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

• Type of Material: Article
• Authors: Skylar Luu, Albany Medical College; Haley Province, Northwestern University; Elizabeth Berry-Kravis, Rush University; Randi Hagerman, University of California Davis; David Hessl, University of California Davis; Dhananjay Vaidya, Johns Hopkins University; Reymundo Lozano, Icahn School of Medicine at Mount Sinai; Hilary Rosselot, National Fragile X Foundation; Craig Erickson, Cincinnati Children's Hospital Medical Center; Walter Kaufmann, Emory University; Dejan B. Budimirovic, Johns Hopkins University
• Language: English
• Date: 2020-09-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/brainsci10090629
• Title of Journal or Parent Work: BRAIN SCIENCES
• Volume: 10
• Issue: 9
• Start Page: 1
• End Page: 17
• Grant/Funding Information: D.V.: This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by Grant Number UL1 TR003098 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH.
• Keywords: Neurosciences; fragile X syndrome; meta-analysis; CHILDREN; Life Sciences & Biomedicine; Science & Technology; ADAPTIVE-BEHAVIOR; DISORDER; clinical trials placebo effect; DOUBLE-BLIND; Neurosciences & Neurology; AUTISM; ADOLESCENTS
• Research Categories: Biology, Neuroscience; Psychology, Cognitive; Psychology, Developmental

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.