MACSIMISE-BRAIN: Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination And Neurodegeneration
Multiple sclerosis (MS) is a common neuroinflammatory and neurodegenerative disease of the central nervous system (CNS), affecting more than two million people worldwide. Due to an aberrant immune response towards one’s own brain and spinal cord, myelin, the conduction layer around nerves, becomes damaged. This leads to the delay of signals passing through the nervous system, which translates to neurological symptoms such as fatigue, vision impairment, weakness in the limbs, sensory changes, bladder and gait problems. 1
This variety of neurological symptoms may occur during relapses (i.e. recurring episodes of neurological deterioration, followed by total or partial recovery, relapsing MS, RMS) or can progress over time, leaving patients with various levels of disability (secondary or primary progressive MS, PMS).2
In PMS, remyelination or restoration of the myelin sheath, is impaired. Currently approved treatment options for MS mainly work through modulation of the immune system but do not directly target remyelination. Remyelinating and neuroprotective treatments are not available in clinical care to date.34
One interesting approach in clinical practice, is combination therapy. Here, suppression of immune system by classic treatment goes side by side with add-on therapy to protect nerves by improving remyelination.5 Several clinical trials have investigated remyelinating molecules in MS patients, unfortunately with very limited success so far.6
Recently, metformin was put forward as a highly promising repurposed drug to undergo immediate testing in clinical trials in PMS. 7 Metformin is a medicine that has been used for years in patients with type 2 diabetes. Recent scientific research has shown that this medication could also induce remyelination. It was shown that Metformin is important for protection of the oligodendrocytes, the precursor of the cells responsible for myelin formation.89 Additionally it was shown that metformin has antioxidant and anti-inflammatory qualities. 10 11Thus this known medication may act on different aspects of the disease mechanisms in multiple sclerosis. Using repurposed drugs, meaning existing or available medication used for new pharmacological or therapeutic indications, has several benefits. A comprehensive knowledge on their pharmacology, dose, possible toxicity, formulation and side effects is available. It reduces the time and cost of development and cost for the patients are significantly lower due to expiration of the patent and availability of generic drugs. 12
During this clinical research fellowship, I will dive into the scientific literature to determine whether the currently used treatment options for MS patients have an (indirect) effect on remyelination and compare different treatment options.
Secondly, a clinical trial investigating the effect of metformin in comparison to a placebo in patients with progressive MS will be set up. The study will be conducted in five different healthcare centers in Flanders. Patients will be followed during the clinical trial with regular clinical examination, measuring of walking speed, fine locomotion and information processing speed. Brain imaging by different MRI measurements will be used as a surrogate outcome to assess remyelination and neuroprotection. Additionally the reported quality of life of the patients and caregiver strain will be studied through questionnaires.
Depending on the outcome of the study, the way patients with progressive MS are treated in clinical care may change.
* All the references are available on request from the Belgian Charcot Foundation.