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difficult recruitment and not achieved
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This study will test whether chronic metformin administration will improve longevity of the cell, improves its machinery by reducing aging-related biochemical parameters and thereby improving physical performance, as measured by short physical performance battery test.
Heart disease is the number one cause of death in the United States and disproportionately affects older adults, underscoring the need to examine determinants of survivorship. Recognizing this gap, current guidelines lay emphasis to assess frailty, a key construct prevalent in elderly and known to impact their prognosis.Older persons are commonly frail, manifest hyperglycemia and their health span is truncated by illnesses during which physiological declines together with accumulation of additional deficits results in multimorbidity and functional dependence. High incidence of functional decline and stress hyperglycemia in patients with coronary artery disease (CAD) makes pharmacologic manipulation, an attractive strategy to improve frailty and reduce adverse cardiovascular outcomes. Metformin exerts its effect on health span as a calorie restriction-mimetic through inhibition of mitochondrial complex 1 and activation of activated protein kinase (AMP).This drug is safe and has been shown to prolong life in mammals. Metformin by reducing effects of cellular senescence and improving glycemic control may improve the functioning of older adults.
In CAD, cellular senescence and inflammation affect organ dysfunction through interference with tissue homeostasis and regeneration. The deleterious effect of senescence includes pro-inflammatory senescence-associated secretory phenotype (SASP). Normal biological function through alteration in cellular homeostasis and restoration of glycemic control may be achieved by metformin. The phenotypic manifestations of these changes are incompletely characterized as it is yet unknown whether cell-intrinsic regenerative mechanisms can be translated into clinical improvement in physical performance and whether it's chronic administration is safe in older adults. These major gaps in knowledge hinder utilization of metformin as an agent to promote cellular regeneration and to reduce the impact of cellular senescence.
Targeting frail individuals with high levels of inflammation and SASP factors would necessitate identification of predictors of improvement with metformin in tissue inflammation and function. A clinomics approach implementing simultaneous assessment of clinical impact coupled with serological profiling would provide enhanced understanding of the local and systemic impact mediated by metformin. Through correlation of molecular profiles with phenotypic expression changes, as proposed herein, investigators will enhance understanding of the regenerative impact of metformin and the basis for clinical improvement in the setting of senescence.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | Metformin 500mg tablet by mouth, every 6 to 8 hours for one year |
|
| Placebo | Active Comparator | Placebo by mouth every 6 to 8 hours for one year |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | Oral metformin (up to 2gm) will be given in divided doses |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Frailty | Frailty will be measured by the Short Physical Performance Battery (SPPB). The short physical performance battery (SPPB) is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older people. The scores range from 0 (worst performance) to 12 (best performance). Frailty is defined as a score of <9. | Baseline, 12 months |
| Change in Balance Score Standing With Feet Close Together | This measure is part of the SPPB. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Baseline, 12 months |
| Change in Balance Score Standing in Semi Tandem Position | This measure is part of the SPPB. The semi tandem position is the heel of one foot place by the big toe of the other foot. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Baseline, 12 months |
| Change in Balance Score Standing in Full Tandem Position | This measure is part of the SPPB. The full tandem position is with the feet directly in front of each other. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Baseline, 12 months |
| Change in Gait Speed | This measure is part of the SPPB. Subjects will be asked to walk 8 feet or 2.44 meters at their usual pace. They will be allowed to use a cane or other walking aid if it is their custom. Scores range from 0 = could not do to 4 =<3.1 seconds. | Baseline, 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Interleukin 6 (pg/ml) | Serum will be collected to measure the effect of metformin on senescent markers. | Baseline, 12 months |
| Change in Matrix Metalloproteinase (ng/ml) | Serum will be collected to measure the effect of metformin on senescent markers. |
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Inclusion Criteria:
Age ≥ 60 years
Stable CAD
Prediabetes (one of the following criteria should be met)
Frailty (Short Physical Performance Battery: Score <9)
Able to return for follow-up
Written informed consent
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mandeep Singh | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Rochester | Minnesota | 55905 | United States |
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| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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No plan to do that
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin | Metformin 500mg tablet by mouth, every 6 to 8 hours for one year Metformin: Oral metformin (up to 2gm) were given in divided doses |
| FG001 | Placebo | Placebo by mouth every 6 to 8 hours for one year Placebo: Oral Placebo were given in divided doses |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Metformin | Metformin 500mg tablet by mouth, every 6 to 8 hours for one year Metformin: Oral metformin (up to 2gm) were given in divided doses |
| BG001 | Placebo | Placebo by mouth every 6 to 8 hours for one year Placebo: Oral Placebo were given in divided doses |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Frailty | Frailty will be measured by the Short Physical Performance Battery (SPPB). The short physical performance battery (SPPB) is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older people. The scores range from 0 (worst performance) to 12 (best performance). Frailty is defined as a score of <9. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
Adverse Events were collected from baseline to end of study, approximately 12 weeks
Study was terminated due to recruitment being difficult and not achieved.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Metformin | Metformin 500mg tablet by mouth, every 6 to 8 hours for one year Metformin: Oral metformin (up to 2gm) were given in divided doses |
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Study was terminated due to recruitment being difficult and not achieved.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mandeep Singh, M.D. | Mayo Clinic | 507-255-2398 | Singh.Mandeep@mayo.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 5, 2020 | Oct 17, 2022 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D007249 | Inflammation |
| D000073496 | Frailty |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Arms Assigned interventions Placebo Comparator: Metformin Chronic metformin administration through augmentation of cellular regeneration and reduction of senescence will improve frailty and physical functioning as studied by the short physical performance battery (SPPB) test. Drug: Metformin versus placebo This will be a pilot, feasibility study. Twelve subjects ≥60 years with stable CAD and prediabetes, who score <9 on SPPB test will be randomized to receive up to 2gm of oral metformin or placebo for 12 months.
Placebo comparator: Placebo Placebo will be compared to chronic metformin administration Drug: Metformin versus placebo This will be a pilot, feasibility study. Twelve subjects ≥60 years with stable CAD and prediabetes, who score <9 on SPPB test will be randomized to receive up to 2gm of oral metformin or placebo for 12 months.
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| Placebo |
| Drug |
Oral Placebo will be given in divided doses |
|
| Change in Score, Standing Test From Chair | This measure is part of the SPPB. Subjects will be asked to try to stand up from a chair 5 times with arms folded across their chest, and will be timed. Scores range from 0 to 4, with 0 = unable to stand without using arms, and 4 = completing 5 stands in <11.1 seconds. | Baseline,12 months |
| Baseline, 12 months |
| Change in Plasminogen Activator Inhibitor | Serum will be collected to measure the effect of metformin on senescent markers. | Baseline, 12 months |
| Change in Monocyte Chemotactic Protein-1 | Serum will be collected to measure the effect of metformin on senescent markers. | Baseline, 12 months |
| Change in Activin | Serum will be collected to measure the effect of metformin on senescent markers. | Baseline, 12 months |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Placebo |
Placebo by mouth every 6 to 8 hours for one year Placebo: Oral Placebo were given in divided doses |
|
| Primary | Change in Balance Score Standing With Feet Close Together | This measure is part of the SPPB. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Primary | Change in Balance Score Standing in Semi Tandem Position | This measure is part of the SPPB. The semi tandem position is the heel of one foot place by the big toe of the other foot. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Primary | Change in Balance Score Standing in Full Tandem Position | This measure is part of the SPPB. The full tandem position is with the feet directly in front of each other. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Primary | Change in Gait Speed | This measure is part of the SPPB. Subjects will be asked to walk 8 feet or 2.44 meters at their usual pace. They will be allowed to use a cane or other walking aid if it is their custom. Scores range from 0 = could not do to 4 =<3.1 seconds. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Primary | Change in Score, Standing Test From Chair | This measure is part of the SPPB. Subjects will be asked to try to stand up from a chair 5 times with arms folded across their chest, and will be timed. Scores range from 0 to 4, with 0 = unable to stand without using arms, and 4 = completing 5 stands in <11.1 seconds. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline,12 months |
|
|
| Secondary | Change in Interleukin 6 (pg/ml) | Serum will be collected to measure the effect of metformin on senescent markers. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Secondary | Change in Matrix Metalloproteinase (ng/ml) | Serum will be collected to measure the effect of metformin on senescent markers. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Secondary | Change in Plasminogen Activator Inhibitor | Serum will be collected to measure the effect of metformin on senescent markers. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Secondary | Change in Monocyte Chemotactic Protein-1 | Serum will be collected to measure the effect of metformin on senescent markers. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| Secondary | Change in Activin | Serum will be collected to measure the effect of metformin on senescent markers. | Study was terminated due to recruitment being difficult and not achieved. Data was not collected nor analyzed. | Posted | Baseline, 12 months |
|
|
| 0 |
| 4 |
| 0 |
| 4 |
| 0 |
| 4 |
| EG001 | Placebo | Placebo by mouth every 6 to 8 hours for one year Placebo: Oral Placebo were given in divided doses | 0 | 3 | 0 | 3 | 0 | 3 |
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