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
Authors: Goeldner Celia , Kishnani Priya S. , Skotko Brian G. , Casero Julian Lirio , Hipp Joerg F. , Derks Michael , Hernandez Maria-Clemencia , Khwaja Omar , Lennon-Chrimes Sian , Noeldeke Jana , Pellicer Sabine , Squassante Lisa , Visootsak Jeannie , Wandel Christoph , Fontoura Paulo , d’Ardhuy Xavier Liogier ,   Clematis Study Group, De La Torre Fornell Rafael , Glue Paul , Hoover-Fong Julie , Uhlmann Sonja , Malagón Valdez Jorge , Marshall Andrew , Martinón-Torres Federico , Redondo-Collazo Lorenzo , Rodriguez-Tenreiro Carmen , Marquez Chin Valeria , Michel Reynoso Adriana G. , Mitchell Ed A. , Slykerman Rebecca F. , Wouldes Trecia , Loveday Sarah , Moldenhauer Fernando , Novell Ramon , Ochoa Cesar , Rafii Michael S. , Rebillat Anne-Sophie , Sanlaville Damien , Sarda Pierre , Shankar Rohit , Pulsifer Margaret , Evans Casey L. , Silva Alexandra M. , McDonough Mary Ellen , Stanley Maria , McCary Lindsay M. , Vicari Stefano , Wilcox William , Zampino Giuseppe , Zuddas Alessandro 
Published: February 2022

Abstract
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.