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

Meredith A Nelson; Lauren M Schmitt; Paul S Horn; Elizabeth Berry-Kravis; David Hessl; Rebecca C Shaffer; Randall Carpenter; Dejan B Budimirovic; Paul Wang; Debra L Reisinger; Karen Walton-Bowen; Craig A Erickson

doi:10.1007/s10803-024-06634-6

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

J Autism Dev Disord. 2024 Nov 23. doi: 10.1007/s10803-024-06634-6. Online ahead of print.

Authors

Meredith A Nelson^{1

2}, Lauren M Schmitt^{3

4}, Paul S Horn^{3

4}, Elizabeth Berry-Kravis⁵, David Hessl⁶, Rebecca C Shaffer^{3

4}, Randall Carpenter⁷, Dejan B Budimirovic⁸, Paul Wang⁹, Debra L Reisinger^{3

4}, Karen Walton-Bowen⁹, Craig A Erickson^{3

10}

Affiliations

¹ Cincinnati Children's Hospital Medical Center, Cincinnati, USA. Meredith.Nelson@cchmc.org.
² Department of Pediatrics , University of Cincinnati College of Medicine, Cincinnati, USA. Meredith.Nelson@cchmc.org.
³ Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
⁴ Department of Pediatrics , University of Cincinnati College of Medicine, Cincinnati, USA.
⁵ Department of Pediatrics, Rush University Medical Center, Chicago, USA.
⁶ MIND Institute, University of California Davis, Davis, USA.
⁷ Allos Pharma, Cambridge, USA.
⁸ Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, USA.
⁹ Clinical Research Associates, LLC, New York, USA.
¹⁰ Department of Psychiatry , University of Cincinnati, Cincinnati, USA.

PMID: 39579284
DOI: 10.1007/s10803-024-06634-6

Abstract

Estimating meaningful change thresholds (MCT) on clinical outcome assessments is an important consideration when evaluating treatments. In fragile X syndrome (FXS) research, there has been no consensus on how to define MCT's on several commonly used outcome measures. The purpose of the current study was to determine clinically relevant MCT's of caregiver-rated assessments using data from a phase 3 clinical trials of arbaclofen (Berry-Kravis et al., 2017). Data were collected as a part of previous phase 3, double-blind, placebo-controlled studies of arbaclofen in individuals with FXS (Berry-Kravis et al., 2017). The two studies enrolled age groups of 5-11-years (n = 159) and 12-50-years (n = 119). The current study examines meaningful within-patient change thresholds from baseline to treatment week 8 across several measures: ABC-C_FXS; PSI; Vineland-II; and a Visual Analog Scale (VAS) of Anxiety and Disruptive Behaviors. MCT's were established by using anchor-based methods, using the CGI-S and CGI-I as anchors. Examining the results of the anchor-based analyses and visual CDF plots, MCT's were observed for the pediatric study for the ABC-C_FXS subscales (with a range depending on use of CGI-S or CGI-I as anchor): Irritability: 11.1-14.8 points; Hyperactivity: 6.7-8.9 points; and Socially Unresponsive/Lethargic: 6.6-8.1 points; as well both VAS subscales: Anxiety: 28.3-36.2 mm; and Disruptive Behavior: 22.4-27.4 mm. Such thresholds were not observed for the Vineland-II and PSI subscales. Our analysis of MCT's helps set the stage for interpreting clinical trial results in FXS. This may include use of relevant subscales of the ABC-C_FXS and VAS as primary outcomes using the MCT's for response definition. This work may help define future study inclusion criteria and enable future interpretation of treatment outcome results in the field.

Keywords: Fragile X syndrome; Meaningful change thresholds; Outcome assessments.