Clinical Trial

. 2022 Feb 5;14(1):10.

doi: 10.1186/s11689-022-09418-0.

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

Celia Goeldner¹, Priya S Kishnani², Brian G Skotko^{3

4}, Julian Lirio Casero⁵, Joerg F Hipp⁶, Michael Derks⁷, Maria-Clemencia Hernandez⁶, Omar Khwaja^{6

8}, Sian Lennon-Chrimes⁷, Jana Noeldeke⁶, Sabine Pellicer⁶, Lisa Squassante⁶, Jeannie Visootsak^{9

10}, Christoph Wandel¹¹, Paulo Fontoura¹², Xavier Liogier d'Ardhuy^{6

13}; Clematis Study Group

Collaborators, Affiliations

Collaborators

Affiliations

¹ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. celia.goeldner@roche.com.
² Duke Clinical Research Institute, Durham, NC, 27710, USA.
³ Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Medical Genetics, Boston, MA, 02114, USA.
⁴ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁵ Hospital Infantil Universitario Niño Jesus, Pediatria Social, 28009, Madrid, Spain.
⁶ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
⁷ Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Welwyn, Welwyn Garden City, UK.
⁸ Current affiliation: VectivBio AG, Basel, Switzerland.
⁹ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, USA.
¹⁰ Current affiliation: Novartis Gene Therapies, New York, USA.
¹¹ Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
¹² Roche Neuroscience Product Development, Basel, Switzerland.
¹³ Current affiliation: Loulou Foundation, London, UK.

PMID: 35123401
PMCID: PMC8903644
DOI: 10.1186/s11689-022-09418-0

Clinical Trial

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

Celia Goeldner et al. J Neurodev Disord. 2022.

. 2022 Feb 5;14(1):10.

doi: 10.1186/s11689-022-09418-0.

Authors

Collaborators

Affiliations

¹ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. celia.goeldner@roche.com.
² Duke Clinical Research Institute, Durham, NC, 27710, USA.
³ Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Medical Genetics, Boston, MA, 02114, USA.
⁴ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁵ Hospital Infantil Universitario Niño Jesus, Pediatria Social, 28009, Madrid, Spain.
⁶ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
⁷ Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Welwyn, Welwyn Garden City, UK.
⁸ Current affiliation: VectivBio AG, Basel, Switzerland.
⁹ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, USA.
¹⁰ Current affiliation: Novartis Gene Therapies, New York, USA.
¹¹ Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
¹² Roche Neuroscience Product Development, Basel, Switzerland.
¹³ Current affiliation: Loulou Foundation, London, UK.

PMID: 35123401
PMCID: PMC8903644
DOI: 10.1186/s11689-022-09418-0

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 GABA_A-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.

Methods: Basmisanil, a selective GABA_A-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.

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Conflict of interest statement

At the time of the study, P Fontoura, C Goeldner, MC Hernandez, JF Hipp, O Khwaja, X Liogier d’Ardhuy, J Noeldeke, S Pellicer, L Squassante, C Wandel were employees of F.Hoffmann-La Roche AG Switzerland; M Derks and S Lennon-Chrimes were employees of Roche Products Ltd. UK; J Visootsak was an employee of Roche New York. All employees (former and current) may be eligible for stock and stock options. P S Kishnani has no disclosures for Down syndrome-related research. J Lirio Casero has no disclosures. B G Skotko occasionally consults on the topic of Down syndrome through the Gerson Lehrman Group. He receives remuneration from Down syndrome non-profit organizations for speaking engagements and associated travel expenses. Dr. Skotko receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past 2 years, he has also received research funding from AC Immune and LuMind Research Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. Dr. Skotko is occasionally asked to serve as an expert witness for legal cases where Down syndrome is discussed. Dr. Skotko serves in a non-paid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. Dr. Skotko has a sister with Down syndrome.

Figures

**Fig. 1**
Participant disposition (CONSORT diagram)

**Fig. 2**
Percent of participants with above-threshold improvement on the composite endpoint. A Primary efficacy endpoint after 6 months of treatment. Percent of participants with above-threshold improvement: B by age group (adolescents, adults) after 6 months of treatment; C combined age group after 3 months of treatment; D by age group (adolescents, adults) after 3 months of treatment. Above-threshold improvement on the composite endpoint was defined as having (1) a relevant increase in raw scores from baseline in at least two out of three tasks from the Repeatable Battery for the Assessment of Neuropsychological Status ([RBANS]; ≥ 2 points for list learning, ≥ 1 point for list recognition, ≥ 1 point for list recall); and (2) either an increase from baseline in the Vineland Adaptive Behavior Scales-II (VABS II) composite score of ≥ 7 or a Down syndrome-specific Clinical Global Impression-Improvement (DS-CGI-I) ≤ 3 (minimally improved). Efficacy assessments were performed at baseline and after 3 and 6 months of treatment. Statistics: *p < 0.05 vs. placebo-treated group

**Fig. 3**
Quantitative EEG. A Change in EEG spectral power (average across week 2 and week 20 visits relative to baseline) for dosed (red) and the placebo (gray) groups. B, C Effects of assessment time-point (week 2 vs. week 20) and dose (low dose vs. high dose) for signal power extracted from the centers of the clusters identified in 1.2.3 (theta cluster, frequency range [3 bins]: ~ 3.5–4.5 Hz, electrodes: F3, Fz, F4, T7, T8, P7, P8, O1, O2; beta cluster, frequency range [3 bins]: ~ 19–22.5 Hz, electrodes: Fz, Cz). The top plots indicate the electrodes used for each extraction of signal power. The numbers at the base of the bars indicate the number of participants entering the analyses

See this image and copyright information in PMC

References

1. de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19(4):439–447. - PubMed
1. de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in Europe. Eur J Hum Genet. 2021;29(3):402–10. - PMC - PubMed
1. Pennington BF, Moon J, Edgin J, Stedron J, Nadel L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 2003;74(1):75–93. - PubMed
1. Grieco J, Pulsifer M, Seligsohn K, Skotko B, Schwartz A. Down syndrome: cognitive and behavioral functioning across the lifespan. Am J Med Genet C Semin Med Genet. 2015;169(2):135–149. - PubMed
1. Golden JA, Hyman BT. Development of the superior temporal neocortex is anomalous in trisomy 21. J Neuropathol Exp Neurol. 1994;53(5):513–520. - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical