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

Skylar Luu,Craig Erickson,Dhananjay Vaidya,Elizabeth Berry-Kravis,Haley Province,Reymundo Lozano,Walter E Kaufmann,David Hessl,Randi Hagerman,Dejan B Budimirovic,Hilary Rosselot

doi:10.3390/brainsci10090629

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.

Highlights

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID)and single-gene disorder associated with autism spectrum disorder (ASD) [1,2,3,4]
Rather than evaluating the impact of the placebo effect on the overall outcome of these trials, we have focused on examining whether the placebo groups showed significant improvements in eight randomized controlled trials (RCTs) of individuals with FXS conducted between 2006 and 2018
The present study shows that patients with FXS receiving placebo demonstrate significant improvements on caregiver-rated efficacy endpoints, which were greater in adolescents and adults than in children

Summary

Introduction

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID)and single-gene disorder associated with autism spectrum disorder (ASD) [1,2,3,4]. FXS is caused by a CGG-repeat expansion in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene (full mutation-FM, >200 CGGs). The FM triggers epigenetic silencing (hyper-methylation) of the gene, which results in marked reduction of the FMR1 product (Fragile X Mental Retardation Protein, FMRP). FMRP is an RNA-binding protein that regulates the translation of ~4% of the brain’s mRNA, including many transcripts from genes implicated in ASD [5,6], and serves as a critical regulatory protein for developmental and ongoing synaptic plasticity. The FMRP expression in the brain is the ultimate factor determining the severity of the neurobehavioral phenotype. Data integration that enables clarification of the relationships between the FMR1 genotype and FMRP and the neurobehavioral phenotype, including ASD, continue to grow [7,8]

Methods

Discussion

Conclusion