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The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit–containing extrasynaptic γ-aminobutyric aci...

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Autores principales: Bird, Lynne M., Ochoa-Lubinoff, Cesar, Tan, Wen-Hann, Heimer, Gali, Melmed, Raun D., Rakhit, Amit, Visootsak, Jeannie, During, Matthew J., Holcroft, Christina, Burdine, Rebecca D., Kolevzon, Alexander, Thibert, Ronald L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055330/
https://www.ncbi.nlm.nih.gov/pubmed/33443117
http://dx.doi.org/10.1212/WNL.0000000000011409
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author Bird, Lynne M.
Ochoa-Lubinoff, Cesar
Tan, Wen-Hann
Heimer, Gali
Melmed, Raun D.
Rakhit, Amit
Visootsak, Jeannie
During, Matthew J.
Holcroft, Christina
Burdine, Rebecca D.
Kolevzon, Alexander
Thibert, Ronald L.
author_facet Bird, Lynne M.
Ochoa-Lubinoff, Cesar
Tan, Wen-Hann
Heimer, Gali
Melmed, Raun D.
Rakhit, Amit
Visootsak, Jeannie
During, Matthew J.
Holcroft, Christina
Burdine, Rebecca D.
Kolevzon, Alexander
Thibert, Ronald L.
author_sort Bird, Lynne M.
collection PubMed
description OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit–containing extrasynaptic γ-aminobutyric acid type A (GABA(A)) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression–Severity and Clinical Global Impression–Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13–45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALS.GOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.
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spelling pubmed-80553302021-04-20 The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome Bird, Lynne M. Ochoa-Lubinoff, Cesar Tan, Wen-Hann Heimer, Gali Melmed, Raun D. Rakhit, Amit Visootsak, Jeannie During, Matthew J. Holcroft, Christina Burdine, Rebecca D. Kolevzon, Alexander Thibert, Ronald L. Neurology Article OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit–containing extrasynaptic γ-aminobutyric acid type A (GABA(A)) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression–Severity and Clinical Global Impression–Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13–45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALS.GOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated. Lippincott Williams & Wilkins 2021-02-16 /pmc/articles/PMC8055330/ /pubmed/33443117 http://dx.doi.org/10.1212/WNL.0000000000011409 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Article
Bird, Lynne M.
Ochoa-Lubinoff, Cesar
Tan, Wen-Hann
Heimer, Gali
Melmed, Raun D.
Rakhit, Amit
Visootsak, Jeannie
During, Matthew J.
Holcroft, Christina
Burdine, Rebecca D.
Kolevzon, Alexander
Thibert, Ronald L.
The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title_full The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title_fullStr The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title_full_unstemmed The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title_short The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome
title_sort stars phase 2 study: a randomized controlled trial of gaboxadol in angelman syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055330/
https://www.ncbi.nlm.nih.gov/pubmed/33443117
http://dx.doi.org/10.1212/WNL.0000000000011409
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