Characterization of Potential Outcome Measures for Future Clinical Trials in Fragile X Syndrome

Abstract

Clinical trials targeting recently elucidated synaptic defects in fragile X syndrome (FXS) will require outcome measures capable of assessing short-term changes in cognitive functioning. Potentially useful measures for FXS were evaluated here in a test-retest setting in males and females with FXS (N = 46). Good reproducibility, determined by an interclass correlation (ICC) or weighted kappa (kappa) of 0.7-0.9 was seen for RBANS List and Story Memory, NEPSY Tower, Woodcock-Johnson Spatial Relations and the commissions score from the Carolina Fragile X Project Continuous Performance Test (CPT). This study demonstrates the feasibility of generating test profiles containing reliability data, ability levels required for test performance, and refusal rates to assist with choice of outcome measures in FXS and other cohorts with cognitive disability.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Only a subset of outcome measures utilized in recent trials have turned out to fulfill the majority of these criteria (Berry-Kravis et al, 2006) suggesting better, FXS-specific measures are needed. Only recently have investigators begun to develop templates to test the feasibility, reproducibility, and validity assessment before using the measure in a trial (Berry-Kravis et al, 2008b;Hessl et al, 2009;Knox and Berry-Kravis, 2009;Farzin et al, 2011). Choice of outcome measures must also balance use of accepted behavioral measures, which are generally caregiver rating scales (such as the ABC), with precedent for use in drug registration/FDA approval versus use of novel measures Knox and Berry-Kravis, 2009;Farzin et al, 2011) that are more quantitative and may objectively measure core phenotypes and electrophysiology (such as eye tracking or PPI).…”

Open-Label Treatment Trial of Lithium to Target the Underlying Defect in Fragile X Syndrome

“…The tests in this panel were chosen because it was thought that they could be accomplished by a high percentage of individuals with FXS, based on a concurrent study of outcome measures in FXS. 32 This panel included the Peabody Picture Vocabulary Test-Third edition (PPVT-III), 33 sure of cognitive flexibility and problem solving, a Computer-Based Card Task which evaluates visual memory, sequential memory, and working memory with pictures of cards, during which the subject must remember a progressively longer sequence of colors followed by combinations of colors and numbers, 32 Non-Verbal Associative Learning Task (NVALT), 32,36 a non-verbal measure of object discrimination learning and object discrimination reversal, and the Carolina Fragile X Project CPT (FXCPT), 32,37 a simplified computerized continuous performance test with separate measures of auditory and visual attention, inhibition, and impulsivity. The measures in the baseline exploratory cognitive battery are all fairly short and the entire battery took about one to two hours depending on the level of function and cooperation of the subject.…”

Medication Utilization for Targeted Symptoms in Children and Adults With Fragile X Syndrome

“…A recent study of AFQ056, a selective mGluR5 antagonist, found no overall main effect on behavioral symptoms of FXS, but an exploratory analysis indicated that individuals with full FMR1 promoter methylation and no detectable FMR1 messenger RNA showed significant improvement in scores on the Aberrant Behavior Checklist, whereas no consistent improvement was seen in individuals with partial promoter methylation. 21 Clinical trials of new medications inevitably will need to be able to detect short-term changes in cognitive functioning if these occur, 22 as well as changes in behavioral features and the range of possible co-occurring conditions. Data are needed on the extent to which outcome measures adequately describe the population of individuals with FXS and are sensitive to hypothesized changes in the nature or severity of primary and secondary conditions associated with FXS.…”