Metformin Treatment in Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of metformin for treatment of progressive multiple sclerosis

Detailed Description
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This will be a single site 1:1 randomized, placebo controlled trial of metformin treatment vs matching placebo in 44 men and women with primary progressive multiple sclerosis and secondary multiple sclerosis, without diabetes, not treated with metformin aged 30-65. The trial will last 12 months and have 3 study visits, baseline, 6 months, and 12 months. The trial will be preceded by a screening period. Over the initial 30 day titration period subjects will be titrated from 500 mg a day to 2,000 mg of metformin in increments of 500 mg every 10 days. Patients will remain on their tolerated dose and included in analysis on an intent to treat basis. Brain MRI, cognitive testing and clinical measures will be collected at baseline, month 6 and month 12. OCT will be collected at baseline and month 12. The primary outcomes are the following safety outcomes: 1) number of patients with adverse events 2) number of patients with laboratory abnormalities 3) number of patients with new T2 lesions on MRI. The secondary outcomes include reduction in localized cortical thinning on brain MRI; reduction in thalamic atrophy on brain MRI. Further exploratory outcomes include 1) improvement in SDMT-oral score, 2) improvement in CVLT-II score, 3) improvement in PACC score 4) improvement in PASAT score. Exploratory outcomes include 1) Decrease in plasma neurofilament light chain levels, 2) Reginal nerve fiber layer preservation on OCT, 3) Ganglion cell inner plexiform layer preservation, and 4) Percentage of phase rim lesions.

Official Title
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A Double-blind, Placebo Controlled Trial of Metformin Treatment in Progressive Multiple Sclerosis

Conditions
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Secondary Progressive Multiple Sclerosis, Primary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: Metformin 500 Mg Oral Tablet, up to 4 tablets a day
* Drug: Placebo oral tablet identical to metformin, up to 4 tablets a day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient signed informed consent. Age 30-65 Primary Progressive Multiple Sclerosis or Secondary Progressive Multiple Sclerosis as defined by the 2017 McDonald Criteria Intent to maintain current MS disease modifying treatment through the trial duration Exclusion Criteria: Clinical relapse in prior 12 months New T2 lesion or gadolinium enhancing lesion in prior 12 months Glucocorticoid use in prior six months outside the context of premedication for disease modifying treatment Changes in disease modifying therapy in prior three months Plans to change current disease modifying therapy Contraindication to MRI, inability to tolerate MRI Use of metformin for any other indication Renal dysfunction (GFR < 60) Hepatic dysfunction (AST or ALT > 1.5 x upper limit of normal) B12 deficiency Prior poor reaction to metformin Congestive heart failure Alcohol abuse Metabolic acidosis Females who are pregnant or who plan to become pregnant during the 12 months of enrollment, or who wish to breastfeed during any part of the 12 months of enrollment Concomitant use of drugs with drug-drug interactions with metformin Previous adverse effect with metformin treatment

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin Treatment<br>Metformin 500 mg tablets up to 2,000 mg (4 tablets) a day divided into two doses. Patients will start on 500 mg Qday and a titration to maximum dose will be attempted during the first 30 day period of the study. | Drug: Metformin 500 Mg Oral Tablet, up to 4 tablets a day<br>* Metformin 500 mg oral tablets to be titrated to 2000 mg/day divided over two doses or maximum tolerated dose<br>|
| Placebo Comparator: Placebo Treatment<br>Placebo tablets identical to metformin 500 mg tablets divided into two doses. Patients will be started on 1 tablet a day and a titration to maximum dose (4 tablets) will be attempted during the first 30 day period of the study. | Drug: Placebo oral tablet identical to metformin, up to 4 tablets a day<br>* Placebo tablets identical to metformin tablets. To be titrated to four tablets divded over two doses or maximum tolerated dose<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 between baseline and conclusion (month 0 and month 12) | number of patients with adverse events comparing the two treatment groups | between month 0 and month 12 | 
| number of patients with laboratory abnormalities between baseline and conclusion (month 0 and month 12) | number of patients with laboratory abnormalities comparing the two treatment groups | between month 0 and month 12 | 
| number of patients with new T2 lesions on MRI from baseline to conclusion (month 0 and month 12) | number of patients with new T2 lesions comparing the two treatment groups | between month 0 and month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| a reduction in localized cortical thinning on brain MRI between baseline and conclusion (month 0 and month 12) | a reduction in localized cortical thinning on brain MRI comparing the two treatment groups | between month 0 and month 12 | 
| a reduction in thalamic atrophy on brain MRI between baseline and conclusion (month 0 and month 12) | a reduction in thalamic atrophy on brain MRI comparing the two treatment groups | between month 0 and month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple sclerosis, Demyelinating disease