Elsevier

The Lancet Neurology

Volume 9, Issue 7, July 2010, Pages 681-688
The Lancet Neurology

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Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial

https://doi.org/10.1016/S1474-4422(10)70131-9Get rights and content

Summary

Background

Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis.

Methods

Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT00257855.

Findings

120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was −3·18 mL (SD −1·25) in the lamotrigine group and −2·48 mL (−0·97) in the placebo group (difference −0·71 mL, 95% CI −2·56 to 1·15; p=0·40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0·04), and volume increased partially after treatment stopped (p=0·04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0·02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group.

Interpretation

The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment. Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease.

Funding

Multiple Sclerosis Society of Great Britain and Northern Ireland.

Introduction

Disease-modifying treatments for multiple sclerosis reduce relapse frequency but have little effect on the disability that characterises progressive forms of the disease.1, 2 There is clear evidence that the primary cause of disability is axonal degeneration,3 and hence there is substantial interest in developing neuroprotective treatments.

Disease-modifying treatments generally act by modifying the immune response. Probably because immune attack is only one of several potential mechanisms of axonal injury, disease-modifying treatments have only a limited neuroprotective effect.3, 4 Excessive accumulation of sodium ions might occur in axons affected by inflammation or demyelination, which might make these axons vulnerable to injury by favouring calcium accumulation via the sodium–calcium exchanger.4 Partial blockade of voltage-gated sodium channels is neuroprotective in several experimental models of inflammatory axonal injury.5, 6, 7, 8, 9 For example, lamotrigine prevents axonal damage and preserves electrophysiological function in the dorsal column in experimental autoimmune encephalomyelitis.9

These findings raise the possibility that partial blockade of voltage-gated sodium channels could result in neuroprotection in multiple sclerosis. We aimed to assess whether the sodium-channel blocker lamotrigine has a neuroprotective, disease-modifying effect on tissue loss and disability in patients with secondary progressive multiple sclerosis.

Section snippets

Patients

We did a double-blind, parallel-group, randomised controlled trial. Patients with secondary progressive multiple sclerosis aged 18–55 years were eligible if they had an expanded disability status scale (EDSS) score of 4–6·5 and if their disability had increased in the preceding 2 years because of steady disease progression rather than relapse. Evidence of steady disease progression was either from clinical documentation or from an increase of at least 1 point in EDSS measurements. Patients were

Results

Patients were recruited between January and December, 2006, and final assessments were done in January, 2009. 120 participants were randomly assigned to receive lamotrigine (n=61) or placebo (n=59; figure 1). The lamotrigine and placebo groups were similar for all baseline variables (table 1). 12 patients (nine in the lamotrigine group and three in the placebo group) were lost to imaging follow-up, leaving 108 who had imaging for the primary outcome at 24 months (52 on lamotrigine and 56 on

Discussion

In this phase 2 clinical trial, we have tested for the first time whether partial blockade of voltage-gated sodium channels is neuroprotective in secondary progressive multiple sclerosis. We did not observe a neuroprotective effect of treatment with lamotrigine. However, further analysis of secondary imaging outcomes and exploratory analyses of the primary outcome suggested that use of lamotrigine was associated with complex brain volume changes: treatment did not affect grey matter volume

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