A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis
Condition: Secondary Progressive Multiple Sclerosis
MeSH terms: Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      A present there is no safe treatment for reducing rate at which disability worsens in people
      with secondary progressive multiple sclerosis. Recent research has suggested the possibility
      that drugs that act by blocking the entry of sodium into nerve cells can protect nerve fibres
      in the brain and spinal cord. In this trial, the investigators will test whether one such
      drug, called lamotrigine, can prevent damage to nerve fibres and reduce the rate at which MS
      worsens. The period of treatment in the trial will run for 2 years.
    

Detailed description: 
      At present, there is no safe, widely applicable treatment that is capable of reducing the
      rate at which disability advances in secondary progressive multiple sclerosis (SPMS). There
      is good evidence that the primary cause of disability is axonal degeneration within the CNS,
      so there is considerable interest in developing treatments which can protect axons from
      degeneration. Experimental work by members of our group has established that axons may
      degenerate upon exposure to the inflammatory mediator nitric oxide. The mechanism of the
      damage implies that protection might be afforded by the novel approach of partially blocking
      sodium channels, and our group and others have recently demonstrated that drugs including
      flecainide, phenytoin and lamotrigine can reduce axonal degeneration when optic nerves or
      spinal roots are exposed to nitric oxide, and in experimental autoimmune encephalomyelitis.

      Aims: To assess whether the sodium channel blocker lamotrigine has a neuroprotective, disease
      modifying effect on a) the rate of axonal degeneration and b) the accumulation of disability
      in patients with SPMS.

      Methodology: We propose to recruit 120 people with SPMS in whom progression rather than
      relapse is the major cause of increasing disability into a double blind parallel group
      controlled trial lasting two years in which random allocation would be made to receive
      treatment with either lamotrigine or placebo. We anticipate that patient recruitment,
      follow-up and trial management could be achieved readily across four proposed sites in
      London. The primary endpoint would be an effect of treatment on cerebral atrophy, which
      correlates with other MR markers of axonal loss, and which can be measured reliably and
      sensitively using recently developed MR techniques. The trial is powered to detect a 60%
      beneficial effect on the rate of development of cerebral atrophy. Secondary endpoints would
      include effects of treatment on spinal cord atrophy and on clinical measurements of
      impairment/disability. MR measures of brain volume and cervical spinal cord cross-sectional
      area and scores of clinical impairment/disability would be determined at entry, and then
      after 12 and 24 months. Brain volume would be measured additionally at 6 and 18 months.
      Clinical follow-up would occur every 3 months, and interim analysis is planned at 12 months.

      Utilization of results: A phase 2 trial of sodium channel blockade in SPMS is timely, given
      recent advances arising from experimental and imaging work. A successful outcome would enable
      sufficiently powered phase 3 trials to be implemented, but perhaps more significantly would
      demonstrate a novel, safe neuroprotective strategy to reduce long-term disability in this
      disorder.
    

Intervention name(s): Lamotrigine
Intervention type(s): Drug
Intervention MeSH terms: Lamotrigine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Secondary Progressive Multiple Sclerosis; Neuroprotection; Axonal loss; Brain atrophy; MRI; Lamotrigine; Sodium Channel Blockers