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

Phase 3

Terminated

• Conditions: Autism Spectrum Disorder (ASD)
• Interventions: Drug: BUMETANIDE (S95008) for week 0 - 26; Drug: PLACEBO for week 0 - 26; Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52

• Registration Number: NCT03715153
• Lead Sponsor: Institut de Recherches Internationales Servier

Brief Summary

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.

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 Timeline

• Study Start: 2018-10-04
• Study First Submitted: 2018-10-12
• Study First Submitted QC: 2018-10-18
• Study First Posted: 2018-10-23
• Primary Completion: 2021-10-26
• Study Completion: 2021-10-26
• Results First Submitted: 2022-10-26
• Status Verified: 2023-05
• Results First Submitted QC: 2023-05-09
• Last Update Submitted: 2023-05-09
• Results First Posted: 2023-06-05
• Last Update Posted: 2023-06-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 211

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BUMETANIDE (S95008) followed by Open-Label S95008	BUMETANIDE (S95008) for week 0 - 26	Participants will receive S95008 for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.
PLACEBO followed by Open-Label S95008	PLACEBO for week 0 - 26	Participants will receive placebo for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.
PLACEBO followed by Open-Label S95008	Open-Label BUMETANIDE (S95008) for weeks 26 - 52	Participants will receive placebo for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.
BUMETANIDE (S95008) followed by Open-Label S95008	Open-Label BUMETANIDE (S95008) for weeks 26 - 52	Participants will receive S95008 for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.

Primary Outcome Measures

Name	Time	Method
Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score	Change from baseline to Week 26	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.

Secondary Outcome Measures

Name	Time	Method
Clinical Global Impression - Global Improvement (CGI-I) Score	At Week 26	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).
Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters	Week 26	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.
Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE)	through week 52
Vineland Adaptative Behaviour Scale II (VABS II)	Change from baseline to Week 26	Scale designated to measure adaptative behaviour The scale for behaviour ranges from 1 to 67. The more the score decreases, the better it is.
Acceptability and Palatability Questionnaires - Only Descriptive Analyses	Week 26	Acceptability and palatability criterion Based on your child's reactions (indirect rating), do you think that he/she found the administration method to be
Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score	Change from baseline to Week 26	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.
Columbia-Suicide Severity Scale Children's Version (C-SSRS-C)	Week 26	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.
Paediatric Quality of Life Inventory (PedsQL) Questionnaire	Change from baseline to week 26	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)

Trial Locations

Locations (50)

Richmond Behavioral Associates; 🇺🇸 Staten Island, New York, United States

Liverpool Hospital; 🇦🇺 Liverpool, Australia

The Royal Children's Hospital Melbourne; 🇦🇺 Parkville, Australia

Trial Tech em Pesquisas com Medicamentos Ltda; 🇧🇷 Curitiba, Brazil

Hospital Universitário Walter Cantídio-Universidade Federal do Ceará; 🇧🇷 Fortaleza, Brazil

Clínica Neurológica e Neurocirúrgica de Joinville; 🇧🇷 Joinville, Brazil

Hospital São Vicente de Paulo; 🇧🇷 Passo Fundo, Brazil

Universidade Federal de São Paulo, Escola Paulista de Medicina; 🇧🇷 São Paulo, Brazil

Faculdade de Medicina da Universidade de São Paulo - Departamento de psiquiatra; 🇧🇷 São Paulo, Brazil

University hospital of Ostrava, Department of Psychiatry; 🇨🇿 Poruba, Ostrava, Czechia

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