Efficacy and Safety of Bumetanide ORAL Liquid Formulation in Children and Adolescents with Autism Spectrum Disorder: Study Protocol of Two Randomised, Double-Blind, Placebo Controlled Phase III Trials

Poster Presentation
Friday, May 3, 2019: 5:30 PM-7:00 PM
Room: 710 (Palais des congres de Montreal)
S. Kyaga1, V. Crutel2, C. Albarran2, Y. Ben-Ari3, D. M. Ravel4 and B. Falissard5, (1)Servier Medical Affairs, Suresnes, France, (2)Institut de Recherches Internationales Servier, Suresnes, France, (3)Neurochlore, Marseille, France, (4)R&D, Neurochlore, Marseille, France, (5)Centre de Recherche en Epidemiologie et Santé des Populations, Paris, France

Autism Spectrum Disorder (ASD) encompasses a heterogeneous set of neurodevelopmental conditions, characterized by core symptoms of abnormal social interactions with impaired communication abilities and repetitive or stereotypical behaviours. Although ASD can cause significant emotional and economic burden on people affected and their families, evidence-based treatment options are limited. Recent studies suggest that GABAergic neurons and circuits may be altered in ASD. Bumetanide is a loop diuretic which may reinstate GABAergic inhibition. A previous phase IIb study involving 88 children and adolescents (2-18 years) with ASD demonstrated a statistically significant improvement with bumetanide in the Childhood Autism Rating Scale (CARS) at day 90 compared to placebo. We here report the international clinical development for bumetanide in moderate to severe ASD, with two simultaneous similar phase III trials in two age subsets (2-7 years; 7-18 years).


The primary objective is to demonstrate the efficacy of bumetanide 0.5 mg (or 0.02 mg/kg for children with a weight<25 kg) twice daily as oral liquid formulation compared to placebo on ASD core symptoms using the CARS-2 after 6 months of double-blind treatment.


Both phase III trials are international, randomized, double-blind, placebo-controlled with a 6-month parallel-group design, followed by a 6-month open-label treatment period and a 6-week discontinuation period after treatment stop. Children and adolescents (N = 200 in each study, diagnosed according to DSM5 and fulfilling ADOS-2 and ADI-R criteria), with confirmed moderate or severe ASD (CARS-2 ≥ 34; CGI–S ≥ 4) will be randomised to bumetanide or placebo. An adaptation of the oral solution volume according to the weight of the patients will be performed at different pre-specified visits. The primary efficacy outcome measure is the CARS-2 total raw score at 6 months. Main secondary efficacy endpoints include individual CARS-2 domains, Social responsiveness Scale (SRS-2) total raw score, CGI-I and the Vineland Adaptative Behaviour Scale II. Efficacy endpoints will be expressed as changes from baseline to the 6-month visit and 12-month visit, respectively. Safety of bumetanide will be assessed throughout the study using adverse events recording, clinical examination, laboratory evaluation, ECG and renal ultrasound. Suicidality will be assessed using the Columbia-Suicide severity scale Children’s version. A Data Monitoring Committee will be responsible for periodic review of patient’s safety data. Pharmacokinetics measurements will be performed at several time points.

Bumetanide will be compared to placebo using a general linear model with baseline and stratification factors (country and gender) as covariates.


Recruitment was initiated in October 2018. The completion date of the two phase 3 trials will be in 2021/2022.


This phase III program will provide further data on long-term efficacy and safety of bumetanide oral solution in children and adolescents with moderate to severe ASD. If positive, the outcome of these studies could contribute to the first available pharmacological treatment for core symptoms in ASD.

See more of: Clinical trial design
See more of: Clinical Trial Design