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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Multiple Sclerosis Society of Great Britain and Northern Ireland.
Kapoor
Raju
R
Department of Neuroinflammation, National Hospital for Neurology and Neurosurgery and the Institute of Neurology, Queen Square, London, UK. raj.kapoor@uclh.nhs.uk
Furby
Julian
J
Hayton
Thomas
T
Smith
Kenneth J
KJ
Altmann
Daniel R
DR
Brenner
Robert
R
Chataway
Jeremy
J
Hughes
Richard A C
RA
Miller
David H
DH
D000293:Adolescent; D000328:Adult; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012720:Severity of Illness Index; D014227:Triazines / Q000627:therapeutic use*; D016138:Walking; D055815:Young Adult
D018696:Neuroprotective Agents; D014227:Triazines; D000077213:Lamotrigine