Glatiramer acetate in combination with minocycline in patients with relapsing—remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial

Abstract

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing-remitting multiple sclerosis.

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…While the reason for the discrepancies is unknown, differences between the various studies include doses and timing of intervention and may reflect the dual role of microglia in inflammation. Indeed, results of clinical trials from various patient cohorts suffering neurological diseases have also revealed differing results; significant toxicity was found after a phase III randomised trial in patients with ALS (Gordon et al, 2007), a phase III futility study in HD recommended that further study of minocycline in HD was not warranted (Schwarz et al, 2010), while the results of a double-blind, placebo-controlled study have suggested the beneficial effects of minocycline 26 as a combination therapy for MS (Metz et al, 2009), and another preliminary study showed efficacy in acute ischemic stroke (Lampl et al, 2007). Despite these contradictory results, a phase II randomized double-blind futility clinical trial of minocycline in PD has been set-up.…”

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

“…This tetracycline antibiotic that inhibits MMP activity and reduces the severity of animals immunized for EAE (22)(23)(24) has shown promise in relapsing-remitting MS in early clinical trials (25)(26)(27)(28) and, more recently, was found to be effective in a phase III trial in early MS (L. M. Metz et al, submitted for publication). We find that both murine and human T cells were reduced in the expression level (MFI) of EMMPRIN by minocycline, as well as in the percentage of T cells with EMMPRIN expression.…”

“…We focus on the potential MS medication minocycline, a tetracycline antibiotic that inhibits MMP activity (21) and reduces the severity of animals immunized for EAE (22)(23)(24). From these animal studies, minocycline was tested and found to have promise in relapsing-remitting MS as suggested by early clinical trials (25)(26)(27)(28). More recently, a phase III trial in patients with a first demyelinating event (clinically isolated syndrome) found that minocycline reduced the acquisition of a second event to become clinically definite MS (L. M. Metz, D. K. B. Li, A. Traboulsee, P. Duquette, M. Eliasziw, G. Cerchiaro, J. Greenfield, A. Riddehough, M. Yeung, M. Kremenchutzky, et al, submitted for publication).…”

Novel Therapeutic Approaches to Autoimmune Demyelinating Disorders

“…A recent phase II trial analysed the effect of minocycline as add-on therapy to GA [68]. RR-MS patients were treated with GA and randomized to receive either minocycline 100mg twice daily or placebo.…”