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J Neurol. 2017 Feb;264(2):304-315. doi: 10.1007/s00415-016-8341-7. Epub 2016 Nov 25.

Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study.

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GSK, Research Triangle Park, Raleigh-Durham, NC, USA.
GSK, Stockley Park, Uxbridge, UK.
McGill University, Montreal, QC, Canada.
GSK, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
University of Leipzig, Leipzig, Germany.
Department of Neurology, NeuroRx Research, Montreal, QC, Canada.


Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.


GSK239512; Magnetic resonance imaging; Magnetisation transfer ratio; Relapsing-remitting multiple sclerosis; Remyelination

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Conflict of interest statement

Compliance with ethical standards Conflicts of interest CJS is a former employee of GSK and holds stocks/shares in GSK. RAG and DT are employees of GSK and hold stocks/shares in GSK; RB has received personal compensation from NeuroRx Research for consulting services. FTB has received an honorarium from GSK for speaking at an investigators´ meeting for the trial reported here; his institution received compensation from GSK for the treatment and documentation of those patients included at his site; he has received personal compensation for speaking or serving on advisory boards from Bayer-Schering, Biogen, Genzyme, Novartis and Teva; through his institution, he received grants from Actelion, Bayer, Novartis and Teva. DLA has an equity interest in NeuroRx Research, has received personal fees from Biogen, EMD Serono, Genentech, Genzyme, Hoffman LaRoche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Acorda, Sanofi-Aventis, and Teva, and Grants from Biogen and Novartis. Ethical standards The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice (ICH-GCP) and the ethical principles outlined in the Declaration of Helsinki 2008 [17]. Ethics approval was obtained from respective countries’ Ethics Committees (Online resource 1). The study protocol is available online at

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