Bumetanide for Irritability in Children With Sensory Processing Problems Across Neurodevelopmental Disorders: A Pilot Randomized Controlled Trial

Abstract

Background: Treatment development for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is impeded by heterogeneity in clinical manifestation and underlying etiologies. Symptom traits such as aberrant sensory reactivity are present across NDDs and might reflect common mechanistic pathways. Here, we test the effectiveness of repurposing a drug candidate, bumetanide, on irritable behavior in a cross-disorder neurodevelopmental cohort defined by the presence of sensory reactivity problems.

Methods: Participants, aged 5-15 years and IQ ≥ 55, with ASD, ADHD, and/or epilepsy and proven aberrant sensory reactivity according to deviant Sensory Profile scores were included. Participants were randomly allocated (1:1) to bumetanide (max 1 mg twice daily) or placebo tablets for 91 days followed by a 28-day wash-out period using permuted block design and minimization. Participants, parents, healthcare providers, and outcome assessors were blinded for treatment allocation. Primary outcome was the differences in ABC-irritability at day 91. Secondary outcomes were differences in SRS-2, RBS-R, SP-NL, BRIEF parent, BRIEF teacher at D91. Differences were analyzed in a modified intention-to-treat sample with linear mixed models and side effects in the intention-to-treat population.

Results: A total of 38 participants (10.1 [SD 3.1] years) were enrolled between June 2017 and June 2019 in the Netherlands. Nineteen children were allocated to bumetanide and nineteen to placebo. Five patients discontinued (n = 3 bumetanide). Bumetanide was superior to placebo on the ABC-irritability [mean difference (MD) -4.78, 95%CI: -8.43 to -1.13, p = 0.0125]. No effects were found on secondary endpoints. No wash-out effects were found. Side effects were as expected: hypokalemia (p = 0.046) and increased diuresis (p = 0.020).

Conclusion: Despite the results being underpowered, this study raises important recommendations for future cross-diagnostic trial designs.

Keywords: ADHD; ASD; RCT; bumetanide; child; epilepsy; irritability; sensory processing.

Figure 1

Timeline of the study visits of the trial. The blue line represents the baseline visits, the green line the medication phase and the yellow line the wash-out phase. The blood drops represent the routine blood checks. D, day.

Figure 2

CONSORT diagram of the trial.

Figure 3

Individual treatment effect on the primary outcome. Absolute change on the Aberrant Behavior Checklist-Irritability subscale (ABC-I) after 91 days of treatment (D91 minus D0). Blue bars indicate bumetanide treatment, orange bars indicate placebo treatment. Each bar (blue or orange) represents the outcome for an individual enrolled in the trial. The primary endpoint shows a significant treatment effect (p = 0.0125) favoring the bumetanide group.

Figure 4

Individual treatment effect on secondary outcomes. (A) Absolute change on the Repetitive Behavior Checklist-Revised (RBS-R) after 91 days of treatment showing no superior treatment effect (p = 0.109). Blue bars indicate bumetanide treatment, orange bars indicate placebo treatment. Each bar (blue or orange) represents the outcome for an individual enrolled in the trial. (B) Absolute change on the Social Responsiveness Scale-2 (SRS-2) total score showing no superior treatment effect (p = 0.181). (C) Absolute change on the Sensory Profile-NL (SP-NL) total score showing no superior treatment effect (p = 0.844).