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

Tracking Information
First Submitted Date ICMJE	November 22, 2005
First Posted Date ICMJE	November 23, 2005
Last Update Posted Date	February 8, 2010
Study Start Date ICMJE	November 2005
Actual Primary Completion Date	January 2009 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: November 22, 2005)	Change in central brain volume on MRI using the 'Loseff method'
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT00257855 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 12, 2009)	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.
Original Secondary Outcome Measures ICMJE; (submitted: November 22, 2005)	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 Imapct Scale.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis
Official Title ICMJE	A Randomised Controlled Trial of Neuroprotection With Lamotrigine in Secondary Progressive Multiple Sclerosis: Single Centre, Phase 2 Trial
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
Condition ICMJE	Secondary Progressive Multiple Sclerosis
Intervention ICMJE	Drug: Lamotrigine
Study Arms	Not Provided
Publications *	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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Enrollment ICMJE; (submitted: November 22, 2005)	120
Original Enrollment ICMJE	Same as current
Actual Study Completion Date	February 2009
Actual Primary Completion Date	January 2009 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 60 Years (Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United Kingdom
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00257855
Other Study ID Numbers ICMJE	2005-001949-42
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Not Provided
Study Sponsor ICMJE	University College London Hospitals
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Raju Kapoor, MD PhD National Hospital for Neurology and Neurosurgery
PRS Account	University College London Hospitals
Verification Date	February 2009
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP