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

The Hospital for Sick Children

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Multiple Sclerosis (MS)

Treatments: Other: Placebo; Drug: Metformin

Study type: Interventional

Funder types: Other

Identifiers

NCT04121468

1000059119

Details and patient eligibility

About

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.

Enrollment: 30 estimated patients

Sex: All

Ages: 10 to 25 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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30 participants in 3 patient groups

Group A

Other group

Description:

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.

Treatment:

Other: Placebo

Drug: Metformin

Group B

Other group

Description:

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.

Treatment:

Other: Placebo

Drug: Metformin

Group C

Other group

Description:

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.

Treatment:

Other: Placebo

Drug: Metformin