Enabling Endpoint Development for Interventional Clinical Trials in Individuals With Angelman Syndrome: A Prospective, Longitudinal, Observational Clinical Study (FREESIAS)

Authors

Jorrit Tjeertes
Carlos A Bacino
Terry Jo Bichell
Lynne M Bird
Mariana Bustamante
Rebecca Crean
Shafali Jeste
Robert W Komorowski
Michelle L Krishnan
Meghan T Miller
David Nobbs
Cesar Ochoa-Lubinoff
Kimberly A Parkerson
Alexander Rotenberg
Anjali Sadhwani
Mark D Shen
Lisa Squassante
Wen-Hann Tan
Brenda Vincenzi
Anne C Wheeler
Joerg F Hipp
Elizabeth Berry-Kravis

Publication Date

7-26-2023

Journal

Journal of Neurodevelopmental Disorders

DOI

10.1186/s11689-023-09494-w

PMID

37495977

PMCID

PMC10373389

PubMedCentral® Posted Date

7-26-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Angelman Syndrome, Prospective Studies, Pandemics, COVID-19, Electroencephalography, Angelman syndrome, Endpoint development, EEG, Sleep, Digital health technology, Clinical outcome assessments, Natural history, Clinical trials, UBE3A

Abstract

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms.

METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits.

RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports.

CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.