Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial

Abstract

Objective: 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. Method: 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 ScaleÀ2 (SRS-2) total score at D91, analyzed by modified intention-to-treat with linear mixed models. Results: 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 À3.16, 95% CI ¼ À9.68 to 3.37, p ¼ .338). A superior effect was found on one of the secondary outcomes, the Repetitive Behavior ScaleÀRevised (mean difference À4.16, 95% CI ¼ À8.06 to À0.25, p ¼ .0375), but not on the Sensory Profile (mean difference 5.64, 95% CI ¼ À11.30 to 22.57, p ¼ .508) or the Aberrant Behavior Checklist Irritability Subscale (mean difference À0.65, 95% CI ¼ À2.83 to 1.52, p ¼ .552). No significant wash-out effect was observed. Significant adverse effects were predominantly diuretic effects (orthostatic hypotension (17 [36%] versus 5 [11%], p ¼ .007); hypokalemia (24 [51%] versus 0 [0%], p < .0001), the occurrence of which did not statistically influence treatment outcome. Conclusion: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. Clinical trial registration information: Bumetanide in Autism Medication and Biomarker Study (BAMBI); https://www.clinicaltrialsregister.eu/;

Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials)

“…Increased diuresis associated with bumetanide treatment could potentially jeopardize the blinding in the Phase III studies reported here. However, this effect was found to be limited in both the BAMBI study and the Phase II trial, as the psychiatrist who assessed outcome measures was blinded to the treatment (Lemonnier et al 2017 ; Sprengers et al 2020 ). Similarly, the primary endpoint in the Phase III studies is being assessed by an independent rater.…”

“…As a secondary endpoint, cognitive and neurophysiological assessments (behavioral questionnaire, neurocognitive test battery, event-related potential paradigms, and resting state paradigms) were used to identify prognostic biomarkers of bumetanide oral liquid formulation treatment, with a view to enabling a more personalized treatment approach in the future. The BAMBI study did not find that bumetanide was superior to placebo based on the primary outcome (SRS-2 total score), although a superior effect was reported based on a secondary endpoint (Repetitive Behavior Scale-Revised; Sprenger et al 2020 ). Another recent study of bumetanide in children (n = 83) with ASD aged 3 to 6 years demonstrated significant benefits compared with control, using the CARS as the primary outcome measure (Zhang et al 2020 ).…”

Treating Autism With Bumetanide: Are Large Multicentric and Monocentric Trials on Selected Populations Complementary?

“…Bruining and colleagues conclude that Bumetanide does not attenuate ASD despite a nominally significant treatment effect in repetitive behaviors (RBS) which is a core-symptom of ASD but was defined as a secondary measure in this trial 1 . Four earlier studies performed by three independent institutes, including two that are not referred to by Bruining and colleagues 2,3 , tested a total of 169 children -vs 122 placebo-have shown a significant amelioration of ASD symptomatology.…”

A causal study of bumetanide on a marker of excitatory-inhibitory balance in the human brain

“…Further, a recent large-scale clinical trial found no improvements in social or sensory symptoms after longitudinal bumetanide treatment in children with autism, as measured using the Social Responsiveness Scale-2 (SRS-2) and Sensory Profile (SP-NL) respectively, and only minor reductions in repetitive behaviors, measured by the Repetitive Behavior Scale Revised (RBS-R) [24]. Taken together, these mixed findings highlight the need to better understand bumetanide's ability to ameliorate the multiplexed symptoms of autism, and underscore the importance of objective measures of drug efficacy.…”

“…Bumetanide is thought to increase the hyperpolarizing potential of GABA by blocking NKCC1 receptors, which are responsible for Cl-entrance into the cell [20]. Further, some studies of bumetanide in humans, specifically children with autism, have shown evidence for attenuation of social symptom severity and improvement of emotion recognition [21][22][23], although, notably, these benefits are not universally observed [24]. Importantly, to date, direct evidence that bumetanide increases inhibition in the human brain is lacking, which complicates linking the reported symptomatic benefits to the drug's predicted physiological effects.…”