A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis

February 5, 2010 updated by: University College London Hospitals

A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis: Single Centre, Phase 2 Trial

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.

Study Overview

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment

120

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • London, United Kingdom, WC1 3BG
        • National Hospital For Neurology and Neurosurgery

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18 to 60
  • Progression rather than clinical relapse is the major cause for increased disability over the preceding 2 years
  • EDSS 4.0-6.5

Exclusion Criteria:

  • Very rapid deterioration in EDSS, >2 points over 6 months
  • Use of Mitoxantrone in the preceding year
  • Use of sodium channel blockers or calcium channel blockers in the preceding 2 weeks
  • Use of corticosteroids in preceding 2 months
  • Use of neuroprotective agents or immunosuppressants in the preceding 6 months
  • Evidence of significant hepatic or renal impairment either in clinical history or blood results.
  • Prior untoward reactions to lamotrigine, or severe temperature dependent symptoms
  • Contraindications to MRI

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Change in central brain volume on MRI using the 'Loseff method'

Secondary Outcome Measures

Outcome Measure
Change in whole brain volume on MRI using Brain Boundary Shift Integral
Number and volume of new T2 high intensity lesion volume on T2 weighted MRI
Number and volume of new T1 low signal lesion volume on T1 weighted MRI
Ratio of new T1 to new T2 lesions on MRI
Change in magnetisation transfer ratio in normal MRI normal appearing white matter and normal appearing grey matter.
Change in upper cervical cord cross sectional area using the 'Loseff method' on MRI
Change in Kurtzke's Extended Disability Scaling Score.
Change in Multiple Sclerosis Functional Composite.
Change in Multiple Sclerosis Impact Scale.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Raju Kapoor, MD PhD, National Hospital For Neurology and Neurosurgery

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2005

Primary Completion (Actual)

January 1, 2009

Study Completion (Actual)

February 1, 2009

Study Registration Dates

First Submitted

November 22, 2005

First Submitted That Met QC Criteria

November 22, 2005

First Posted (Estimate)

November 23, 2005

Study Record Updates

Last Update Posted (Estimate)

February 8, 2010

Last Update Submitted That Met QC Criteria

February 5, 2010

Last Verified

February 1, 2009

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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