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

This study has been completed.
Sponsor:
Information provided by:
University College London Hospitals
ClinicalTrials.gov Identifier:
NCT00257855
First received: November 22, 2005
Last updated: February 5, 2010
Last verified: February 2009
  Purpose

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.


Condition Intervention Phase
Secondary Progressive Multiple Sclerosis
Drug: Lamotrigine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis: Single Centre, Phase 2 Trial

Resource links provided by NLM:


Further study details as provided by University College London Hospitals:

Primary Outcome Measures:
  • Change in central brain volume on MRI using the 'Loseff method'

Secondary Outcome Measures:
  • 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.

Estimated Enrollment: 120
Study Start Date: November 2005
Study Completion Date: February 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00257855

Locations
United Kingdom
National Hospital for Neurology and Neurosurgery
London, United Kingdom, WC1 3BG
Sponsors and Collaborators
University College London Hospitals
Investigators
Study Director: Raju Kapoor, MD PhD National Hospital for Neurology and Neurosurgery
  More Information

No publications provided by University College London Hospitals

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00257855     History of Changes
Other Study ID Numbers: 2005-001949-42
Study First Received: November 22, 2005
Last Updated: February 5, 2010
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University College London Hospitals:
Secondary Progressive Multiple Sclerosis
Neuroprotection
Axonal loss
Brain atrophy
MRI
Lamotrigine
Sodium Channel Blockers

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Multiple Sclerosis, Chronic Progressive
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Lamotrigine
Sodium Channel Blockers
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Anticonvulsants
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 26, 2014