A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
Primary Purpose
PreDiabetes, Aging
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Metformin
Placebo Oral Tablet
Sponsored by
About this trial
This is an interventional treatment trial for PreDiabetes focused on measuring Autophagy
Eligibility Criteria
Inclusion Criteria:
- Adults with prediabetes (defined as an A1c of 5.7-6.4%)
- BMI between 27 and 40 kg/m2 (inclusive).
Exclusion Criteria:
- Prior treatment with metformin or other diabetes medications,
- Pregnancy,
- Significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for women, > 1.4 mg/dl for men),
- Severe hepatic dysfunction (aspartate amnotransferease [AST] or alanine aminotransferase [ALT] > 3 times the upper limit of normal),
- Ongoing alcohol or substance abuse,
- Inflammatory bowel disease,
- Ongoing glucocorticoid therapy,
- Or inability to render informed consent.
Sites / Locations
- University of New Mexico Clincal & Translational Science Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Metformin
Placebo Oral Tablet
Arm Description
Metformin started at 500 mg po twice daily (BID), and then titrated up to 1000 mg po q morning (AM) and 500 po q evening (PM) over the course of 1 month, as tolerated.
Near-identical CaCO3 as a Placebo Oral Tablet will be started at 648 mg po BID, and then titrated up to 1296 mg po q AM and 648 mg po q PM over the course of 1 month, as tolerated.
Outcomes
Primary Outcome Measures
Change in Leucocyte LC3 Score
During the process of autophagy, autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or "dots") per cell detected by fluorescence microscopy. An increase in LC3 puncta formation denotes an increase in autophagic activity.
Secondary Outcome Measures
Full Information
NCT ID
NCT03309007
First Posted
July 7, 2017
Last Updated
February 25, 2022
Sponsor
University of New Mexico
1. Study Identification
Unique Protocol Identification Number
NCT03309007
Brief Title
A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
Official Title
A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
Study Type
Interventional
2. Study Status
Record Verification Date
April 2019
Overall Recruitment Status
Completed
Study Start Date
September 1, 2017 (Actual)
Primary Completion Date
August 20, 2020 (Actual)
Study Completion Date
August 20, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of New Mexico
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The goal of this pilot and feasibility study is to investigate the effects of a short course of metformin therapy on a surrogate marker of cellular senescence and autophagy among adult patients with prediabetes. The overall hypothesis is that metformin will have beneficial effects on longevity and quality of life by inducing autophagy downstream of activating adenosine monophosphate-activated protein kinase (AMPK) and inhibiting mechanistic target of rapamycin (mTOR) through potential effects of reduced inflammation, reduced degeneration of muscle and tendon tissue, antineoplastic effects, reduced obesity and hyperglycemia, preserved cardiovascular functions, and/or the prevention of neurodegeneration (such as age-associated dementia). This pilot study will address the following aim:
Demonstrate that metformin therapy will increase cellular autophagy as an inverse correlate of aging as measured by increases in Microtubule-associated protein 1A/1B-light chain 3 (LC3) scores.
Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy and aging.
Primary outcome: Increased levels of LC3 in leukocytes.
Detailed Description
Anti-aging medicine is a burgeoning field. Accumulating evidence implicates the cellular process of autophagy as a primary mechanism of normal aging and the diseases associated with it. Autophagy is a process of "cellular recycling" and is known to affect a spectrum of health and disease states associated with aging, including inflammatory disorders, metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer, and neurodegeneration. The dynamics of autophagy are controlled by autophagy-related genes and by one of the central regulators of metabolism, AMPK (the target of metformin). Autophagy also affects stem cells and cellular senescence. When the process of autophagy fails, the result is a state of chronic inflammation and degeneration in many organ systems.
Numerous studies have documented the metabolic benefits conferred by the glucose lowering agent metformin. In animal models, metformin has been shown to increase both lifespan and health-span, and a clinical trial (NCT02432287) is currently ongoing to determine whether this effect translates to humans, with additional investigation into how the medication alters the adult human transcriptome. In vitro studies demonstrate metformin's ability to mitigate aging- and disease-related inflammation, oxidative damage, and diminished autophagy. Additionally, there are numerous cohort, case-control and meta-analysis studies confirming metformin's reduction in cancer-related death via hypothesized activity in the relevant mTOR, human epidermal growth factor receptor 2 (HER2), micro-Ribosomal Nucleic Acid (miRNA) and transcription growth factor alpha (TGF-alpha) pathways and processes. As such, the National Institutes of Health (NIH) has issued an Funding Opportunity Announcement (FOA) parent announcement PA-17-073 (https://grants.nih.gov/grants/guide/pa-files/PA-17-073.html) to solicit additional clinical studies that will evaluate metformin's effects on aging and age-related conditions.
The long term goal of this study is to develop a Phase III study in response to this FOA using leucocyte LC3, transcription factor EB (TFEB) scores, total DNA methylation and galectin-3 to gauge the magnitude of metformin's effects on autophagy and cellular senescence as proxies for aging in adults with prediabetes. This study will provide preliminary data for such a proposal, and it will fill a knowledge gap regarding the use of validated biomarkers in this arena. It will also contribute significantly to the anti-aging literature. The primary objective of this proposal is to validate the autophagy-related experimental design by using leucocyte LC3 as a marker of autophagy and cellular senescence in humans.
Aim: Demonstrate that metformin therapy will increase cellular autophagy as an inverse correlate of aging as measured by increases in LC3 scores.
Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy and aging.
Primary outcome: Increased levels of LC3.
FUTURE DIRECTIONS Confirmation of improvement in markers of autophagy resulting from treatment with metformin will justify the submission of grant proposals for more definitive clinical trials examining the effect of metformin on actual clinical outcomes (as opposed to surrogate measures) in pursuit of a potential Food and Drug Administration (FDA) indication for metformin as an anti-aging therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
PreDiabetes, Aging
Keywords
Autophagy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This is a double-blind, approximate placebo-controlled trial of 12 weeks of metformin vs. CaCO3 (Placebo) among adult patients with prediabetes.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Only the study research pharmacy will have access to the randomization list.
Allocation
Randomized
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metformin
Arm Type
Experimental
Arm Description
Metformin started at 500 mg po twice daily (BID), and then titrated up to 1000 mg po q morning (AM) and 500 po q evening (PM) over the course of 1 month, as tolerated.
Arm Title
Placebo Oral Tablet
Arm Type
Placebo Comparator
Arm Description
Near-identical CaCO3 as a Placebo Oral Tablet will be started at 648 mg po BID, and then titrated up to 1296 mg po q AM and 648 mg po q PM over the course of 1 month, as tolerated.
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Intervention Description
Total daily dose titrated up to 1500 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Other Intervention Name(s)
Calcium Carbonate
Intervention Description
Total daily dose titrated up to 1944 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.
Primary Outcome Measure Information:
Title
Change in Leucocyte LC3 Score
Description
During the process of autophagy, autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or "dots") per cell detected by fluorescence microscopy. An increase in LC3 puncta formation denotes an increase in autophagic activity.
Time Frame
Data will be collected at 0, 4 and 12 weeks and analyzed within 8 weeks of sample collection.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults with prediabetes (defined as an A1c of 5.7-6.4%)
BMI between 27 and 40 kg/m2 (inclusive).
Exclusion Criteria:
Prior treatment with metformin or other diabetes medications,
Pregnancy,
Significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for women, > 1.4 mg/dl for men),
Severe hepatic dysfunction (aspartate amnotransferease [AST] or alanine aminotransferase [ALT] > 3 times the upper limit of normal),
Ongoing alcohol or substance abuse,
Inflammatory bowel disease,
Ongoing glucocorticoid therapy,
Or inability to render informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark R Burge, MD
Organizational Affiliation
Professor Medicine, UNM HSC Endocrinology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of New Mexico Clincal & Translational Science Center
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
De-identified data will be made available for data sharing as is consistent with current NIH guidelines.
IPD Sharing Time Frame
After the study is completed and published. The data should be available in perpetuity in the University of New Mexico (UNM) Digital Repository.
IPD Sharing Access Criteria
No restrictions.
IPD Sharing URL
http://digitalrepository.unm.edu/
Learn more about this trial
A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
We'll reach out to this number within 24 hrs