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

Study Overview
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Brief Summary
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A randomized multiple baseline feasibility trial where participants will start taking metformin at one of 3 randomly determined points (3-months, 6-months or 9 months) during the 12-month trial. All subjects will be on a daily dose of metformin for a minimum of 3 months and a maximum of 9 months.

Official Title
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A Phase I Double Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children With Multiple Sclerosis

Conditions
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Multiple Sclerosis (MS)

Intervention / Treatment
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* Drug: Metformin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 Retinal Nerve Fiber Layer (RNFL) Thickness on baseline OCT ≥60 µm Stable immunomodulatory therapy - no switch or planned switch in > 6 months and no change in doses in 30 days prior to screening 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 (male)=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) Severe refractive error (± 6 diopters) 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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multiple baseline
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A<br>Placebo for 3 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. Metformin for 9 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. | Drug: Metformin<br>* Each tablet contains 500mg of metformin hydrochloride<br>* Other names: Glucophage;Other: Placebo<br>* Each tablet contains no active drug ingredient<br>|
| Other: Group B<br>Placebo for 6 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. Metformin for 6 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. | Drug: Metformin<br>* Each tablet contains 500mg of metformin hydrochloride<br>* Other names: Glucophage;Other: Placebo<br>* Each tablet contains no active drug ingredient<br>|
| Other: Group C<br>Placebo for 9 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. Metformin for 3 months at dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day. | Drug: Metformin<br>* Each tablet contains 500mg of metformin hydrochloride<br>* Other names: Glucophage;Other: Placebo<br>* Each tablet contains no active drug ingredient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events (safety and tolerability) |  | 3 years | 
| Number of patients who were approached to participate, declined participation and consented to participate (recruitment) |  | 3 years | 
| Proportion of patients who completed each visit within the trial (retention) |  | 3 years | 
| Proportion of patients who completed each of the outcome measures at the appropriate time points (adherence with outcome measures) |  | 3 years | 
| Number of patients enrolled in the study compared to the number of patients who were able to complete study measures (tolerability with outcome measures) |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optical Coherence Tomography (OCT) - Retinal Nerve Fiber Layer Thickness |  | 3 years | 
| Optical Coherence Tomography (OCT) - Ganglion Cell Inner Plexiform Layer Thickness |  | 3 years | 
| Optical Coherence Tomography (OCT) - Optic Nerve Head Volume |  | 3 years | 
| Visual Evoked Potentials (VEP) - p100 |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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remyelination, youth, white matter, neural precursor cells, clinical trial, metformin