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A randomised placebo-controlled study of the safety and tolerability of a retinoid-X receptor agonist's ability to promote remyelination in people with relapsing-remitting multiple sclerosis already on interferon-beta therapy: a phase 2a trial
Multiple sclerosis is an autoimmune disease of the central nervous system, in which focal lymphocytic infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs; hence early in the disease patients experience episodes of neurological dysfunction from which they recover. However, with time remyelination fails and axons remain demyelinated. Over time, such demyelinated axons degenerate. The accumulation of this neurodegeneration leads to the secondary progressive phase of the disease in which people with multiple sclerosis experience the gradual worsening of pre-existing deficits. It is the secondary progressive phase of the disease that brings most morbidity with increasing frequency of unemployment, depression, marital breakup and diminished life expectancy.
One strategy to prevent the secondary progressive phase of the disease is early treatment with powerful immunotherapies. We adopted this approach with our trials of alemtuzumab from 1999 onwards, both in open-label studies and controlled phase 2 and phase 3 trials. The experience has been gratifying: not only did the mean disability of patients stabilise after alemtuzumab, it actually improved. From such data, expectations are raised that the inflammatory phase of multiple sclerosis will soon be treatable.
However, not all people with multiple sclerosis will receive or tolerate potent immunotherapy early in the course of their disease, and there are many who have “missed the boat” and are already in the secondary progressive phase. Thus the greatest unmet need in the current treatment of multiple sclerosis is the prevention or treatment of the secondary progressive phase. Here we propose a trial to test such a treatment, using a strategy to promote remyelination in people with relapsing-remitting multiple sclerosis with residual disability from previous relapses, by directly stimulating oligodendrocyte precursors.
The scientific rationale for this trial rests on the work of Professor Robin Franklin and colleagues at the University of Cambridge. They discovered that the retinoid acid receptor RXR-gamma was expressed during remyelination in the rat and that human oligodendrocyte lineage cells expressed
RXR-gamma in active and remyelinated multiple sclerosis lesions. Antagonism of RXR-gamma severely inhibited oligodendrocyte differentiation in culture, and in RXR-gamma knock-outs differentiation of oligodendrocyte precursor cells after demyelination was delayed. The key finding, that informs this trial, was that administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures, and to aged rats after demyelination, caused increased remyelination of axons. The scientific motivation behind this trial is to assess whether RXRagonists promote remyelination in people with multiple sclerosis.
An important observation from the Franklin group is that remyelination is normally effective and rapid in young animals but declines in efficiency with age. Initial discussions suggested that equivalent human ages would be over 30 years, but further advice suggests that patients as young as 18 years may have delayed remyelinating efficiency. Bexarotene is an agonist of the retinoid X receptor (RXR) (acting on the alpha, beta and gamma subtypes), which is licensed for human use. Whilst there is recognition that more selective agonists might have fewer adverse effects, none of the newly synthesised compounds are licensed. We, therefore, propose bexarotene as the most suitable agent to test the role of RXR agonists in human
No therapy has been shown to slow or reverse the secondary progressive phase of multiple sclerosis, nor the late relapsing-remitting phase beforehand. This unmet need has enormous clinical, social, psychological and economic ramifications. In vitro and vivo work confirms that remyelination may be promoted by stimulation of the retinoid-X-receptor. Bexarotene, an RXRagonist, is already licensed for an alternative indication in humans, and is generally well tolerated; the side effects in the proposed population (which are largely amenable to treatment and normalise with drug reduction or cessation) would appear outweighed by the potential for slowing or reversing disability.
We aim to first establish the safety and tolerability of bexarotene in the treatment of relapsing-remitting multiple sclerosis. Bexarotene has significant adverse effects (detailed in later sections). We have therefore chosen to minimise the number of patients exposed to the drug by using an efficacy (secondary) endpoint based on an MRI biomarker of remyelination ("MTR"), which increases the power of the study. This particular MRI measure is possible to standardise across sites14 Thus, patients from the Cambridge cohort will be asked to attend the Institute of Neurology in London or the Wolfson Brain Imaging Centre in Cambridge for their scan, and patients from the Edinburgh cohort will be asked to attend the local MRI scanning Unit, at the Clinical Research Imaging Centre in Edinburgh or the Brain Research Imaging Centre in Edinburgh. Patients will undergo their repeat MRI scan on the same scanner.
CCMR One is a Phase 2a randomised, multicentre, double-blind, placebo-controlled parallel trial of the safety and tolerability of six months of add-on therapy with a retinoid-X receptor agonist (bexarotene) in people with relapsing-remitting multiple sclerosis already being treated with disease-modifying therapy. Each patient will have a maximum of 13 visits to the trial centre and two visits to the MRI unit. After a screening assessment, recruited patients will have six months of therapy, with monthly visits to the trial centre (weekly for the first month) and a single visit at month nine to ensure any adverse events have resolved. For these visits, ‘weekly’ is defined as one week plus or minus two working days, and ‘monthly’ is defined as one calendar month plus or minus five working days.
Main inclusion criteria
To be included, patients must fulfil all inclusion criteria:
- Willing and able to give informed consent for participation in the trial;
- Male or female, aged between 18 and 50 years (inclusive);
- Relapsing-remitting multiple sclerosis as per the McDonald 2010 criteria, including a MRI brain satisfying the 2010 radiological criteria;
- At least five T2 lesions, attributable to MS, on most recent MRI brain scan;
- Kurtzke1 EDSS 0.0-6.0;
- At the time of screening (and for at least the preceding 6 months) being treated with ABN guidelines category 1 disease-modifying therapy;
- Able (in the Investigator’s opinion) and willing to comply with all trial requirements;
Main exclusion criteria
The presence of any of the following will preclude patient inclusion:
- Female patients who are pregnant, lactating or planning pregnancy during the course of the trial;
- Female patients of child bearing potential and male patients whose partner is of child bearing potential who are unwilling or unable to use two reliable methods of contraception during the trial and for one month thereafter (see section 10.7 Trial Restrictions);
- They require treatment with gemfibrozil, or CYP3A4-substrates (ketoconazole, itraconazole, protease inhibitors, clarithromycin and erythromycin) or CYP3A4-inducers (rifampicin, phenytoin, dexamethasone or phenobarbital) unless patients are willing to stop these (and it is safe to do so);
- They have ever had a category 2 disease-modifying therapy for MS (e.g. natalizumab, alemtuzumab);
- Significant renal or hepatic impairment (Grade III or worse);
- Significant cardiovascular disease that, in the opinion of the investigator, would compromise effective trial participation;
- Significant lymphopenia; (lymphocyte counts must be equal to, or greater than, 0.7 x 109/L for at least six months prior to screening);
- Known hypersensitivity to bexarotene or to any of the excipients of the product;
- Unwillingness to take product-containing gelatin;
- Known reaction to gadolinium (component of contrast agent);
- History of pancreatitis;
- Fasting triglycerides >2.3 mmol/L or baseline dyslipidaemia requiring treatment;
- Known hypervitaminosis A;
- Uncontrolled thyroid disease;
- Excessive alcohol consumption >14 units/week for men and women);
- Diabetes mellitus;
- Biliary tract disease;
- Hereditary fructose intolerance;
- Known contraindication(s) to MRI scanning procedures;
- Any other significant disease, disability or investigation result which, in the opinion of the Investigator, may either put the patient at risk, or may influence the result of the trial, or the patient’s ability to participate in the trial.
Funders and sponsors
Funders: MS Society
Prof Alasdair Coles
Clinical Trials Manager: Dr Paula Kareclas
Telephone: 01223 596473 | Email: email@example.com