Abstract
Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD). We tested efficacy of bumetanide on core symptom domains using a single center, parallel-group, participant-randomized, double-blind, placebo-controlled phase-2 superiority trial in a tertiary hospital in the Netherlands. Unmedicated children aged 7 to 15 years with ASD and IQ ≥55 were block-randomized 1:1 to oral-solution bumetanide versus placebo, titrated to a maximum of 1.0 mg twice daily for 91 days (D91), followed by a 28-day wash-out period. The primary outcome was difference in Social Responsiveness Scale-2 (SRS-2) total score at D91, analyzed by modified intention-to-treat with linear mixed models. A total of 92 participants (mean age 10.5 [SD 2.4] years) enrolled between June 2016 and December 2018. In all, 47 children were allocated to bumetanide and 45 to placebo. Two participants dropped out per treatment arm. After 91 days, bumetanide was not superior to placebo on the primary outcome, the SRS-2 (mean difference-3.16, 95% CI=-9.68 to 3.37, p= .338). A superior effect was found on one of the secondary outcomes, the Repetitive Behavior Scale-Revised (mean difference-4.16, 95% CI=-8.06 to-0.25, p= .0375), but not on the Sensory Profile (mean difference 5.64, 95% CI=-11.30 to 22.57, p= .508) or the Aberrant Behavior Checklist Irritability Subscale (mean difference-0.65, 95% CI=-2.83 to 1.52, p= .552). No significant wash-out effect was observed. Significant adverse effects were predominantly diuretic effects (orthostatic hypotension (17 [36%] versus 5 [11%], p= .007); hypokalemia (24 [51%] versus 0 [0%], p< .0001), the occurrence of which did not statistically influence treatment outcome. The trial outcome was negative in terms of no superior effect on the primary outcome. The secondary outcomes suggest efficacy on repetitive behavior symptoms for a subset of patients. Bumetanide in Autism Medication and Biomarker Study (BAMBI); https://www.clinicaltrialsregister.eu/; 2014-001560-35.
Highlights
Analysis of treatment effects revealed that bumetanide was not superior to placebo in Social Responsiveness ScaleÀ2 (SRS-2) total scores, the primary outcome of the study (Table 2, Figure 2)
These results from the BAMBI trial did not show a superior effect of bumetanide over placebo on the primary outcome of a broad scale of Autism spectrum disorder (ASD) symptomatology, and indicated a nominal significant superior effect on a secondary outcome measure of repetitive behaviors
There is an ongoing debate on selecting outcome measures for randomized controlled trials (RCTs) in ASD
Summary
Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD). Compelling evidence shows that deficits in GABAergic inhibition can contribute to ASD development.[8] The efficacy of GABAergic inhibition depends on Journal of the American Academy of Child & Adolescent Psychiatry Volume 60 / Number 7 / July 2021 www.jaacap.org the regulation of the intracellular neuronal chloride ([ClÀ]i) concentrations.[9,10] Pathologically high [ClÀ]i can reverse the polarity of GABA binding its receptor from inhibition to excitation, a converging mechanism that has been linked to a variety of disorders including ASD.[10] Elevated levels of neuronal chloride and excitatory actions of GABA receptor signaling have been established in animal models of ASD and associated conditions These observations have raised interest in the development of pharmacological treatments that restore chloride homeostasis and GABAergic inhibition in pathological conditions.[10] The [ClÀ]i is predominantly regulated by the chloride importer. In this first report of the trial, we describe the protocol and treatment effects on clinical behavioral outcome measures
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