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.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Goeldner, C; Kishnani, PS; Skotko, BG; Casero, JL; Hipp, JF; Derks, M; Hernandez, M-C; Khwaja, O; Lennon-Chrimes, S; Noeldeke, J; Pellicer, S; Squassante, L; Visootsak, J; Wandel, C; Fontoura, P; d'Ardhuy, XL; Clematis Study Group,

Published Date

  • February 5, 2022

Published In

Volume / Issue

  • 14 / 1

Start / End Page

  • 10 -

PubMed ID

  • 35123401

Pubmed Central ID

  • PMC8903644

Electronic International Standard Serial Number (EISSN)

  • 1866-1955

Digital Object Identifier (DOI)

  • 10.1186/s11689-022-09418-0


  • eng

Conference Location

  • England