布美他尼治疗孤独症谱系障碍核心症状（BAMBI）：一项单中心、双盲、随机、安慰剂对照、2 期优效性试验。
Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial.
机构信息
UMC Utrecht Brain Centre, University Medical Centre Utrecht, the Netherlands.
Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, the Netherlands.
出版信息
J Am Acad Child Adolesc Psychiatry. 2021 Jul;60(7):865-876. doi: 10.1016/j.jaac.2020.07.888. Epub 2020 Jul 27.
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.
目的
最近的试验表明布美他尼对自闭症谱系障碍（ASD）有积极影响。我们在荷兰的一家三级医院进行了一项单中心、平行组、参与者随机、双盲、安慰剂对照的 2 期优效性试验，以测试布美他尼在核心症状领域的疗效。
方法
未接受药物治疗的年龄在 7 至 15 岁、ASD 和智商≥55 的儿童，按 1:1 比例随机分为口服布美他尼组或安慰剂组，滴定至每日 2 次、每次 1.0mg 的最大剂量，共 91 天（D91），随后进行 28 天的洗脱期。主要结局为 D91 时社交反应量表-2（SRS-2）总分的差异，采用改良意向治疗的线性混合模型进行分析。
结果
共有 92 名参与者（平均年龄 10.5[SD 2.4]岁）于 2016 年 6 月至 2018 年 12 月入组。共有 47 名儿童分配至布美他尼组，45 名儿童分配至安慰剂组。每个治疗组各有 2 名参与者退出。91 天后，布美他尼在主要结局（SRS-2）上并不优于安慰剂，差异为-3.16（95%CI=-9.68 至 3.37，p=.338）。在一个次要结局（重复行为量表修订版[RRBS]）上发现了更好的效果，差异为-4.16（95%CI=-8.06 至-0.25，p=.0375），但在感官评估量表（Sensory Profile）或异常行为检查表易激惹分量表（Aberrant Behavior Checklist Irritability Subscale）上没有发现差异，差异分别为 5.64（95%CI=-11.30 至 22.57，p=.508）和-0.65（95%CI=-2.83 至 1.52，p=.552）。未观察到明显的洗脱效应。显著的不良反应主要是利尿剂效应（直立性低血压（17 [36%]与 5 [11%]，p=.007）；低血钾症（24 [51%]与 0 [0%]，p<.0001），但其发生并未对治疗结果产生统计学影响。
结论
就主要结局而言，该试验结果为阴性，即布美他尼对主要结局没有更好的效果。次要结局表明，对于一部分患者，布美他尼对重复行为症状有疗效。
临床试验注册信息
布美他尼在自闭症药物和生物标志物研究（BAMBI）；https://www.clinicaltrialsregister.eu/；2014-001560-35。
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