ArticlesMitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial
Introduction
Multiple sclerosis, an autoimmune disease involving predominantly the white matter of the brain and spinal cord, is one of the most common neurological disorders of younger adults and a substantial cause of lasting neurological disability.1 Clinical patterns of multiple sclerosis have been defined by international consensus.2 About 85% of patients initially experience one or more relapses followed by complete or incomplete recovery; this clinical pattern is referred to as the relapsing-remitting phase. Over 10 years, roughly 50% of these patients will experience a transition to the secondary progressive phase,3 which is characterised by gradually worsening disability with or without superimposed relapses. About 10% of patients experience a clinical course that is progressive from onset, primary progressive multiple sclerosis. The remaining 5% of patients experience progressive disability from onset that is later accompanied by one or more superimposed relapses; this pattern is referred to as progressive relapsing multiple sclerosis.
Three disease-modifying therapies are approved for patients with relapsing-remitting multiple sclerosis: interferon beta-lb (Betaferon, Betaseron), interferon beta-la (Avonex, Rebif), and glatiramer acetate. Each of these treatments significantly lowers mean annual exacerbation rates and curtails progression of the underlying disorder, as shown by serial magnetic resonance imaging (MRI) of the brain and spinal cord.1, 4 Similar clinical and imaging benefits have been observed in phase III clinical trials of interferon beta in patients with secondary progressive multiple sclerosis.5, 8 However, only interferon beta-lb, as used in the European trial of Betaferon in Secondary Progressive Multiple Sclerosis (EUSP),5 convincingly lengthened time to onset of sustained progression of disability as measured by the expanded disability status scale (EDSS).9 This treatment effect, independent of baseline EDSS score and previous relapses, led to the approval of interferon beta-lb for patients with secondary progressive multiple sclerosis in Europe and Canada. However, similar benefits were not evident in the other phase III trials: the North American trial of interferon beta-lb (Betaseron),6 the Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-la in Multiple Sclerosis (SPECTRIMS) trial of interferon beta-la (Rebif),7 and the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT) of interferon beta-la (Avonex).8 Some investigators have suggested that different treatment effects measured by the EDSS in these clinical trials reflect fundamental differences in the cohorts of patients.6 For example, patients in the European trial were, on average, younger and less likely to be free of exacerbations for 2 years before study enrolment than those in the other trials. These differences suggest that the effects of interferon beta as measured by the EDSS are most easily demonstrated early in the secondary progressive phase when exacerbations are commonly superimposed on gradual progression of disability. Consistent with this interpretation, the National Institute for Clinical Excellence in the UK recommended withdrawal of approval for interferon beta-Ib, then the only approved treatment for patients with secondary progressive multiple sclerosis without superimposed relapses.
Mitoxantrone is an anthrecenedione used to treat various malignant disorders.10 Several immunosup-pressant properties of this drug provide a rationale for its use in multiple sclerosis, which is associated with dysregulated responses of T and B cells to antigens in the central nervous system and macrophage-mediated myelin damage and axonal injury.1 Mitoxantrone inhibits T-cell activation, abrogates proliferation of B and T cells, diminishes antibody production, and deactivates macrophages.11, 13 Mitoxantrone also effectively suppresses experimental autoimmune encephalomyelitis in rodents, an animal model of multiple sclerosis.14, 15
Several pilot trials of mitoxantrone were effective and showed no adverse events.16, 19
The encouraging results and tolerability during pilot studies of mitoxantrone prompted this placebo-controlled, double-blind, randomised, multicentre, phase III trial of mitoxantrone in secondary progressive multiple sclerosis (the MIMS study). We hypothesised that, over 24 months, mitoxantrone 12 mg/m2 recipients would experience significantly less progression of disability and fewer relapses than placebo recipients.
Section snippets
Study design
The study was a multicentre, double-blind, phase III trial with patients randomly assigned treatment with placebo, mitoxantrone 5 mg/m2, or mitoxantrone 12 mg/m2 administered intravenously every 3 months for 24 months. Randomisation was done by means of a computer-generated schedule prepared for each site with a block size of three, without stratification. The primary efficacy assessment was based on experience from the pilot trial with 12 mg/m2 mitoxantrone. The 5 mg/m2 dose was included as an
Results
194 patients were enrolled between June, 1993, and July, 1997, at 17 centres in Belgium, Germany, Hungary, and Poland. 63 were assigned treatment with 12 mg/m2 mitoxantrone, 66 were assigned 5 mg/m2, and 65 were assigned placebo. 191 patients received at least one dose of study treatment and 188 underwent at least one clinical assessment and were available for efficacy analyses (figure 1). Baseline clinical and MRI characteristics were similar for evaluable patients across treatment groups (
Discussion
Mitoxantrone 12 mg/m2, as administered during this study, was effective and generally well tolerated by patients with worsening relapsing-remitting and secondary progressive multiple sclerosis. Significant treatment effects were detected with a novel multivariate test of five primary efficacy variables that collectively captured clinically relevant features of the disease. Unlike other methods of analysis of multiple outcomes, which either condense the multiple endpoints to a single endpoint or
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