For a study, it was determined that there were no pharmaceutical treatments available to help people with Down syndrome who had intellectual disabilities. It was suggested that an excitatory/inhibitory imbalance contributed to Down syndrome’s cognitive deficiencies. Negative regulation of the GABAA-α5receptor had been postulated to restore the excitatory/inhibitory balance by attenuating GABAergic action. In a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis), basmisanil, a selective GABAA-α5 negative allosteric modulator, was assessed for efficacy and safety in adolescents and young adults with Down syndrome at 120 or 240 mg BID (80 or 160 mg for 12–13 years). The primary outcome was based on a composite examination of working memory, independent functioning, and adaptive behavior (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). The Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL) were used as secondary measures. In adolescents, EEG was used to check the safety and was quantitatively examined. Basmisanil was shown to be safe and well-tolerated, with similar rates and types of adverse events in the basmisanil and placebo groups. EEG demonstrated treatment-related spectral power changes (increase in low ~4-Hz frequencies and decrease in high ~20-Hz frequencies), indicating functional target engagement. On the primary composite endpoint, which assessed concurrent responses in cognition and independent functioning, the same proportion of participants in all treatment arms showed above-threshold improvement (29% in placebo, 20% in low dose, and 25% in high dose). In both adolescents and adults, further analysis of the various variables contributing to the primary endpoint found no differences between the placebo and basmisanil-treated groups. There were no differences in the secondary endpoints, which measured changes in executive function, language, and quality of life. Despite evidence of target engagement, Basmisanil failed to reach the primary efficacy– the goal of concurrent improvement in cognition and adaptive functioning after 6 months of treatment. The research gave important information for future Down syndrome clinical research.