Development of an adapted Clinical Global Impression scale for use in Angelman syndrome

Alexander Kolevzon,Christopher J Keary,Gali Heimer,Jeffrey L Neul,Mathews Adera,Judith Jaeger,Pamela Ventola

doi:10.1186/s11689-020-09349-8

Abstract

BackgroundThe Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician’s impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder. Angelman syndrome (AS) is a rare, clinically heterogeneous condition for which there is no disease-specific rating scale. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials.MethodsIn order to develop adapted CGI scales specific to AS, we (1) reviewed literature and interviewed caregivers and clinicians to determine the most impactful symptoms, (2) engaged expert panels to define and operationalize the symptom domains identified, (3) developed detailed rating anchors for each domain and for global severity and improvement ratings, (4) reviewed the anchors with expert clinicians and established minimally clinically meaningful change for each symptom domain, and (5) generated mock patient vignettes to test the reliability of the resulting scales and to standardize rater training. This systematic approach to developing, validating, and training raters on a standardized, adapted CGI scale specifically for AS is described herein.ResultsThe resulting CGI-S/I-AS scales capture six critical domains (behavior, gross and fine motor function, expressive and receptive communication, and sleep) defined by caregivers and expert clinicians as the most challenging for patients with AS and their families.ConclusionsRigorous training and careful calibration for clinicians will allow the CGI-S/-I-AS scales to be reliable in the context of randomized controlled trials. The CGI-S/-I-AS scales are being utilized in a Phase 3 trial of gaboxadol for the treatment of AS.

Highlights

Rating scales Neurodevelopmental disorders are associated with a wide range of symptoms that have varying degrees of severity and relative impact on the individual
We developed the Clinical Global Impression-Severity (CGI-S)-Angelman syndrome (AS) and CGI-I-AS using AS-specific domains and clearly defined anchors within each domain based on expert clinical judgment for use in clinical trials
The narrative capture form that was developed as part of the CGI-I-AS to record in detail the specific changes that have occurred in each domain will allow this information to be available for later examination

Summary

Introduction

Rating scales Neurodevelopmental disorders are associated with a wide range of symptoms that have varying degrees of severity and relative impact on the individual. Because of this heterogeneity, quantifying severity of symptoms and their change over time is uniquely challenging in these populations. In the field of psychiatry, disease-specific ratings scales have been developed to quantify symptom domain or disease-specific treatment effects. These scales are composed of individual symptom ratings (items) selected to assess the range of symptoms and signs associated with a specific diagnosis or treatment response. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials

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