Abstract
Large placebo responses in many clinical trials limit our capacity to identify effective therapeutics. Although it is often assumed that core behaviors in children with autism spectrum disorders (ASDs) rarely remit spontaneously, there has been limited investigation of the size of the placebo response in relevant clinical trials. These trials also rely on caregiver and clinical observer reports as outcome measures. The objectives of this meta-analysis are to identify the pooled placebo response and the predictors of placebo response in pharmacological and dietary supplement treatment trials for participants with a diagnosis of ASD. Randomized controlled trials (RCTs) in pediatric ASD, conducted between 1980 and August 2014, were identified through a search of Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews and clinicaltrials.gov. RCTs of at least 14 days duration, comparing the treatment response for an oral active agent and placebo using at least one of the common outcome measures, were included. Analysis of 25 data sets (1315 participants) revealed a moderate effect size for overall placebo response (Hedges' g=0.45, 95% confidence interval (0.34–0.56), P<0.001). Five factors were associated with an increase in response to placebo, namely: an increased response to the active intervention; outcome ratings by clinicians (as compared with caregivers); trials of pharmacological and adjunctive interventions; and trials located in Iran. There is a clear need for the identification of objective measures of change in clinical trials for ASD, such as evaluation of biological activity or markers, and for consideration of how best to deal with placebo response effects in trial design and analyses.
Highlights
Autism spectrum disorder (ASD) is characterized by core deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior, interests or activities
It is often assumed that core behaviors are unlikely to remit spontaneously in children with severe ASD, randomized controlled trials (RCTs) have found that up to 30% of child ASD participants respond to placebo treatments.[11]
This study has shown that the level of response to placebo varied depending on the geographical location of the Randomized controlled trials (RCTs), with response being greater for trials conducted in Iran compared with the United States
Summary
Autism spectrum disorder (ASD) is characterized by core deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior, interests or activities. Prevalence is estimated to be as high as 1 in 68.1 There are currently no medication treatments approved for the core symptoms of ASD. The US Food and Drug Administration has approved two atypical antipsychotics for children with ASD, risperidone and aripiprazole, for irritability symptoms, including tantrums, aggression and self-injury behaviors. Established pharmacological and dietary supplement interventions have been trialed as treatments for behavioral symptoms, such as repetitive behavior, aggression, hyperactivity and irritability,[2,3,4,5] and for social impairment.[6] little evidence exists to support the efficacy for most of these treatments.[7,8] Notwithstanding the lack of established evidence for medications, it has been estimated that at least 25% of children with ASD take at least one medication.[9]
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