Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis

Abstract

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and autism spectrum disorder. Individuals with FXS often present with a wide range of cognitive deficits and problem behaviors. Educational, behavioral and pharmacological interventions are used to manage these and other complex issues affecting individuals with FXS. Despite the success of preclinical models and early-phase drug clinical studies in FXS, large-scale randomized-controlled trials have failed to meet primary endpoints. Currently, no targeted or disease-modifying treatments for FXS have received regulatory approval. Here, we examined the placebo response in FXS clinical trials conducted between 2006 and 2018. Specifically, we performed a meta-analysis of placebo-treated groups in eight double-blind, randomized controlled trials. Placebo groups demonstrated significant improvements on caregiver-rated efficacy endpoints, which were greater in adolescents and adults than in children. Among the latter measures, the Visual Analog Scale scores displayed the greatest improvements, whereas the positive effects on the Vineland-II Adaptive Behavior Composite and the Aberrant Behavior Checklist-Community/fragile X version were statistically significant in both children and adolescents/adults. Although the Clinical Global Impression scale Improvement appears to have exhibited a substantial placebo effect in multiple clinical trials in FXS, limited data availability for meta-analysis, prevented us from drawing conclusions. No placebo-related improvements were observed in performance-rated measures. These findings raise substantial concerns about placebo effects in outcome measures commonly used in the randomized-controlled trials in FXS and suggest several potential improvements in the study design and implementation of such trials. Considering the small number of trials available for this study, larger and more detailed follow up meta-analyses are needed. Meanwhile, efforts to improve the measurement properties of endpoints and rater training in drug trials in FXS should be prioritized.

Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study

“…There were several limitations in the design of this study, the first being the lack of a placebo-control arm. FXS studies have been shown to have large placebo effect for behavioral measures (Berry-Kravis et al, 2018;Luu et al, 2020), with some reporting a placebo effect size similar to the OV101 effect size observed in the present study (Berry-Kravis et al, 2016;Youssef et al, 2018). Another limitation was the small sample size (n 23), which may have been insufficient to assess behavioral efficacy, as prior studies that enrolled more than 100 participants have yielded ambiguous results (Berry-Kravis et al, 2016;Berry-Kravis et al, 2018;Youssef et al, 2018;Berry-Kravis et al, 2020).…”

“…The identification and evaluation of valid, sensitive-to-treatment biomarkers is increasingly necessary to reliably track treatment changes in the unfolding wave of clinical studies in FXS (Budimirovic et al, 2017;Erickson et al, 2018;Lee et al, 2018) and to substantially mitigate the large placebo effect in FXS studies. Indeed, an effort to differentiate objective from subjective improvements in individuals with FXS is recommended by experts in the field of FXS (Luu et al, 2020). For example, electroencephalography is a potential neural biomarker sensitive to treatment (Erickson et al, 2018;Ethridge et al, 2019), and molecular studies have shown a link between FMR1 expansion, gene methylation, and FMRP deficit and the overall severity of the neurobehavioral phenotype (Berry-Kravis et al, 2018;Budimirovic et al, 2020).…”

Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments

“…Although additional studies with a larger cohort on higher doses would be required to confirm this finding, these results suggested potential dose- and age-related effects as well as a possible optimization of primary study endpoints, pointing toward a potential benefit of arbaclofen in future optimized clinical trials. Double-blind, randomized, placebo-controlled studies in FXS are also highly recommended to properly assess the sensitivity and specificity of clinical endpoints ( 63 , 72 , 73 ).…”

EEG as a translational biomarker and outcome measure in fragile X syndrome

“…Most measures employed in clinical trials have been deemed moderately effective as outcome tools and there exists limited data on their sensitivity to detect pharmaceutically driven changes [ 26 ]. The majority of outcome measures involve parent/caregiver reports, which are inherently susceptible to scoring variability and placebo effects [ 127 ]. The most widely used primary outcome measure for clinical trials in FXS has been the Aberrant Behaviour Checklist- Community (ABC-C), a parent or caregiver report which assesses maladaptive behaviours as perceived in the weeks prior to rating.…”