Metformin Treatment in Progressive Multiple Sclerosis

• ClinicalTrials.gov Identifier: NCT05349474
• Recruitment Status: Recruiting
• First Posted: April 27, 2022
• Last Update Posted: May 6, 2022
• Sponsor: University of California, Los Angeles
• Information provided by (Responsible Party): Kevin Patel, University of California, Los Angeles

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis	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	Early Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo Controlled Trial of Metformin Treatment in Progressive Multiple Sclerosis
• Estimated Study Start Date: April 26, 2022
• Estimated Primary Completion Date: May 26, 2024
• Estimated Study Completion Date: May 26, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin Treatment; 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; Metformin 500 mg oral tablets to be titrated to 2000 mg/day divided over two doses or maximum tolerated dose
Placebo Comparator: Placebo Treatment; 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; Placebo tablets identical to metformin tablets. To be titrated to four tablets divded over two doses or maximum tolerated dose

Outcome Measures

Primary Outcome Measures :

1. number of patients with adverse events between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   number of patients with adverse events comparing the two treatment groups
2. number of patients with laboratory abnormalities between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   number of patients with laboratory abnormalities comparing the two treatment groups
3. number of patients with new T2 lesions on MRI from baseline to conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   number of patients with new T2 lesions comparing the two treatment groups

Secondary Outcome Measures :

1. a reduction in localized cortical thinning on brain MRI between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   a reduction in localized cortical thinning on brain MRI comparing the two treatment groups
2. a reduction in thalamic atrophy on brain MRI between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   a reduction in thalamic atrophy on brain MRI comparing the two treatment groups

Other Outcome Measures:

1. improvement in SDMT-oral score between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   improvement in SDMT-oral score between comparing the two treatment groups
2. improvement in CVLT-II score between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   improvement in CVLT-II score between comparing the two treatment groups
3. improvement in PACC score between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   improvement in PACC score between comparing the two treatment groups
4. improvement in PASAT score between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   improvement in PASAT score between comparing the two treatment groups
5. decrease in plasma neurofilament light chain levels between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   decrease in plasma neurofilament light chain levels comparing the two treatment groups
6. preservation of retinal nerve fiber layer density between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   preservation of retinal nerve fiber layer density comparing the two treatment groups
7. preservation of ganglion cell inner plexiform layer density between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   preservation of ganglion cell inner plexiform layer density comparing the two treatment groups
8. decrease in number of phase rimmed lesions between baseline and conclusion (month 0 and month 12) [ Time Frame: between month 0 and month 12 ]
   decrease in number of phase rimmed lesions comparing the two treatment groups

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient signed informed consent.
2. Age 30-65
3. Primary Progressive Multiple Sclerosis or Secondary Progressive Multiple Sclerosis as defined by the 2017 McDonald Criteria
4. Intent to maintain current MS disease modifying treatment through the trial duration

Exclusion Criteria:

1. Clinical relapse in prior 12 months
2. New T2 lesion or gadolinium enhancing lesion in prior 12 months
3. Glucocorticoid use in prior six months outside the context of premedication for disease modifying treatment
4. Changes in disease modifying therapy in prior three months
5. Plans to change current disease modifying therapy
6. Contraindication to MRI, inability to tolerate MRI
7. Use of metformin for any other indication
8. Renal dysfunction (GFR < 60)
9. Hepatic dysfunction (AST or ALT > 1.5 x upper limit of normal)
10. B12 deficiency
11. Prior poor reaction to metformin
12. Congestive heart failure
13. Alcohol abuse
14. Metabolic acidosis
15. 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
16. Concomitant use of drugs with drug-drug interactions with metformin
17. Previous adverse effect with metformin treatment

Contacts and Locations

Contacts

Contact: Kevin R Patel, MD; 310 205 2176; KevinPatel@mednet.ucla.edu

Locations

United States, California

University of California, Los Angeles; Recruiting

Los Angeles, California, United States, 90095

Contact: Michael Montag 310-205-2176 mmontag@mednet.ucla.edu

Sponsors and Collaborators

University of California, Los Angeles

Investigators

• Principal Investigator: Kevin R Patel, MD; University of California, Los Angeles

More Information

• Responsible Party: Kevin Patel, Assistant Professor, Department of Neurology, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT05349474
• Other Study ID Numbers: 22-000020
• First Posted: April 27, 2022
• Last Update Posted: May 6, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kevin Patel, University of California, Los Angeles:

Multiple sclerosis; Demyelinating disease

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs