo-controlled, parallel groups followed by an open label active 6-month treatment period with bumetanide.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
211 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bumetanide/S95008
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Bumetanide Oral Solution
Intervention Description
Oral Solution dosed at 0.5mg/mL Taken twice daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral Solution Taken twice daily
Primary Outcome Measure Information:
Title
Childhood Autism Rating Scale, Second Edition (CARS2) total raw score
Description
Efficacy criterion The CARS2 is a 15 item rated instrument. The rating values given for the 15 areas are summed to produce a Total score.
Time Frame
Change from baseline to 6 month
Secondary Outcome Measure Information:
Title
Social Responsiveness Scale, Second Edition (SRS-2) total raw score
Description
Efficacy criterion 65 items scale measuring symptoms associated with autism
Time Frame
Change from baseline to 6 month
Title
Clinical Global Impression - Global Improvement (CGI-I) score
Description
Efficacy criterion Scale which assesses the severity of the illness and the global improvement of the patient under study treatment
Time Frame
At 6 months
Title
Vineland Adaptative Behaviour Sales, Second Edition (VABS II) subscores
Description
Efficacy criterion Scale designated to measure adaptative behaviour
Time Frame
Change from baseline to 6 month
Title
Adverse events and Paediatric Adverse Event Rating Scale (PAERS)
Description
Safety criterion Inventory report used to identify signs/symptoms experienced by the patient since the study treatment initiation.
Time Frame
On average of 52 weeks
Title
Abnormalities in 12-leads electrocardiogram (ECG) parameters
Description
Safety criterion
Time Frame
selection visit/Week004/Week008/Week012/Week 026/Week030/Week034/Week038/Week052
Title
Renal ultrasound
Description
Safety criterion Assessment of the renal function
Time Frame
selection visit/Week026/Week052
Title
the Columbia Suicide Severity Rating Scale Children's version (C-SSRS-C)
Description
Scale which assesses suicidal ideation and suicidal behaviour
Time Frame
Week000/Week012/Week026/Week038/Week052
Title
Tanner stage
Description
Safety criterion Assessment of Pubertal development
Time Frame
Week000/Week026/Week052
Title
Acceptability and palatability questionnaire
Description
Acceptability and palatability criterion Assessment of the ease of use to use the dosing device
Time Frame
Week026
Title
Paediatric Quality of Life Inventory (PedsQL) questionnaire
Description
Quality of Life criterion Assessment of parent/legal representative perception of patient health related quality of life
Time Frame
Week000/Week004/Week012/Week026/Week030/Week038/Week052

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female patients from 7 to less than 18 years Out patients Primary diagnosis of ASD as per Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria Criteria met for ASD on Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnosis Interview Revised (ADI-R) CGI (Clinical Global Impression) - Severity rating Score ≥ 4 Childhood Autism Rating Scale second edition (CARS2-ST or HF) total raw score ≥ 34 Social responsiveness Scale second edition total score (SRS-2 T-Score) ≥ 66 Absence of known monogenic syndrome (Fragile X, Rett syndrome ...) Absence of any clinically significant abnormality likely to interfere with the conduct of the study according to the judgment of the investigator Exclusion Criteria: Patients not able to follow the study assessments defined by the protocol, with the exception of self-rating questionnaires which will be assessed by parent/legal representative/caregiver for those patients unable to complete them Patients having a high suicidal risk according to the investigator judgement Chronic renal dysfunction Chronic cardiac dysfunction Patient with unstable psychotherapy, behavioural, cognitive or cognitive-behavioural therapy Severe electrolyte imbalance that is likely to interfere with the study conduct or evaluation
Facility Information:
Facility Name
Trial Tech em Pesquisas com Medicamentos Ltda
City
Curitiba
ZIP/Postal Code
80240-280
Country
Brazil
Facility Name
Hospital Universitário Walter Cantídio - Universidade Federal do Ceará
City
Fortaleza
ZIP/Postal Code
60430-370
Country
Brazil
Facility Name
Hospital São Vicente de Paulo
City
Passo Fundo
ZIP/Postal Code
99010-080
Country
Brazil
Facility Name
Universidade Federal de São Paulo, Escola Paulista de Medicina
City
São Paulo
ZIP/Postal Code
04017-030
Country
Brazil
Facility Name
Faculdade de Medicina da Universidade de São Paulo - Departamento de Psiquiatria
City
São Paulo
ZIP/Postal Code
054030-010
Country
Brazil
Facility Name
GSC CHU-LENVAL Centre ressource autisme
City
Nice
State/Province
Alpes-Maritimes
ZIP/Postal Code
6200
Country
France
Facility Name
Hôpitaux Universitaires de Strasbourg Service de Psychiatrie de l'Enfant et de l'Adolescent
City
Strasbourg
State/Province
Alsace-Champagne-Ardenne-Lorraine
ZIP/Postal Code
67091
Country
France
Facility Name
Centre d'Investigation Clinique de Lyon
City
Bron
State/Province
Auvergne Rhone Alpes
ZIP/Postal Code
69677
Country
France
Facility Name
Hôpital Le Vinatier CRA Rhône-Alpes, Bat 211
City
Bron
State/Province
Auvergne-Rhône-Alpes
ZIP/Postal Code
69678
Country
France
Facility Name
Hôpital Robert Debré Service de Psychiatrie de l'enfant et de l'adolescent
City
Paris
State/Province
Il De France
ZIP/Postal Code
75019
Country
France
Facility Name
CHU Rouen
City
Rouen
State/Province
Normandie
ZIP/Postal Code
76000
Country
France
Facility Name
Centre Hospitalier du Rouvray Centre de Ressources pour l'Autisme
City
Sotteville-lès-Rouen
State/Province
Normandie
ZIP/Postal Code
76301
Country
France
Facility Name
Hôpital des Enfants-Pellegrin
City
Bordeaux
State/Province
Nouvelle Aquitaine
ZIP/Postal Code
33076
Country
France
Facility Name
Centre Hospitalier Charles Perrens CRA Aquitaine
City
Bordeaux
State/Province
Nouvelle-Aquitaine
ZIP/Postal Code
33076
Country
France
Facility Name
Universitätsklinikum Freiburg, Zentrum für Psychische Erkrankungen, Klinik für Psychiatrie, Psychotherapie und Psychosomatik im Kindes- und Jugendalter
City
Freiburg
State/Province
Baden-Württemberg
ZIP/Postal Code
79104
Country
Germany
Facility Name
Klinik für Psychiatrie und Psychotherapie des Kindes- und Jugendalters am Zentralinstitut für Seelische Gesundheit
City
Mannheim
State/Province
Baden-Württemberg
ZIP/Postal Code
68159
Country
Germany
Facility Name
Universitätsklinikum Carl Gustav Carus an der TU Dresden, Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und
City
Dresden
State/Province
Saxony (Sachsen)
ZIP/Postal Code
01307
Country
Germany
Facility Name
Vadaskert Korhaz es Szakambulancia
City
Budapest
ZIP/Postal Code
1021
Country
Hungary
Facility Name
Servus Salvus Kft.
City
Budapest
ZIP/Postal Code
1026
Country
Hungary
Facility Name
Bekes Megyei Kozponti Korhaz Gyermek es ifjusagpszichiatriai osztaly
City
Gyula
ZIP/Postal Code
5700
Country
Hungary
Facility Name
Szegedi Tudományegyetem Szent-Gyorgy Albert Klinikai Kozpont Gyermekgyógyászati Klinika Gyermek es Ifjusagpszichiátriai o
City
Szeged
ZIP/Postal Code
6725
Country
Hungary
Facility Name
Unità Semplice di Psichiatria Infantile Policlinico Universitario di Napoli - Università Federico II
City
Napoli
State/Province
Campania
ZIP/Postal Code
80131
Country
Italy
Facility Name
Neuro Riabilitazione/Psicopatologia dell'età evolutiva Istituto Scientifico Medea - Bosisio Parini
City
Bosisio Parini
State/Province
Lombardia
ZIP/Postal Code
23842
Country
Italy
Facility Name
U.O. di Neuropsichiatria Infantile Fondazione Istituto Neurologico Nazionale Casimiro Mondino Istituto di Ricovero e Cura a Carattere Scientifico
City
Pavia
State/Province
Lombardia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Clinica di Neuropsichiatria dell'Infanzia e dell'Adolescenza Ospedale Pediatrico-Microcitemico
City
Cagliari
State/Province
Sardegna
ZIP/Postal Code
09131
Country
Italy
Facility Name
Programma Interdipartimentale "Autismo 0-90" A.O.U. Policlinico "Gaetano Martino"
City
Messina
State/Province
Sicilia
ZIP/Postal Code
98125
Country
Italy
Facility Name
U.O.C. Psichiatria dello Sviluppo IRCCS Fondazione Stella Maris
City
Calambrone
State/Province
Toscana
ZIP/Postal Code
56128
Country
Italy
Facility Name
U.O. di Neuropsichiatria Infantile Azienda Ospedaliera Universitaria Senese
City
Siena
State/Province
Toscana
ZIP/Postal Code
53100
Country
Italy
Facility Name
Accare Groningen
City
Groningen
ZIP/Postal Code
9713 GZ
Country
Netherlands
Facility Name
NAVICULA Centrum Diagnozy i Terapii Autyzmu w Łodzi
City
Lodz
State/Province
Wojewodztwo Lodzkie
ZIP/Postal Code
91-129
Country
Poland
Facility Name
Samodzielny Publiczny Dziecięcy Szpital Kliniczny w Warszawie Oddział Kliniczny Psychiatrii Wieku Rozwojowego
City
Warszawa
State/Province
Wojewodztwo Mazowieckie
ZIP/Postal Code
02-091
Country
Poland
Facility Name
Niepubliczny Zakład Opieki Zdrowotnej Gdańskie Centrum Zdrowia Sp. z o.o.
City
Gdansk
State/Province
Wojewodztwo Pomorskie
ZIP/Postal Code
80-542
Country
Poland
Facility Name
Centrum Badań Klinicznych PI-House sp. z o.o
City
Gdansk
ZIP/Postal Code
80-546
Country
Poland
Facility Name
Fundacja SYNAPSIS ul.
City
Warszawa
ZIP/Postal Code
02-085
Country
Poland
Facility Name
Centro Hospitalar e Universitario de Coimbra Hospital Pediatrico
City
Coimbra
ZIP/Postal Code
300-062
Country
Portugal
Facility Name
Hospita Mutua de Terrassa
City
Terrassa
State/Province
Barcelona
ZIP/Postal Code
08221
Country
Spain
Facility Name
Policlinica Guipuzcoa
City
San Sebastian
State/Province
Guipuzcoa
ZIP/Postal Code
20014
Country
Spain
Facility Name
Hospital Puerta de Hierro
City
Majadahonda
State/Province
Madrid
ZIP/Postal Code
28222
Country
Spain
Facility Name
Hospital General Universitario de Alicante
City
Alicante
ZIP/Postal Code
03007
Country
Spain
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital Niño Jesus
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Hospital Universitario Gregorio Marañon
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Forward Thinking Birmingham_Birmingham Women's and Children's NHS Foundation Trust
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
ReCognition Health
City
London
ZIP/Postal Code
W1G 9JF
Country
United Kingdom
Facility Name
The Winnicott Centre
City
Manchester
ZIP/Postal Code
M13 0JE
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data. Access can be requested for all interventional clinical studies: used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US). where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope. In addition, access can be requested for all interventional clinical studies in patients: sponsored by Servier with a first patient enrolled as of 1 January 2004 onwards for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.
IPD Sharing Time Frame
After Marketing Authorisation in EEA or US if the study is used for the approval.
IPD Sharing Access Criteria
Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
IPD Sharing URL
https://clinicaltrials.servier.com/
Links:
URL
https://clinicaltrials.servier.com/wp-content/uploads/CL3-95008-001-anonymisedsynopsis-2022.01.19.pdf
Description
Results summary
URL
https://clinicaltrials.servier.com/wp-content/uploads/CL3-95008-001-laysummary-2022.01.27.pdf
Description
Lay summary
Available IPD and Supporting Information:
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Study Protocol
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Statistical Analysis Plan
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Clinical Study Report
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
study-level clinical trial data
Available IPD/Information URL
https://clinicaltrials.servier.com/

Learn more about this trial

Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder

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