TY - JOUR
T1 - Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI)
T2 - A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial
AU - Sprengers, Jan J
AU - van Andel, Dorinde M
AU - Zuithoff, Nicolaas Pa
AU - Keijzer-Veen, Mandy G
AU - Schulp, Annelien Ja
AU - Scheepers, Floortje E
AU - Lilien, Marc R
AU - Oranje, Bob
AU - Bruining, Hilgo
N1 - Funding Information:
The study was funded by the Netherlands Organisation for Health Research and Development (ZonMw; GGG - #836041015). Neither the funder of the study, nor Neurochlore, who provided the study medication, had a role in study design, data collection, data analysis, data interpretation, or writing of the report. Data on (S)AEs were shared with Neurochlore for the Development Safety Update Report of the oral bumetanide solution. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Funding acquisition: Oranje, Bruining Disclosure: Prof. Dr. Scheepers has received grant support by ZonMW and NOW. Dr. Bruining has reported being a shareholder of Aspect Neuroprofiles BV, which provides EEG-analysis services for clinical trials. He has received grant support by ZonMW rational treatment program (GGG) and TOP program, the Dutch Research Council (NWO) NWA-ORC program, and the Dutch Brain society GGG program. Drs. Sprengers, Zuithoff, Keijzer-Veen, Lilien, Oranje, Mr. van Andel and Ms. Schulp have reported no biomedical financial interests or potential conflicts of interest.
Funding Information:
The study was funded by the Netherlands Organisation for Health Research and Development (ZonMw; GGG - #836041015). Neither the funder of the study, nor Neurochlore, who provided the study medication, had a role in study design, data collection, data analysis, data interpretation, or writing of the report. Data on (S)AEs were shared with Neurochlore for the Development Safety Update Report of the oral bumetanide solution. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2020 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - 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 Scale−2 (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 −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. 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/; 2014-001560-35.
AB - 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 Scale−2 (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 −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. 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/; 2014-001560-35.
KW - ASD
KW - bumetanide
KW - children
KW - RCT
KW - SRS
UR - http://www.scopus.com/inward/record.url?scp=85092757587&partnerID=8YFLogxK
U2 - 10.1016/j.jaac.2020.07.888
DO - 10.1016/j.jaac.2020.07.888
M3 - Article
C2 - 32730977
SN - 0890-8567
VL - 60
SP - 865
EP - 876
JO - Journal of the American Academy of Child and Adolescent Psychiatry
JF - Journal of the American Academy of Child and Adolescent Psychiatry
IS - 7
ER -