A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome

J Neurodev Disord. 2022 Feb 5;14(1):10. doi: 10.1186/s11689-022-09418-0.


Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.

Methods: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included 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). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents.

Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life.

Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome.

Trial registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Keywords: Adaptive behavior; Cognition; Down syndrome; EEG; GABAA-α5.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Down Syndrome* / complications
  • Down Syndrome* / drug therapy
  • Humans
  • Intellectual Disability* / complications
  • Intellectual Disability* / drug therapy
  • Morpholines
  • Oxazoles
  • Pyridines
  • Quality of Life
  • Treatment Outcome
  • Young Adult
  • gamma-Aminobutyric Acid / therapeutic use


  • Morpholines
  • Oxazoles
  • Pyridines
  • gamma-Aminobutyric Acid
  • basmisanil

Associated data

  • ClinicalTrials.gov/NCT02024789