<h3>Objective:</h3> To describe the study design of the pivotal Phase 3 NEPTUNE trial of gaboxadol (OV101) in Angelman syndrome (AS). <h3>Background:</h3> AS is a rare, genetic, neurodevelopmental condition caused by disruption of the maternally inherited ubiquitin protein ligase E3A (<i>UBE3A</i>) gene and associated with increased uptake of GABA and reduced tonic inhibition. The clinical presentation of AS is heterogenous, and individuals may have motor, sleep, communication, and cognitive impairments, along with severe behavioral disturbances. Current therapies address symptoms but do not target the underlying mechanism affecting neuronal function. Gaboxadol is a highly selective orthosteric agonist that activates the δ-containing subunit of extrasynaptic GABA<sub>A</sub> receptors, potentially normalizing tonic inhibition. In the Phase 2 STARS trial, gaboxadol was demonstrated to be generally safe and well-tolerated with a significant effect on the Clinical Global Impressions-Improvement (CGI-I) efficacy outcome measure. <h3>Design/Methods:</h3> The pivotal Phase 3 NEPTUNE trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of gaboxadol in pediatric participants with AS (age, 4–14 years), after 12 weeks of treatment. The primary outcome measure will be the CGI-I-Angelman syndrome (CGI-I-AS), which is a clinical rating scale that detects the patient’s change in AS symptoms (improvement/worsening) after the initiation of treatment. Secondary measures will evaluate motor function, behavior, communication, and sleep, and include CGI-Severity-AS, Vineland Adaptive Behavior Scales 3rd Edition, actigraphy, and sleep diary. Furthermore, safety alone will be assessed in subjects 2–3 years old. <h3>Results:</h3> The trial is ongoing and anticipated to be completed in 2H 2020. <h3>Conclusions:</h3> The study design will evaluate the efficacy and safety of gaboxadol in the treatment of AS using the sole primary outcome measure CGI-I-AS. The adaptation and use of the CGI-I in the NEPTUNE trial may support the applicability of the CGI-I in the development of treatments for other neurodevelopment conditions. <b>Disclosure:</b> Dr. Keary has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics Inc. Dr. Keary has received research support from Ovid Therapeutics Inc.Dr. Burdine has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with National Center for Faculty Development and Diversity, and Ovid Therapeutics. Dr. Burdine has received compensation for serving on the Board of Directors of Perlara Inc. Dr. Saulnier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pearson Clinical. Dr. Chen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics Inc. Dr. Chen holds stock and/or stock options in Ovid Therapeutics. Dr. Pudussery has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics Inc.. Dr. Pudussery holds stock and/or stock options in Ovid Therapeutics. Dr. Rakhit has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics Inc.. Dr. Rakhit holds stock and/or stock options in Ovid Therapeutics. Dr. Kolevzon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics, Coronis Neurosciences, 5AM Ventures, SEMA4, Labcorp. Dr. Kolevzon has received research support from Amo Pharma.