CCMR Two
A Trial of Metformin and Clemastine in Multiple Sclerosis
BACKGROUND
In multiple sclerosis (MS), the immune system attacks the protective layer around nerve fibres (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 licensed for diabetes and hay fever respectively, have recently been found to work together to promote remyelination in animals [Neumann, Cell stem cell 2019]. We believed that this combination may also promote remyelination in people with multiple sclerosis, which could potentially reverse or alleviate symptoms. The purpose of this trial was therefore to assess whether metformin and clemastine really can promote remyelination in people.
TRIAL DESIGN
The trial was conducted in Cambridge and recruited 70 participants. Participants all had relapsing remitting multiple sclerosis and had to be stable on an MS treatment for at least the last 6 months. This group was selected as we believed people with relapsing MS would have more numerable nerve fibres healthy enough to remyelinate. To be clear, we still believe in remyelination as a strategy for progressive forms of MS, but our hypothesis was that we could demonstrate the presence of remyelination with a smaller number of people with relapsing MS, and so get a rapid answer as to whether these drugs worked to promote remyelination in people living with MS.
The trial was a big commitment (at least 7 visits over a 38 week period) and recruited individuals from across the UK. Participants in the trial took several capsules twice daily for 6 months and there was a 50% chance (much like flipping a coin) that these contained metformin and clemastine. The other half of participants received “dummy drugs” called placebos. Neither the participant, nor the trial doctor, knew which treatment they were taking. This was important to allow us to determine the effect of metformin and clemastine on myelin repair.
Remyelination was assessed by two primary methods. An eye test called the visual evoked potential (VEP) and an MRI scan with special sequences that are sensitive to changes in myelin.
TRIAL RESULT
The “primary endpoint” was met. In the people taking metformin and clemastine, there was a small difference in the speed of conduction along the visual nerves, consistent with remyelination. In addition, there were other signals that the drugs were having an effect. There was an improvement in people's visual field testing and the MRI brain scans showed some improvements in those MS lesions that had higher myelin content at the beginning of the trial.
People taking part also had tests of physical disability and visual function (using letter charts). These didn’t show a difference between the groups. But that was not surprising as we wouldn’t expect to see changes in symptoms in only six months. Our main reflection was that the drugs were having a biological effect on remyelination and that further research is required to test the clinical impact of these treatments.
CONCLUSION FROM CCMR TWO
This trial, following the original ReBUILD trial of clemastine, and our CCMR One trial of bexarotene, is the third myelin repair trial to successfully promote remyelination. Together, these results give us hope that myelin repair could be part of future treatments for MS. However, we have yet to demonstrate an effect on MS disability over these short term (3-6 month) clinical trials and we do not currently advocate taking any of these experimental medicines for MS.
Our main reflection is that these trials provide justification for longer term research, and we are planning on conducting follow up of participants from our previous remyelination trials. We are also highly motivated to test new drug treatments aimed at promoting the process of myelin repair, which we believe will be more potent and better tolerated.