title: Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study.
abstract: Histamine H3receptor 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 H3receptor 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.
authors.affiliation: GSK, Research Triangle Park, Raleigh-Durham, NC, USA. Schwartzbach@mindspring.com.
authors.forename: Caryl J
authors.initials: CJ
authors.lastname: Schwartzbach
authors.affiliation: GSK, Stockley Park, Uxbridge, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Grove
authors.affiliation: McGill University, Montreal, QC, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: GSK, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Tompson
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Then Bergh
authors.affiliation: McGill University, Montreal, QC, Canada.|Department of Neurology, NeuroRx Research, Montreal, QC, Canada.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D000068717:Glatiramer Acetate / Q000008:administration & dosage; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000187:drug effects; D006633:Histamine Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007273:Injections, Intramuscular; D000068556:Interferon beta-1a / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000523:psychology; D009186:Myelin Sheath / Q000187:drug effects; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016037:Single-Blind Method; D066127:White Matter / Q000000981:diagnostic imaging / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D001552:Benzazepines; C584220:GSK239512; D006633:Histamine Antagonists; D018696:Neuroprotective Agents; D000068717:Glatiramer Acetate; D000068556:Interferon beta-1a
keywords: GSK239512; Magnetic resonance imaging; Magnetisation transfer ratio; Relapsing-remitting multiple sclerosis; Remyelination