Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.

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.

The purpose of this study was to evaluate the efficacity and the safety of bumetanide/S95008 in the improvement of Autism Spectrum Disorder core symptoms.

Study Overview

• Status: Terminated
• Conditions: Autism Spectrum Disorder (ASD)
• Intervention / Treatment: Drug: BUMETANIDE (S95008) for week 0 - 26; Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52; Drug: PLACEBO for week 0 - 26

Detailed Description

The present study (CL3-95008-002) was performed in children from 2 to less than 7 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 twice daily in which long term safety was evaluated.

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Liverpool, Australia, 2170
    • Liverpool Hospital
  • Parkville, Australia, 3052
    • The Royal Children's Hospital Melbourne
• Brazil
  • Curitiba, Brazil, 80240-280
    • Trial Tech em Pesquisas com Medicamentos Ltda
  • Fortaleza, Brazil, 60430-370
    • Hospital Universitário Walter Cantídio-Universidade Federal do Ceará
  • Joinville, Brazil, 89202-190
    • Clinica Neurologica e Neurocirurgica de Joinville
  • Passo Fundo, Brazil, 99010-080
    • Hospital Sao Vicente de Paulo
  • São Paulo, Brazil, 04017-030
    • Universidade Federal de São Paulo, Escola Paulista de Medicina
  • São Paulo, Brazil, 054030-010
    • Faculdade de Medicina da Universidade de São Paulo - Departamento de psiquiatra
• Czechia
  • Brno, Czechia, 613 00
    • University Hospital Brno, Department of Child Neurology
  • Praha, Czechia, 186 00
    • Institute of Neuropsychiatric Care, Department of Child Psychiatry
  • Ostrava
    • Poruba, Ostrava, Czechia
      • University hospital of Ostrava, Department of Psychiatry
• France
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 6200
      • GSC CHU-LENVAL Centre ressource autisme
  • Alsace-Champagne-Ardenne-Lorraine
    • Strasbourg, Alsace-Champagne-Ardenne-Lorraine, France, 67091
      • Hôpitaux Universitaires de Strasbourg Service de Psychiatrie de l'Enfant et de l'Adolescent
  • Auvergne Rhone Alpes
    • Bron, Auvergne Rhone Alpes, France, 69677
      • Centre d'Investigation Clinique de Lyon
  • Auvergne-Rhône-Alpes
    • Bron Cedex, Auvergne-Rhône-Alpes, France, 69678
      • Hôpital Le Vinatier CRA Rhône-Alpes, Bat 211
  • Ile De France
    • Paris, Ile De France, France, 75019
      • Hôpital Robert Debré Service de Psychiatrie de l'enfant et de l'adolescent
  • Normandie
    • Rouen, Normandie, France, 76000
      • CHU Rouen
    • Sotteville-lès-Rouen, Normandie, France, 76301
      • Centre Hospitalier du Rouvray Centre de Ressources pour l'Autisme
  • Nouvelle Aquitaine
    • Bordeaux, Nouvelle Aquitaine, France, 33076
      • Hôpital des Enfants-Pellegrin
  • Nouvelle-Aquitaine
    • Bordeaux, Nouvelle-Aquitaine, France, 33076
      • Centre Hospitalier Charles Perrens CRA Aquitaine
• Hungary
  • Budapest, Hungary, 1021
    • Vadaskert Korhaz es Szakambulancia
  • Budapest, Hungary, 1026
    • Servus Salvus Kft.
  • Budapest, Hungary, 1143
    • Magyar Református Egyház Bethesda Gyermekkórháza
  • Gyula, Hungary, 5700
    • Bekes Megyei Kozponti Korhaz Gyermek es ifjusagpszichiatriai osztaly
  • Szeged, Hungary, 6725
    • Szegedi Tudományegyetem Szent-Gyorgy Albert Klinikai Kozpont Gyermekgyógyászati Klinika Gyermek es Ifjusagpszichiátriai o
• Italy
  • Lombardia
    • Bosisio Parini, Lombardia, Italy, 23842
      • Neuro Riabilitazione/Psicopatologia dell'età evolutiva Istituto Scientifico Medea - Bosisio Parini
    • Pavia, Lombardia, Italy, 27100
      • U.O. di Neuropsichiatria Infantile Fondazione Istituto Neurologico Nazionale Casimiro Mondino Istituto di Ricovero e Cura a Carattere Scientifico
  • Sardegna
    • Cagliari, Sardegna, Italy, 09131
      • Clinica di Neuropsichiatria dell'Infanzia e dell'Adolescenza Ospedale Pediatrico-Microcitemico
  • Sicilia
    • Messina, Sicilia, Italy, 98125
      • Programma Interdipartimentale "Autismo 0-90" A.O.U. Policlinico "Gaetano Martino"
  • Toscana
    • Calambrone, Toscana, Italy, 56128
      • U.O.C. Psichiatria dello Sviluppo IRCCS Fondazione Stella Maris
    • Siena, Toscana, Italy, 53100
      • U.O. di Neuropsichiatria Infantile Azienda Ospedaliera Universitaria Senese
• Poland
  • Gdansk, Poland, 80-546
    • Centrum Badań Klinicznych PI-House sp. z o.o
  • Gdansk, Poland, 80-542
    • "Niepubliczny Zakład Opieki Zdrowotnej Gdańskie Centrum Zdrowia Sp. z o.o.
  • Lodz, Poland, 91-126
    • NAVICULA Centrum Diagnozy i Terapii Autyzmu w Łodzi
  • Warszawa, Poland, 02-085
    • Fundacja SYNAPSIS ul.
  • Warszawa, Poland, 02-091
    • Samodzielny Publiczny Dziecięcy Szpital Kliniczny w Warszawie Oddział Kliniczny Psychiatrii Wieku Rozwojowego
• Portugal
  • Coimbra, Portugal, 300-062
    • Centro Hospitalar e Universitario de Coimbra Hospital Pediatrico
• Slovakia
  • Bratislava, Slovakia, 833 40
    • National Institute of Children Diseases, Department of Child Psychiatry
  • Košice, Slovakia, 040 01
    • EPAMED, s.r.o.
• Spain
  • Alicante, Spain, 03007
    • Hospital General Universitario de Alicante
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Madrid, Spain, 28009
    • Hospital Universitario Gregorio Marañón
  • Madrid, Spain, 28009
    • Hospital Niño Jesús
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
      • Hospita Mutua de Terrassa
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain, 20014
      • Policlinica Guipuzcoa
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Puerta de Hierro
• United Kingdom
  • Colchester, United Kingdom, CO4 5JL
    • Colchester Hospital
  • London, United Kingdom, W1G 9JF
    • Recognition Health
  • Manchester, United Kingdom, M13 0JE
    • The Winnicott Centre 195-197 Hathersage Road
• United States
  • New York
    • Staten Island, New York, United States, 10312
      • Richmond Behavioral Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients from 2 to less than 7
• 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-Generic (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 (SRS-2) total score ≥ 66 T-Score
• Absence of diagnosis of Fragile X or 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BUMETANIDE (S95008) followed by Open-Label S95008; Participants will receive S95008 for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.	Drug: BUMETANIDE (S95008) for week 0 - 26; Oral solution dosed at 0.5 mg/mL Taken twice daily.; Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52; Oral solution dosed at 0.5 mg/mL Taken twice daily.
Placebo Comparator: PLACEBO followed by Open-Label S95008; Participants will receive placebo for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.	Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52; Oral solution dosed at 0.5 mg/mL Taken twice daily.; Drug: PLACEBO for week 0 - 26; Oral solution Taken twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score	The CARS2 total raw score range from 15 to 60. This scale is a behaviour rating scale intended to diagnose autism. A total score of 15 indicates that an individual behaviour is within normal limits, whereas a value of 60 indicates that the individual's behaviour is severly abnormal. In term of change from baseline, the greater the mean value decreases, the better it is.	Change from baseline to Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score	The SRS-2 total raw score serves as an index of severity of social deficits in the autism spectrum. The total raw score ranges from 65 to 260. A value of 65 represents no symptoms disorders, a value of 260 represents a severe autism spectrum disorder. In terms of change from baseline, the greater the mean value decreases, the better it is.	Change from baseline to Week 26
Clinical Global Impression - Global Improvement (CGI-I) Score	Scale which assesses the severity of the illness and the global improvement of the patient under study treatment. It ranges from 1 (normal) through to 7 (amongst the most severely ill patients).	At Week 26
Vineland Adaptative Behaviour Scale II (VABS II)	Scale designated to measure adaptative behaviour The scale for behaviour ranges from 1 to 67. The more the score decreases, the better it is.	Change from baseline to Week 26
Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters	Number of patients with clinically significant ECG abnormalities The 12-lead electrocardiogram (ECG) is a medical test that is recorded using leads, or nodes, attached to the body. Electrocardiograms (ECGs), capture the electrical activity of the heart and transfer it to graphed paper where abnormalities are reported and interpretated by the cardiologist.	Week 26
Columbia-Suicide Severity Scale Children's Version (C-SSRS-C)	Number of patients with suicidal ideation or suicidal behavior. The scale is 0 to 5 with the highest suicidal behavior being a 5 and the absence of suicidal behavior or very minor behaviors are 0. However, statistical analysis was done by looking at the number of patients with suicidal behavior or suicidal ideation during their lifetime and during the last 6 months of treatment.	Week 26
Acceptability and Palatability Questionnaires - Only Descriptive Analyses	Acceptability and palatability criterion Based on your child's reactions (indirect rating), do you think that he/she found the administration method to be	Week 26
Paediatric Quality of Life Inventory (PedsQL) Questionnaire	It represents the assessment of parent/legal representative perception of patient health related quality of life The values of the questionnaire range from 0 to 100. Higher scores indicate better HRQOL (Health-Related Quality of Life)	Change from baseline to week 26
Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE)		through week 52

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: ADIR, a Servier Group company

Publications and helpful links

Helpful Links

• Results summary
• Lay summary

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2018
• Primary Completion (Actual): October 26, 2021
• Study Completion (Actual): October 26, 2021

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 18, 2018
• First Posted (Actual): October 23, 2018

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Bumetanide
• Other Study ID Numbers: CL3-95008-002; 2017-004420-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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 Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
2. Study Protocol
3. Statistical Analysis Plan
4. Informed Consent Form
5. Clinical Study Report
6. study-level clinical trial data]

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No