Lemonnier 2017.

Study characteristics
Methods	3‐month parallel trial of bumetanide versus placebo
Participants	Inclusion criteria: children and adolescents aged 2–18 years fulfil diagnosis criteria of Childhood Autism (F84.0) or Asperger's Syndrome (F84.5) according to ICD‐10; and ADOS G and ADI‐R CARS total score 434 points weight ≥ 11 kg Exclusion criteria: serious, unstable illnesses including, gastroenterological, respiratory, cardiovascular (QT interval lengthening), endocrinology, immunologic or hematologic disease; renal or hepatic dysfunction and neurological disorders such as seizures and microcephaly psychotropic medications were not allowed during the trial and had to be discontinued at least 4 weeks before entering the trial Location/setting: France; the patients were enroled in six French specialised centres (hospitals of Brest, Limoges, Rouen, Nice, Lyon and Marseilles) Mean IQ: details not provided Mean age: 7.8 ± 4.1 (0.5 mg), 7.9 ± 4.6 (1.0 mg), 8.4 ± 4.6 (2.0 mg) and 8.8 ± 4.5 (placebo) Gender: 78 male, 10 female Sample size: 88 Reasons for dropouts: 0.5 mg ‐ no LTFU reported, 1.0 mg ‐ 3 AEs and 1 LTFU, 2.0 mg ‐ 6 AEs, 3 LTFU; placebo ‐ 1 AE, 2 LTFU Baseline ABC‐I or other BoC scale: not an outcome Timing of outcome assessments: end of month 4 Concomitant medications: psychotropic medications (including antipsychotic, psychostimulant, antidepressant, anxiolytics, mood stabilisers and neuroleptic agents) had to be discontinued at least 4 weeks before entering the trial Previous medications: not reported
Interventions	Intervention (bumetanide) 0.5 mg, 1 mg or 2 mg twice daily for 90 days Comparator: equivalent placebo for 90 days
Outcomes	Primary outcomes: AEs Secondary outcomes: tolerability
Notes	Study start date: January 2014 Study end date: March 2015 Funding: "The study was sponsored by Neurochlore, a biotech company dedicated to the development of novel therapies to autism and other developmental disorders'. 'Funding of the trial comes from an investment of Symmetry Capital, a grant from France's Agence Nationale de la Recherche (ANR‐12‐ RPIB‐0001‐01) and French Government loans". Conflicts of interest: "Three of the authors are founders and shareholders of the company funding the study. The remaining authors declare no conflicts of interest" Trial registry: NCT01078714
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated age‐stratified randomisation schedule prepared by Amatsi group used
Allocation concealment (selection bias)	Unclear risk	No information beyond "randomised"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blinded ‐ no further details provided
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Each patient was seen and assessed by two clinicians who were unaware of the treatment assignment. Quote "Finally, the diuretic actions of bumetanide also impact the blinding procedure. To reduce this impact, the psychiatrist was separated from the pediatrician who treated the children and was thus blinded to the treatment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	LTFU participants included in final analyses
Selective reporting (reporting bias)	Unclear risk	Protocol not published
Other bias	High risk	Quote: "The study was sponsored by Neurochlore, a biotech company dedicated to the development of novel therapies to autism and other developmental disorders. EL, DR and YB‐A are founders and shareholders of the company"