Clinical improvements among participants receiving a placebo — known as the placebo effect — are common in clinical trials of fragile X syndrome, a study conducted by scientists across the U.S. suggests.
The findings indicate that better trial designs, including different efficacy measurements, may be necessary in future clinical studies.
Titled “Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis,” the study was published in the journal Brain Sciences.
Research efforts in recent years have identified many potential treatments for fragile X that showed promise in animal models of the disorder. However, to date, no definitive large-scale clinical trial using a placebo group has met its primary efficacy goals.
“All these large-scale and well-powered trials failed, suggesting issues with the predictive value of animal models, adequacy of trial design, age of treated [groups], and, to some extent, outcome measure selection,” the scientists wrote.
One of the factors that could have affected these trials is the well-documented placebo effect, which refers to a reported improvement in the absence of an active treatment.
In placebo-controlled trials, some participants are given the potential medication, while others are given a placebo. However, neither the researchers nor the patients know which participants received which one. In theory, this can allow researchers to rule out the placebo effect by comparing outcomes among the two groups. But having a strong placebo effect can obscure any real effect of the therapy being investigated.
The placebo effect is of particular interest in fragile X, because clinical trials tend to rely on fairly subjective measures, such as symptom severity, which are reported by caregivers or clinicians. In such instances, “the reporter must believe there are actual improvements in behavioral symptoms or cognition of the participant,” the researchers wrote.
“This is important, as positive changes subjectively reported by caregivers could be due to caregiver expectations of treatment efficacy,” they added.
In the new study, the investigators examined data from participants given a placebo in eight clinical trials in fragile X, conducted between 2002 and 2015. Specifically, the team evaluated whether patients taking a placebo showed significant improvements relative to the start of the study, whether age influenced their response, and if clinician- and caregiver-rated measures were equally affected.
In other words, the goal of the analysis was not to compare the results from the placebo groups to any active medication, but rather to determine the effect of the placebo itself.
Among clinician-rated measures, only the Clinician Global Impression scale-Improvement was used in more than one trial. Although a substantial placebo effect was found in multiple studies, the available data did not enable the researchers to draw conclusions.
Meanwhile, caregiver-rated assessments included the Aberrant Behavior Checklist-Community (ABC-C) and its fragile X-specific variant (ABC-CFX), the Vineland Adaptive Behavior Scales-II Composite — Vineland-II Comp — and visual analogue scales (VAS).
Results showed significant improvements in the Vineland-II Comp scores in six studies, two conducted in children younger than age 12, and four in adolescents/adults. VAS scores significantly improved in two studies, both done in children.
ABC-C and ABC-CFX scores were analyzed based on subscales, with improvements being more common among adolescents/adults than in children.
“Our findings are consistent with the suggestion that placebo responses have a greater impact on trials of older individuals with FXS [fragile X syndrome],” the investigators wrote.
Further analyses suggested that these improvements were not just statistically significant, but also clinically meaningful — that is, the differences were large enough that they would be noticeable by the trials’ participants.
This was especially the case for VAS, while the change in other scales, such as the Vineland-II Comp, was relatively small. However, the researchers said scores on the Vineland-II Comp would normally be expected to get worse over time in the absence of treatment, so even a relatively small improvement is noteworthy.
“These data emphasize the potential large magnitude of responses to placebo administration in individuals with FXS and the importance of identifying and minimizing them,” the scientists wrote.
In particular, the results raise concerns about the use of caregiver-rated tools in future studies, the scientists said.
“Our results have other implications, including the need for improvement of currently available endpoints [goals], decreased dependence on caregiver-rated instruments, enhanced rater training to mitigate placebo response, enrollment of younger participants and utilization of study designs directly addressing the placebo effect,” they concluded.
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