Elsevier

The Lancet

Volume 360, Issue 9350, 21–28 December 2002, Pages 2018-2025
The Lancet

Articles
Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial

https://doi.org/10.1016/S0140-6736(02)12023-XGet rights and content

Summary

Background

Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients.

Methods

194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m2 [exploratory group] or 12 mg/m2 intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m2 versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy.

Findings

Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0·30 [95% Cl 0·17–0·44]; p<0·0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0·24 [0·04–0·44]; p=0·0194), change in ambulation index (0·21 [0·02–0·40]; p=0·0306), adjusted total number of treated relapses (0·38 [0·18–0·59]; p=0·0002), time to first treated relapse (0·44 [0·20–0·69]; p=0·0004), and change in standardised neurological status (0·23 [0·03–0·43]; p=0·0268).

Interpretation

Mitoxantrone 12 mg/m2 was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

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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