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

Primary Purpose

Secondary Progressive Multiple Sclerosis

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Lamotrigine
Sponsored by
University College London Hospitals
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Secondary Progressive Multiple Sclerosis focused on measuring Secondary Progressive Multiple Sclerosis, Neuroprotection, Axonal loss, Brain atrophy, MRI, Lamotrigine, Sodium Channel Blockers

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • National Hospital for Neurology and Neurosurgery

Outcomes

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.

Full Information

First Posted
November 22, 2005
Last Updated
February 5, 2010
Sponsor
University College London Hospitals
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1. Study Identification

Unique Protocol Identification Number
NCT00257855
Brief Title
A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis
Official Title
A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis: Single Centre, Phase 2 Trial
Study Type
Interventional

2. Study Status

Record Verification Date
February 2009
Overall Recruitment Status
Completed
Study Start Date
November 2005 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
February 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
University College London Hospitals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Secondary Progressive Multiple Sclerosis
Keywords
Secondary Progressive Multiple Sclerosis, Neuroprotection, Axonal loss, Brain atrophy, MRI, Lamotrigine, Sodium Channel Blockers

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Double
Allocation
Randomized
Enrollment
120 (false)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raju Kapoor, MD PhD
Organizational Affiliation
National Hospital for Neurology and Neurosurgery
Official's Role
Study Director
Facility Information:
Facility Name
National Hospital for Neurology and Neurosurgery
City
London
ZIP/Postal Code
WC1 3BG
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
20621711
Citation
Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010 Jul;9(7):681-8. doi: 10.1016/S1474-4422(10)70131-9. Epub 2010 Jun 8.
Results Reference
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A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis

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