E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The clinical trial we are proposing directly addresses the problem that at the moment there is no treatment that can stop people with multiple sclerosis (MS) from becoming permanently disabled in the long term by their illness: this usually occurs when people develop the secondary progressive form of MS, where it is believed that the disability arises because of permanent damage to the nerve fibres (axons) in the brain and spinal cord. We propose to test the possibility that the drug lamotrigine has the ability to protect axons from damage in people with secondary progressive MS, and that it can thereby prevent the accumulation of disability. |
|
E.2.2 | Secondary objectives of the trial |
To assess whether treatment of patients with lamotrigine is well tolerated over a period of two years, and to assess the utility of several magnetic resonance imaging techniques for measuring the degeneration of axons in patients with secondary progressive multiple sclerosis. |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
a) Age 18−60 years. The lower limit has been chosen to enable informed consent, and the upper limit to avoid the possible inclusion of patients with cerebrovascular disease, which would potentially influence the cerebral volumes and white matter lesion numbers and thereby affect the MR outcome measures.
b) Sex. Men and women will be included, but women of childbearing age would be required to use appropriate methods of contraception to avoid any teratogenic effects of lamotrigine.
c) Patients with a diagnosis of secondary progressive MS where steady progression rather than relapse is the major cause of increased disability in the preceding 2 years, and who are therefore not eligible for treatment with disease modifying therapies according to the criteria of the Association of British Neurologists (available at www.theabn.org/downloads/msdoc.pdf) that are used as the current standard for practice in the UK National Health Service. Evidence of progression can be from either 1) clinical documentation of steadily increasing disability, or 2) an increase of at least 1 point in disability as measured using the EDSS.
d) EDSS 4.0−6.5. Disability progresses at a relatively stable rate within this range of disability. |
|
E.4 | Principal exclusion criteria |
a) Secondary progressive MS with very rapid deterioration of disability, if eligible for treatment with mitoxantrone at the National Hospital for Neurology and Neurosurgery using a protocol recently approved by the Trust’s Pharmaceutical Committee, making it unethical to offer an alternative, experimental treatment in a clinical trial.
b) Use of sodium or calcium channel blockers in the previous 2 weeks, corticosteroids in the previous 2 months, or immunosuppressive drugs in the previous 6 months (12 months for mitoxantrone), as these have potential neuroprotective properties which may interact with the effects of lamotrigine and therefore dilute the power of the trial.
c) Evidence of significant hepatic or renal abnormalities, either in the clinical history or in blood tests prior to entry into the trial. Patients with other major systemic diseases will also be excluded.
d) Past untoward reactions to lamotrigine, or disabling temperature−dependent symptoms related to MS, which may render participants vulnerable to side−effects of lamotrigine.
e) Contraindications to magnetic resonance imaging. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Based on the assumption that axonal loss is a key mechanism of progressive cerebral atrophy in MS, the primary outcome will be the rate of reduction of partial cerebral volume over two years. We have chosen a method that has very good reproducibility, is sensitive in detecting progressive cerebral atrophy in secondary progressive MS and has been used effectively in a previous multi−centre placebo controlled trial in secondary progressive MS. Data using the method were also available to allow sample size calculations to be generated in designing the present trial. Imaging studies will be carried out on a 1.5 Tesla scanner at the Institute of Neurology. Measurements will be made from all five scans (baseline, 6, 12, 18 and 24 months). The primary outcome will be measured from the 6 x 3mm thick axial slices that are located immediately rostral to the velum interpositum. These slices will be selected from a 2D T1−weighted spin echo sequence (TR 550ms, TE 15ms) acquired through the whole brain with 3mm thick, axial, contiguous slices oriented to the bicallosal line. On each of
the selected slices, the brain will be segmented from surrounding tissues and CSF using an automated segmentation ("Losseff cerebral method”), which has a scan−reposition−rescan reproducibility of 0.5%. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end point will be the last visit of the last subject undergoing the trail. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |