Abstracts

Rationale: Pathogenic variants in the Cyclin-dependent kinase like 5 (CDKL5) gene cause CDKL5 deficiency disorder (CDD), a severe developmental and epileptic encephalopathy associated with cognitive and motor impairments and cortical visual impairment. While capability for disease-modifying therapies is accelerating, there is a critical barrier for clinical trial readiness that may result in failure of these therapies, not due to lack of efficacy but due to lack of validated clinical outcome measures (COMs) and biomarkers.

Methods: We established the International CDKL5 Clinical Research Network sites (ICCRN: University of Colorado/Children’s Hospital Colorado, Telethon Kids/Curtin University, Children’s Hospital of Philadelphia, Boston Children’s Hospital, Baylor College of Medicine, UCLA School of Medicine, Washington University-St Louis School of Medicine, NYU Langone Health) with a common IRB and data use agreement (cdkl5researchnetwork.com).  Our overall goals are to: (1) refine and validate appropriate quantitative COMS and biomarkers and (2) conduct a multi-site clinical trial readiness study to inform implementation methods. We will refine, psychometrically test and create training materials for multiple measures._x000D_ These include a general severity assessment, the CDKL5 Clinical Severity Assessment for Clinician (CCSA-Clinician) and the companion CDKL5 Clinical Severity Assessment for Parent/Caregiver (CCSA-P) and CDKL5 Deficiency Disorder - Development Assessment (CDD-DA). For functional abilities, we will validate the Communication and Symbolic Behavior Scale – Developmental Profile (CSBS-DP) and are adapting video measures of gross motor and fine motor skills that were developed for Rett syndrome. We are also validating a measure of quality of life (Quality of Life Inventory-Disability or QI-Disability) and sleep (Sleep Disturbance Scale for Children or SDSC). We will correlate these with EEG and Evoked Potentials (EEG/EP: EEG background, auditory evoked potentials, and visual evoked potentials). Our goal is to complete 100 unique data sets by SEP 2022 (first data cut) for data review with FDA in fall 2022.

Results: To date (May 2022), we have collected 81 complete, unique data sets. Of those, 28 have accompanying EEG/EP.  Content validation for the CCSA-Clinician, CCSA –Parent/Caregiver and CDD-DA is complete (see accompanying poster).  Training materials for all measures are being developed. The CSBS-DP saturates at low scores with plans for modifications. Favorable psychometrics have been determined for the QI-Disability (see accompanying poster). Validation and correlation of COMs and EEG/EP is on-going with plans for analysis after first data cut (~100 complete data sets with 50 EEG/EP); additional analysis on ~150-200 data sets is planned for early 2023. 

Conclusions: We have rapidly developed a functioning network for the development and validation of CDD-specific COMs. Using validated COMs and EEG/EP with appropriate psychometric properties, a multi-site clinical trial readiness study will follow. The approach, measures and biomarkers validated here may be adaptable to other developmental and epileptic encephalopathies.

Funding: NIH/NINDS U01NS114312 (Benke/PD)