Parent-Reported Outcome Measures for Individuals with Fragile X Syndrome: Clinically Meaningful Change Thresholds.

Area of Science:

• Clinical Neuroscience
• Psychometrics
• Genetics

Background:

• Meaningful Change Thresholds (MCT) are vital for evaluating treatment efficacy in clinical outcome assessments.
• No established consensus exists for MCTs in fragile X syndrome (FXS) outcome measures.
• Previous phase 3 clinical trials of arbaclofen in FXS provide a valuable dataset for this analysis.

Purpose of the Study:

• To determine clinically relevant MCTs for caregiver-rated assessments in individuals with FXS.
• To establish consensus on MCTs for commonly used outcome measures in FXS research.
• To inform the interpretation of clinical trial results and guide future study designs in FXS.

Main Methods:

• Utilized data from phase 3, double-blind, placebo-controlled studies of arbaclofen in FXS (ages 5-50).
• Employed anchor-based methods using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) as anchors.
• Analyzed changes from baseline to week 8 on the ABC-CFXS, PSI, Vineland-II, and Visual Analog Scale (VAS) for Anxiety and Disruptive Behaviors.

Main Results:

• Established MCTs for the ABC-CFXS subscales (Irritability, Hyperactivity, Socially Unresponsive/Lethargic) and VAS subscales (Anxiety, Disruptive Behavior) in the pediatric cohort.
• Observed ranges for MCTs: ABC-CFXS Irritability (11.1-14.8), Hyperactivity (6.7-8.9), Socially Unresponsive/Lethargic (6.6-8.1); VAS Anxiety (28.3-36.2 mm), Disruptive Behavior (22.4-27.4 mm).
• No significant MCTs were identified for the Vineland-II and PSI subscales.

Conclusions:

• The defined MCTs provide a framework for interpreting clinical trial outcomes in FXS.
• Suggests utilizing specific ABC-CFXS and VAS subscales with defined MCTs as primary outcomes for response definition.
• Aids in setting future study inclusion criteria and enhancing the interpretation of treatment results in FXS research.