Metformin to activate neural progenitor cells in children and young adults with MS

A Phase I Double Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children and Young Adults With Multiple Sclerosis

This trial will try giving metformin or placebo to children and young adults with MS to see if metformin helps the brain cells that repair myelin.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 10 Years to 25 Years
• Sex: All
• Sponsor: The Hospital for Sick Children (Academic / other)
• Locations: 1 site (Toronto, Ontario)
• Trial ID: NCT04121468 on ClinicalTrials.gov

What this trial studies

This is a double-blind, randomized multiple-baseline feasibility trial in participants aged 10 to 25 that staggers the start of daily metformin (or placebo) at one of three randomized timepoints over a 12-month follow-up. Each participant will receive metformin for at least 3 months and up to 9 months, with clinical and eye-based measures (like visual evoked potentials and OCT RNFL thickness) used to track change. The design focuses on safety, tolerability, and signals of remyelination in the anterior visual pathway in youth with prior optic pathway involvement. The trial is Phase I/II and conducted at a single pediatric center with external academic collaborators.

Who should consider this trial

Good fit: Ideal candidates are people aged 10 to 25 years 11 months with MS and prior anterior visual pathway involvement (optic neuritis or an acute demyelinating event >6 months prior), with electrophysiological or OCT evidence of demyelination (VEP latency delay or RNFL thinning ≥10 µm inter-eye difference or RNFL <90 µm) but RNFL ≥60 µm, EDSS 0–6.0, stable disease-modifying therapy for 6 months if applicable, and no significant renal or liver abnormalities with sufficient English comprehension for testing.

Not a fit: People with advanced disability (EDSS >6), very thin RNFL below the required threshold (<60 µm), recent relapses or recent changes in MS therapy, or significant renal or liver impairment are unlikely to qualify and therefore would not be expected to benefit from this trial.

Why it matters

Potential benefit: If successful, metformin could help stimulate remyelination and lead to measurable improvements in visual nerve measures and potentially clinical function in young people with MS.

How similar studies have performed: Preclinical studies in animals show metformin can boost neural precursor activity and promote remyelination, but clinical evidence for this approach in MS is very limited so human efficacy remains unproven.

Eligibility criteria

Inclusion Criteria:

* Patients with a history of MS with anterior visual pathway involvement and longer than 6 months after presentation with ON or an acute demyelinating event/relapse
* Age 10 year to 25 years and 11 months
* Latency delay \> 115 milliseconds on baseline full-field transient pattern reversal VEP in at least one eye (electrophysiological evidence of demyelination) or \> 10 milliseconds difference between eyes, or Retinal Nerve Fiber Layer (RNFL) thickness on OCT of \< 90 µm in at least one eye or an inter-eye difference in the RNFL of 10 µm or more
* Retinal Nerve Fiber Layer (RNFL) Thickness on baseline OCT ≥60 µm
* If on an MS disease-modifying therapy, no changes in the therapeutic agent or dosing in the 6 months prior to study initiation
* No significant renal or liver abnormalities
* Expanded Disability Status Scale (EDSS) 0-6.0 (inclusive)
* Has either English as his or her native language or English comprehension needed to complete the neuropsychological testing
* Meet criteria for adequate organ function requirements as described below:

Adequate renal function defined as:

Creatinine clearance or radioisotope glomerular filtration rate (GFR) \> 70 mL/min/1.73 m2 or serum creatinine based on age/gender as follows:

Range Serum Creatinine Level (µmol/L): Age 5 to \<12 years (male)=25-50, Age 5 to \<12 years (female)=25-50; Age 12 to \<15 years (male)=37-67, Age 12 to \<15 years (female)=37-67; Age 15 to \<19 years (male)=51-89, Age 15 to \<19 years (female)=40-69; Age ≥19 years (male)=58-110; Age ≥19 years (female)=46-92

Adequate liver function defined as:

Total bilirubin \< 1.5 x upper limit of normal (ULN) for age SGOT (AST) or SGPT (ALT) \< 1.5 x upper limit of normal (ULN) for age

Exclusion Criteria:

* A history of retinal pathology (major ophthalmologic disease / concomitant ophthalmologic disorders)
* Unstable and/or insulin-dependent (Type 1) diabetes, metabolic acidosis and/or lactic acidosis
* History of unexplained hypoglycemia (\<2.8 mmol/L)
* Already on metformin
* Concomitant use of any other putative remyelinating therapy as determined by the Principal/Qualified Investigator
* Treatment for an acute attack with corticosteroids within 30 days prior to screening / relapse within 30 days prior to screening
* Concomitant use of insulin
* Concomitant use of any drugs that are listed to have drug-drug interactions with metformin (i.e. calcium channel blockers, diuretics, etc.) as determined by Principal/Qualified Investigator
* Lactate levels \> 1.5x upper limit of normal
* Pregnancy

Where this trial is running

Toronto, Ontario

• The Hospital for Sick Children — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: E. Ann Yeh, MA, MD, FRCPC, Dip ABPN — The Hospital for Sick Children
• Study coordinator: E. Ann Yeh, MA, MD, FRCPC, Dip ABPN

Conditions Multiple Sclerosis; remyelination; youth; white matter; neural precursor cells; clinical trial; metformin