Clinical MS Research Group
Clinical Trials
CCMR2: a trial of metformin and clemastine as remyelinating drugs in MS
Fully recruited as of September 2024
Background
Nerves in the brain and spinal cord are normally surrounded by a protective layer of a substance called myelin (similar to the plastic insulation of an electric cable). In multiple sclerosis (MS), the immune system attacks the myelin, leaving nerve fibres (similar to the metal wire in the cable) unprotected. This causes nerves to malfunction, resulting in multiple sclerosis symptoms. Over time, unprotected nerve fibres die, leading to the progressive phase of MS. To avoid this happening, we are trying to promote remyelination – the process by which myelin is regenerated.
Metformin and clemastine, two drugs that are already licenced for diabetes and hay fever respectively, have recently been found to work together to promote remyelination in animals [Neumann, Cell stem cell 2019]. We believe that this combination may also promote remyelination in people with multiple sclerosis, which could potentially reverse or alleviate symptoms. The purpose of this research is therefore to assess whether metformin and clemastine really can promote remyelination in people.
Figure legend: preclinical research that has shown that metformin significantly increases the proportion of demyelinated axons in animal models of MS (left) and increases the differentiation of oligodendrocyte stem cells into mature, myelinating, oligodendrocytes (right).
Trial design
The trial is being conducted in Cambridge and has recruited 70 participants. People are required to attend fairly frequently: at least 7 visits over a 38-week period are required. Participants in the trial take several capsules twice daily for 6 months. There is a 50% chance (much like flipping a coin) that these will contain metformin and clemastine. The other half of participants will receive “dummy drugs” called placebos. Neither the participant, nor the trial doctor, knows which treatment they are taking. Remyelination is assessed by an eye test (the visual evoked potential – VEP) and an MRI scan at the beginning of this six-month period and again at the end.
Progress
The trial started in March 2022, and in the last 2 years we have had overwhelming support from the MS community. We have met with over 170 people to screen them for eligibility and our 70 participants have started or completed treatment. An early reflection is that our screening pass rate has been lower than we had expected (about 40%). The main reason for this is that we have found many potential participants have had normal visual evoked potential (VEP) eye tests. As this VEP is one of the most sensitive ways to measure remyelination in people living with MS, it is a requirement to have an abnormal VEP to join the trial (so we can measure the repair/recovery of this). People living with MS will not know whether they have an abnormal VEP, which is why we invite people to have screening eye tests, to see if they are eligible.
Given the trial fully recruited in September 2024, we are now waiting for the final participants to complete the trial, which will run into Q2 2025. We anticipate to report the trial results late 2025.
CCMR1: A Trial of Bexarotene in Multiple Sclerosis
Background
This trial had its roots in research undertaken in Cambridge that showed that RXR-gamma agonism increases endogenous remyelination in animal models of MS (Huang, Nat Neuroscience 2011). Bexarotene, a drug that is already in use for cutaneous T cell lymphoma, was known to agonise the alpha, beta and gamma isoforms of the RXR receptor. It followed that this drug could be repurposed in a clinical trial of people with MS.
Trial design
This led us to undertake the “Cambridge Centre for Myelin Repair” One trial of bexarotene in people with relapsing-remitting MS. We recruited participants across 2 sites, in Edinburgh and Cambridge. All had relapsing remitting MS, were aged 18-50 and were stable on dimethyl fumarate (an MS disease modifying treatment). It has to be emphasised that this was a very significant undertaking for our participants. Due to the known side effects of the drug we monitored participants very closely and 13 visits were required over the course of the trial for each participant. We measured the effects of the drugs over 6 months in two main ways. First, with a test of nerve structure, using MRI brain scans, and second with tests of nerve function, using the change in the latency of the visual evoked potential (VEP).
Trial Result
The “primary endpoint” was not met, in that the people taking bexarotene did not have an overall improvement in the level of “MTR” in their MRI brain lesions. However, we learned that not all MS lesions respond equally to bexarotene. And it emerged that there were improvements in lesional MTR in particular parts of the brain, for instance grey matter regions.
The “primary endpoint” was not met, in that the people taking bexarotene did not have an overall improvement in the level of “MTR” in their MRI brain lesions. However, we learned that not all MS lesions respond equally to bexarotene. And it emerged that there were improvements in lesional MTR in particular parts of the brain, for instance grey matter regions.
Therefore CCMR1 was the first clinical trial to show a pro-remyelinating effect of a repurposed compound using converging evidence from both MRI and visual evoked potentials. Unfortunately, bexarotene was poorly tolerated at this dose causing hypothyroidism in all participants, hypertriglyceridaemia in most and 5/26 had to withdraw from treatment.
Future
We believe there is compelling evidence that this dose of bexarotene promotes remyelination. We are currently working to see if the same pro-remyelinating effects can be seen at smaller doses (which are associated with far fewer adverse effects), and hope to test this hypothesis in a future clinical trial.
The CCMR1 Clinical Trial Protocol is open access and can be download in PDF by clicking the image below.
SINAPPS-2: A Psychosis Clinical Trial
SINAPPS2 is a phase II ongoing clinical trial aiming to test the efficacy and safety of immunotherapy (intravenous immunoglobulin combined with rituximab) vs placebo treatment in people with acute symptoms of psychosis and anti-neuronal membrane antibodies.
More information here.
Tests for antibodies in psychosis
We are offering tests for antibodies in people experiencing psychotic symptoms through the Prevalence of Pathogenic Autoantibodies in Psychosis study (PPiP2).
Those who may be eligible to take part in our study will be:
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Experiencing a current first episode of psychosis lasting less than 2 years. This can be a first episode or relapse
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18-70 years
If this is you or someone you know who is receiving treatment from an NHS Mental Health Trust, details of who to contact in your local area are listed here. This will enable you to contact the relevant PPiP2 Study Team.
If the treating trust is not listed but you or someone you know meets of eligibility criteria then your/their clinician (GP/psychiatrist) can request the antibodies blood test if they feel it is clinically indicated.
The particular antibodies we recommend they test for are NMDAR -live assay, LGI1. The details for how clinicians can request the test and the request card to use are here.