Failed study of bumetanide in Autism: limitations of the Dutch trial and what does it means for bumetanide treatment

Bruining and colleagues reported, in a 3-month mono-centric trial in 92 verbal ASD children (7-15 years old) without severe mental disability, that bumetanide did not significantly attenuate the severity of autism. This trial is at odds with 5 earlier trials from 3 independent groups who reported significant ameliorations. Astonishingly, the same group reported earlier that bumetanide significantly attenuates autism traits in children with Tuberous Sclerosis. Based on this failed study, the authors yet propose that bumetanide might be efficient in only a subpopulation of ASD persons.

Failed studies are not infrequent in clinical development, especially when dealing with heterogeneous CNS pathologies such as ASD. Many reasons could explain a failure for the BAMBI study including, for example, the restricted – and perhaps inappropriate – population selection to children with low severity of autism, operative language and IQ > 50, the intensity of the performed clinical examinations which may have increased the placebo response, or the monocentric nature of the study, with a substantially higher risk of evaluation bias compared to a multi-centre study. All these reasons may have accounted to the observed high placebo-response in the BAMBI study, that prevented the identification of potential drug-placebo differences in efficacy. In addition, excluding from the trial younger children 2-7 years old is a strong limitation considering the higher efficacy of early treatments.

The conclusion drawn by Bruining and colleagues from this single failed – and not negative – study is that bumetanide is unlikely to be successful in trials using a large panel of children and adolescents with autism. Bruining also challenges the use of a single drug to treat all children with autism. Indeed, one does not expect as in all CNS areas to successfully treat with a single agent all children with autism. However, positive effects were reported in earlier trials who included children with both light and severe autism manifestations. Therefore, even if restricting a trial to a small highly selective population-using for instance EEG or other biomarkers- might in the future be more readily positive than large studies who included a more representative population, we are not convinced that leaving aside children who do not fit in this highly selective process is an option.

In summary, restricting treatments to a highly selective, non-representative population of children with ASD is not the best approach to take into account the heterogeneity of ASD. We hope that the two phase-3 trials presently conducted by the French Pharma Servier and Neurochlore (400 children in 40 centres in many countries, covering the entire paediatric population) will provide more clarity leading the regulatory approval of a much awaited treatment for ASD persons. These larger trials may also enable to better understand the features that are best impacted by bumetanide oral solution and the mechanisms underlying the heterogeneity of the syndrome. It will hopefully validate our inaugurating experimental studies and pilot trials on bumetanide in autism initiated almost 10 years ( E. Lemonnier & Y. Ben-Ari). At any rate, the Dutch trial like other experimental studies validate the promises of bumetanide.

Y. Ben-Ari, CEO Neurochlore,
Neuroscientist, Recipient of the grand prix of the French Medical Research Institute and that of the European and Us foundations for epilepsies.

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