VanAndel 2022.

Study characteristics
Methods	13‐week parallel trial of bumetanide versus placebo
Participants	Inclusion criteria: current ASD, ADHD (according to DSM‐4‐TR or DSM‐5 criteria), and/or epilepsy diagnosis aged 5–15 years IQ ≥ 55 diagnosis accompanied by altered sensory reactivity, defined as a deviant score (> 1 SD deviant) on the Sensory Profile for parents or teachers (SP‐NL or SP‐SC) use of concomitant psychoactive and antiepileptic drugs (AED) was allowed, when being taken on an unadjusted dosage at least 2 months prior to baseline measures Exclusion criteria: renal or liver insufficiency serious unstable illnesses (including gastroenterological, respiratory, cardiovascular, endocrinologic, immunologic, haematologic disease, dehydration or hypotension, electrolyte disturbances) treatment with nonsteroidal anti‐inflammatory drugs, aminoglycosides, digitalis, antihypertensive agents, indomethacin, probenecid, acetazolamide, lithium, other diuretics, stimulants (like methylphenidate and dexamphetamine, due to it assumed diametrical effects), and drugs known to have a nephrotoxic potentia children were allowed to receive care as usual when it was initiated minimally 2 months prior to baseline measures Location/setting: The Netherlands Sample size: 38 (19 to each group) Reasons for withdrawals/dropouts: 4 in each group dropped out (bumetanide: discontinued treatment (3), excluded due to incomplete parent reports (1); placebo group discontinued treatment (2), excluded due to incomplete or unreliable parent reports (2)) Gender: 22 male, 8 female Mean age: bumetanide group 10.9 years, placebo group 8.7 years IQ: approx 99 in both groups Baseline ABC‐I or other BoC scale: bumetanide group 13.1, placebo group 17.1 Diagnoses: 22/30 participants had an ASD diagnosis, of whom 15 only had an ASD diagnosis (another 6 had ASD and ADHD, and 1 participant had ASD and epilepsy) Concomitant medications: during the trial 68.4% in both groups did not receive any other medications. Of those who were taking other medications 15.8% in bumetanide group and 5.3% in placebo group were taking antipsychotics; 5.3% in placebo group were taking a benzodiazepine in addition to an antipsychotic; 15.8% in the placebo group were taking an anticonvulsant; 10.5% in the bumetanide group were taking an SSRI; and 5.3% in both groups were taking an SSRI in addition to an antipsychotic. Previous medications: 47.4% in both groups did not take medications prior to the trial. Of those who took medications 21.1% in bumetanide group and 10.5 in placebo group were taking antipsychotics; 5.3% in the placebo group were taking a benzodiazepine; 5.3% and 31.6% in the bumetanide and placebo groups respectively were taking an anticonvulsant; 10.5% and 5.3% in the bumetanide and placebo groups respectively were taking an SSRI; 31.6% and 26.3% in the bumetanide and placebo groups respectively were taking stimulants; 5.3% and 10.5% in the bumetanide and placebo groups respectively were taking an alpha adrenergic agonist.
Interventions	Intervention (bumetanide) for 13 weeks: maximum of 1 mg bumetanide twice daily followed by a 28‐day washout period Comparator (placebo) for 13 weeks: equivalent placebo twice daily followed by a 28‐day washout period
Outcomes	Primary outcomes: irritability (measured using the ABC‐I subscale) (Aman 1985) AEs self injurious behaviour (measured using the Repetitive Behaviour Scale self‐injury subscale) (Bodfish 2000) Secondary outcomes: none reported Timing of outcome assessments: AEs were monitored on days 4, 7, 14, 28, 56, 91, and 119; other outcomes were measured at day 91 (endpoint) and day 119 following washout
Notes	Study start date: June 2017 Study end date: June 2019 Funding: "This study was supported by a grant from Dutch Brain Foundation (Hersenstichting #HA2015‐01‐04)." Conflicts of interest: HB (the contact author) has reported being a shareholder of Aspect Neuroprofiles BV, which provides EEG‐analysis services for clinical trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Sequence generation, concealment, and treatment allocation was overseen by a third‐party not involved in the study (i.e., Julius Center, a consultant support agency for clinical research and trials located in the UMC Utrecht). Restricted randomization was used with permuted block design randomly varying between two, four, and six participants. Treatment allocation was done automatically using minimization with a probability of 0.75 on the participant factors active epilepsy (y/n), IQ (55–75; 76–110; >110) and study center (UMC/Jonx)"
Allocation concealment (selection bias)	Low risk	"Sequence generation, concealment, and treatment allocation was overseen by a third‐party not involved in the study"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, parents, healthcare providers, and outcome assessors were blinded for randomisation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, parents, healthcare providers, and outcome assessors were blinded for randomisation
Incomplete outcome data (attrition bias) All outcomes	High risk	> 25% dropout, "one participant was excluded from analyses as questionnaires were not reliable"
Selective reporting (reporting bias)	Unclear risk	Can't find outcomes on either trial reg (EudraCT trial registry (2016‐002875‐81) and Dutch trial registry (NL6178)
Other bias	Low risk	Funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript