Authors :
Presenting Author: Peter Jacoby, MSc – The Kids Research Institute Australia
Jenny Downs, MSc – The Kids Research Institute Australia
Eric Marsh, MD, PhD – Children's Hospital of Philadelphia
Jacinta Saldaris, PhD – The Kids Research Institute Australia
Helen Leonard, MBChB – The Kids Research Institute Australia
Bernhard Suter, MD – Baylor College of Medicine
Elia Pestana Knight, MD – Cleveland Clinic Epilepsy Center
Heather Olson, MD, MS – Boston Children's Hospital, Harvard Medical School
Dana Price, MD – NYU Langone Health
Judith Weisenberg, MD – Washington University of St. Louis
Rajsekar Rajaraman, MD, MS – UCLA Mattel Children's Hospital
Scott Demarest, MD – Children's Hospital Colorado
Tim Benke, MD – University of Colorado School of Medicine
Rationale:
CDKL5 deficiency disorder (CDD) is a developmental epileptic encephalopathy characterized by early onset seizures and significant global developmental delays. Upcoming trials of precision therapies for CDD require reliable, valid, and sensitive clinical outcome assessments (COAs) to demonstrate impacts across the affected domains in CDD. Our team has undertaken a comprehensive program of research investigating the psychometric properties of multiple COAs for CDD. We have shown how our suite of measures of functional ability and comorbidities can be combined to reflect global severity in CDD. A structural equation model (SEM) (Figure 1) was constructed with measured domains within the COAs reflecting a latent global severity variable. The current study investigated the stability of a global severity score as a clinical trial outcome and potential to generate a Minimal Clinically Important Difference (MCID) which would be used in trial design.
Methods:
We recruited families with a child with CDD enrolled in the International CDKL5 Clinical Research Network, comprising 8 Centers of Excellence (CoE). Data on multiple COAs for functional abilities and comorbidities were collected comprising (1) parent-reported severity of seizures, alertness, insomnia, excessive daytime sleepiness and communication, and (2) clinician-reported communication, motor skills and vision. Families were subsequently recruited to a longitudinal study with COA data collected at 6-monthly intervals in addition to a clinician reported Clinical Global Impression of Change (CGI-C) on a 7-point scale. Parameters from the earlier SEM enabled estimation of global severity, on a scale of 0 to 100, as a weighted average of COA scores. Stability of global severity between baseline and the 6-month assessment was examined and changes in severity score correlated with CGI-C scores.
Results:
Eighty-seven individuals from the CoE provided complete COA data for the baseline and 6-month assessment. Age at baseline ranged from 1.0 to 41.5 years (median age 7.5 years). The change in severity from 0 to 6 months was normally distributed around a mean of -1.3 (standard deviation 6.8). There was a moderate correlation between change in severity and CGI-C (r=0.38). The mean difference in change scores between CGI-C level 4 (“about the same”) and level 5 (“a little bit better”) was 4.5 (p< 0.05) (Figure 2). This value can be interpreted as a MCID for improvement in global severity.