A Phase II study of a histamine H3 receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy☆
Introduction
Cognitive impairment associated with schizophrenia (CIAS) constitutes a major unmet therapeutic need for people with schizophrenia. Available antipsychotics provide little, if any, benefit for these cognitive deficits and no treatments are currently approved for CIAS. Histamine H3 receptors are widely distributed in the central nervous system and antagonism of H3 receptors is known to release acetylcholine, dopamine, norepinephrine and histamine in specific brain regions involved with cognitive function (Brown et al., 2001), including the frontal cortex, an area implicated in CIAS (Jin et al., 2009, Barch and Ceaser, 2012). Limited post-mortem evidence also suggests altered H3 receptor expression in schizophrenia in the prefrontal cortex (Jin et al., 2009). The role of histamine H3 receptor is presently being investigated for potential impact on cognition in CIAS (Egan et al., 2013, Haig et al., 2014). GSK239512, a potent, selective, orally bioavailable and brain penetrant histamine H3 receptor antagonist (Ashworth et al., 2014), has shown efficacy in several preclinical cognition models (Wilson et al., 2013a, Wilson et al., 2013b). Additionally, signals of efficacy in the episodic memory cognitive domain have been observed in Alzheimer's disease trials (Nathan et al., 2013, Grove et al., 2014). Thus, selective H3 receptor antagonists may have therapeutic benefits in CIAS, and this exploratory pilot study was designed to investigate GSK239512 in the symptomatic treatment of CIAS.
Section snippets
Trial design
This Phase II, randomized, double-blind, placebo-controlled, parallel group study (GSK H3B113147) was conducted in adult outpatients (18–55 years) with DSM IV-TR schizophrenia (American Psychiatric Association, 1994) who were symptomatically stable and taking stable doses of antipsychotic medication (Buchanan et al., 2005). Subjects were determined to be ‘stable’ if they were on a stable dose of antipsychotic medications, believed to be unlikely to require a dose change during study
Subjects
Demographic characteristics were comparable across treatment groups (Table 1). The majority of subjects completed the study (41 [82%]), with 8 of the 9 withdrawn subjects discontinuing during dose titration. Two GSK239512 subjects (8%) and one (4%) placebo subject withdrew due to adverse events. Study PK data on file suggest that dosing and compliance were adequate within the study.
Neurocognition
The CSSB Composite Score suggested a small advantage for GSK239512 versus placebo with an ES of 0.29 (90% CI −
Conclusions
GSK239512 at a maximum dose of 80 μg per day up-titrated over a four week period and maintained for three weeks was generally well-tolerated with an AE profile consistent with the known pharmacology of the class. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population. The most consistent effects were decrements in Processing Speed for GSK23912 versus placebo in both the CSSB and MCCB measures. An important limitation of the study was the small sample size
Role of funding source
Not applicable.
Contributors
This study was designed collaboratively by GlaxoSmithKline and members of the TENETS group. Drs. Breier, Buchanan, Goff, Green, Jarskog, Keefe, Leiberman, Marder, McMahon, Ms. Ball (TENETS group members), and Dr. Lowy, Dr. Maruff, Dr. Laurelle and Mr. Grove contributed to the original design of the study. Mr. Grove undertook the statistical analyses with contributions from Dr. McMahon. Drs. Breier, Buchanan, Cameron, Jarskog, Kantrowitz, Keshavan, Leiberman, and Marder participated as study
Conflict of interest
L. Fredrik Jarskog has received/receives/research funding support from GlaxoSmithKline, Sunovion, Genentech, Auspex Pharmaceuticals and Amgen, and has served on a Data Safety and Monitoring Board for Janssen. Richard Grove and Margaret Peykamian are employees of GlaxoSmithKline and receive payment and stock remuneration as part of that employment, but have no other financial interests or conflicts of interest. Martin Lowy, Joseph P Horrigan, and Marc Laurelle were employed by GlaxoSmithKline
Acknowledgments
Research was funded by GlaxoSmithKline. Results submitted in collaboration with the Treatment and Evaluation Network for Trials in Schizophrenia (TENETS) group. The sponsor and authors of this paper would like to thank the patients and investigators who made this research possible, including study investigators Mohommad Bari, Christopher Benbow, Alan Breier, Robert W. Buchanan, Carter S. Cameron, Stephen Glass, Armen Goenjian, Morris Goldman, L. Fredrik Jarskog, Joshua Kantrowitz, Matcheri S.
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2019, Handbook of Behavioral NeuroscienceCitation Excerpt :It is worthwhile highlighting here that impairment in psychomotor function is not sufficient for a clinical classification of CIAS (Nuechterlein et al., 2008). In clinical trials conducted to date, this clinical construct has required evidence of impairment across multiple domains of cognition (Jarskog, Lowy, Grove, et al., 2015; Lieberman, Dunbar, Segreti, et al., 2013; Walling, Marder, Kane, et al., 2015). Decisions made in these studies measuring psychomotor function are about the extent to which the study drugs act on the CNS generally, and in CIAS specifically.
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Registry Name/URL, Registration: www.ClinicalTrials.gov/Identifier NCT01009060, www.gsk-clinicalstudyregister.com/Identifier 113147.
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Member of TENETS group.
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Current affiliation: PPD, Morrisville, NC.
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Current affiliation: Neuren Pharmaceuticals Limited, Auckland, NZ.
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Current affiliation: Columbia University, New York, NY.