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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Autism Spectrum Disorder (ASD)

Intervention / Treatment
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* Drug: Bumetanide Oral Solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 6-month, randomized, double-blind, placebo-controlled, parallel groups followed by an open label active 6-month treatment period with bumetanide.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bumetanide/S95008<br> | Drug: Bumetanide Oral Solution<br>* Oral Solution dosed at 0.5mg/mL Taken twice daily<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Oral Solution Taken twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from baseline to 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Social Responsiveness Scale, Second Edition (SRS-2) total raw score | Efficacy criterion 65 items scale measuring symptoms associated with autism | Change from baseline to 6 month | 
| 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 | At 6 months | 
| Vineland Adaptative Behaviour Sales, Second Edition (VABS II) subscores | Efficacy criterion Scale designated to measure adaptative behaviour | Change from baseline to 6 month | 
| 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. | On average of 52 weeks | 
| Abnormalities in 12-leads electrocardiogram (ECG) parameters | Safety criterion | selection visit/Week004/Week008/Week012/Week 026/Week030/Week034/Week038/Week052 | 
| Renal ultrasound | Safety criterion Assessment of the renal function | selection visit/Week026/Week052 | 
| the Columbia Suicide Severity Rating Scale Children's version (C-SSRS-C) | Scale which assesses suicidal ideation and suicidal behaviour | Week000/Week012/Week026/Week038/Week052 | 
| Tanner stage | Safety criterion Assessment of Pubertal development | Week000/Week026/Week052 | 
| Acceptability and palatability questionnaire | Acceptability and palatability criterion Assessment of the ease of use to use the dosing device | Week026 | 
| Paediatric Quality of Life Inventory (PedsQL) questionnaire | Quality of Life criterion Assessment of parent/legal representative perception of patient health related quality of life | Week000/Week004/Week012/Week026/Week030/Week038/Week052 |