Alexander Kolevzon1, Pamela Ventola2,3, Christopher J Keary4,5, Gali Heimer6, Jeffrey L Neul7, Mathews Adera8, Judith Jaeger9,10. 1. Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 2. Yale University Child Study Center, New Haven, CT, USA. 3. Cogstate, New Haven, CT, USA. 4. Angelman Syndrome Program, Massachusetts General Hospital for Children, Boston, MA, USA. 5. Harvard Medical School, Boston, MA, USA. 6. Pediatric Neurology Unit, Safra Children Hospital, Sheba Medical Center, Tel Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 7. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, USA. 8. Ovid Therapeutics, Inc, New York, NY, USA. 9. CognitionMetrics, LLC, Wilmington, DE, USA. JJaeger@cognitionmetrics.com. 10. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA. JJaeger@cognitionmetrics.com.
Abstract
BACKGROUND: The 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Rigorous 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.
BACKGROUND: The 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Rigorous 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.
Authors: Joan Busner; Gahan Pandina; SilviaZaragoza Domingo; Anna-Karin Berger; Maria T Acosta; Nahome Fisseha; Joseph Horrigan; Jelena Ivkovic; William Jacobson; Dennis Revicki; Victoria Villalta-Gil Journal: Innov Clin Neurosci Date: 2021 Oct-Dec
Authors: Christopher A Ours; Mia B Hodges; Neal Oden; Julie C Sapp; Leslie G Biesecker Journal: Orphanet J Rare Dis Date: 2022-04-23 Impact factor: 4.303