Award Title: Examining the long-term effects of the combination of metformin and clemastine on remyelination and neuroprotection; a follow-up study of the Cambridge Centre for Myelin Repair trial Two
Funder: The Academy of Medical Sciences

Abstract: Background: 
My research aim is to promote brain repair in people with multiple sclerosis (MS). Specifically, I work to identify treatments that regenerate myelin, which restores function and protects demyelinated axons. CCMR Two is a randomised, placebo-controlled, phase 2 trial, which is testing the ability of 6-months of treatment with the combination of metformin and clemastine to promote remyelination in people with relapsing-remitting MS. However, the required duration of treatment, and the durability of repair, is unknown. In this proposal I aim to assess the long-term efficacy of a strategy to promote brain repair.

Objectives: 
1. To examine the durability of visual evoked potential (VEP) latency improvements in response to treatment with metformin and clemastine. 
2. To compare the effectiveness of different outcome measures in a follow-up study to a remyelination trial.
3. To gain insights into how a remyelination-promoting drug should be deployed in clinical practice.

Methods: 
In a follow up study of the CCMR Two participants (n=50), I will re-examine full-field VEP, alongside multifocal-VEP (MF-VEP), and repeat assessments of visual acuity, optical coherence tomography and serum neurofilament light. Participants will be invited at 6 and 12-months after their discontinuation of the investigational medicinal product. Treatment effects between follow-up and baseline will be tested using linear mixed models. 
 
Impact:
We anticipate that this research will support the increasingly clear position that pharmacological promotion of remyelination in people living with MS is achievable. We further anticipate that we will find a sustainability to repair following treatment with a remyelinating drug.

Lay Abstract: Multiple sclerosis affects over 125,000 people in the United Kingdom and is the leading non-traumatic cause of disability in young adults. The most urgent need for people with MS are treatments which slow, stop or reverse disability progression. Many believe that the most effective way to prevent progression is through remyelination: repairing the primary defect (demyelination) and thus protecting the underlying nerve fibre from degeneration.

The Cambridge Centre for Myelin Repair (CCMR) has recently shown that the anti-diabetes drug metformin, especially when given alongside clemastine, promotes remyelination in rats. These drugs are now being tested against matched placebos in a clinical trial of 50 people with relapsing-remitting multiple sclerosis (the CCMR Two trial). However, there is a risk that a positive effect of the drugs might be missed over this short-duration trial, and there is additionally a one-off opportunity to study how durable the repair process can be in people with MS.

This project is therefore designed to determine whether myelin repair, measured through visual and blood markers of nerve damage, are maintained over time. This will be achieved by inviting each of the 50 participants from CCMR-Two to return for further assessments at 6 and 12 months after they complete the trial. Our conclusions will have big impact for people with MS. These drugs represent a safe and cost-effective strategy to treat progression and the lessons we learn will allow us to better understand how to deploy these drugs to improve the lives of people with MS.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: NEUROLOGICAL