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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.

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ClinicalTrials.gov Identifier: NCT03715153
Recruitment Status : Terminated (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.)
First Posted : October 23, 2018
Results First Posted : June 5, 2023
Last Update Posted : June 5, 2023
Sponsor:
Collaborator:
ADIR, a Servier Group company
Information provided by (Responsible Party):
Servier ( Institut de Recherches Internationales Servier )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder (ASD) Drug: BUMETANIDE (S95008) for week 0 - 26 Drug: PLACEBO for week 0 - 26 Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52 Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 211 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : October 4, 2018
Actual Primary Completion Date : October 26, 2021
Actual Study Completion Date : October 26, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Bumetanide

Arms and Interventions
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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: PLACEBO for week 0 - 26
Oral solution Taken twice daily.

Drug: Open-Label BUMETANIDE (S95008) for weeks 26 - 52
Oral solution dosed at 0.5 mg/mL Taken twice daily.


Outcome Measures
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Primary Outcome Measures :
  1. Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score [ Time Frame: 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 :
  1. Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score [ Time Frame: 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.


  2. Clinical Global Impression - Global Improvement (CGI-I) Score [ Time Frame: 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).


  3. Vineland Adaptative Behaviour Scale II (VABS II) [ Time Frame: 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.

  4. Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters [ Time Frame: 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.


  5. Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) [ Time Frame: 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.

  6. Acceptability and Palatability Questionnaires - Only Descriptive Analyses [ Time Frame: 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

  7. Paediatric Quality of Life Inventory (PedsQL) Questionnaire [ Time Frame: 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)

  8. Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) [ Time Frame: through week 52 ]

Eligibility Criteria
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Ages Eligible for Study:   2 Years to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03715153


Locations
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Sponsors and Collaborators
Institut de Recherches Internationales Servier
ADIR, a Servier Group company
  Study Documents (Full-Text)

Documents provided by Servier ( Institut de Recherches Internationales Servier ):
Study Protocol  [PDF] March 25, 2021
Statistical Analysis Plan  [PDF] July 21, 2021

More Information
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Additional Information:

Study Data/Documents: Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Study Protocol  This link exits the ClinicalTrials.gov site
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Informed Consent Form  This link exits the ClinicalTrials.gov site
Clinical Study Report  This link exits the ClinicalTrials.gov site
study-level clinical trial data]  This link exits the ClinicalTrials.gov site

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Responsible Party: Institut de Recherches Internationales Servier
ClinicalTrials.gov Identifier: NCT03715153    
Other Study ID Numbers: CL3-95008-002
2017-004420-30 ( EudraCT Number )
First Posted: October 23, 2018    Key Record Dates
Results First Posted: June 5, 2023
Last Update Posted: June 5, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
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.
URL: https://clinicaltrials.servier.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Bumetanide
 Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action