Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 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 efficacity and the safety of bumetanide/S95008 in the improvement of Autism Spectrum Disorder core symptoms.

Detailed Description
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The present study (CL3-95008-002) 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.

Official Title
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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.

Conditions
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Autism Spectrum Disorder (ASD)

Intervention / Treatment
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* Drug: BUMETANIDE (S95008) for week 0 - 26
* Drug: PLACEBO for week 0 - 26
* Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 6 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) followed by Open-Label S95008<br>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<br>* Oral solution dosed at 0.5 mg/mL Taken twice daily.<br>Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52<br>* Oral solution dosed at 0.5 mg/mL Taken twice daily.<br>|
| Placebo Comparator: PLACEBO followed by Open-Label S95008<br>Participants will receive placebo for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008. | Drug: PLACEBO for week 0 - 26<br>* Oral solution Taken twice daily.<br>Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52<br>* Oral solution dosed at 0.5 mg/mL 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 | 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 |