ArticleOA
Author: Goeldner, Celia ; Glue, Paul ; Skotko, Brian G. ; Moldenhauer, Fernando ; Zuddas, Alessandro ; Martinón-Torres, Federico ; Silva, Alexandra M. ; Derks, Michael ; Mitchell, Ed A. ; Michel Reynoso, Adriana G. ; Rebillat, Anne-Sophie ; Hoover-Fong, Julie ; Uhlmann, Sonja ; Loveday, Sarah ; Khwaja, Omar ; Stanley, Maria ; Rodriguez-Tenreiro, Carmen ; Evans, Casey L. ; McDonough, Mary Ellen ; Kishnani, Priya S. ; Sarda, Pierre ; Hernandez, Maria-Clemencia ; Marquez Chin, Valeria ; Pellicer, Sabine ; Noeldeke, Jana ; Ochoa, Cesar ; Pulsifer, Margaret ; Wandel, Christoph ; McCary, Lindsay M. ; Vicari, Stefano ; Rafii, Michael S. ; Sanlaville, Damien ; Shankar, Rohit ; Wilcox, William ; Casero, Julian Lirio ; Fontoura, Paulo ; Malagón Valdez, Jorge ; Squassante, Lisa ; Slykerman, Rebecca F. ; Novell, Ramon ; Lennon-Chrimes, Sian ; De La Torre Fornell, Rafael ; Redondo-Collazo, Lorenzo ; Visootsak, Jeannie ; d’Ardhuy, Xavier Liogier ; Wouldes, Trecia ; Zampino, Giuseppe ; Hipp, Joerg F. ; Marshall, Andrew
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.