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| Name | Class |
|---|---|
| University of Alabama at Birmingham | OTHER |
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The purpose of this study is to determine whether a commonly prescribed drug, metformin, can enhance the benefits seen during resistance exercise such as increased muscle mass and strength.
Muscle mass and strength are critical determinants not only of a person's quality of life and functional independence, but also metabolic health, as muscle is the organ primarily responsible for insulin-mediated glucose uptake. The elderly suffer obligatory losses of muscle mass and strength, exacerbated by illness and physical inactivity. Progressive resistance exercise training (PRT) is the most effective intervention identified to improve muscular strength, and combat the muscle atrophy of aging (sarcopenia); however, overall the muscle response to PRT is blunted in the elderly and variability of response increased, with some individuals actually losing muscle mass. The Bamman and Peterson labs have independently been studying the molecular and cellular mechanisms underlying the "non-responder" phenotype, with the goal of identifying novel intervention strategies to promote mass and strength gains to improve function. We hypothesize that the abundance of anti-inflammatory, alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further, we determined that metformin treatment increased M2 macrophage abundance, and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment, thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training. |
|
| Placebo, Sugar Pill | Placebo Comparator | Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Progressive Resistance Training | Behavioral | Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Type 2 Myofiber Cross Sectional Area | The ability of metformin to improve the hypertrophic response to resistance training will be determined. Muscle biopsies of the vastus lateralis will be used to quantify myofiber cross-sectional area. The percent change in type 2 myofiber size between week 16 and week 0 was used. | 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Normal Density Muscle Size by Computed Tomography | The ability of metformin to improve the hypertrophic response at the whole muscle level will be quantified by computed tomography. Percent change in normal density muscle area will be calculated as the difference between week 16 and week 0. | 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Muscle Strength | Determine if metformin treatment augments strength gains in conjunction with progressive resistance training by one repetition maximum assessments. Maximum (1RM) leg extension muscle strength was assessed at week 4 (to account for neurological adaptations during the initial stages of the resistance program) and week 16. The percent change from week 4 to week 16 is reported. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Charlotte Peterson, Ph.D. | University of Kentucky | Principal Investigator |
| Philip Kern, M.D. | University of Kentucky | Principal Investigator |
| Marcas Bamman, Ph.D | University of Alabama at Birmingham | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama Birmingham | Birmingham | Alabama | 35294 | United States | ||
| University of Kentucky |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35492586 | Derived | Long DE, Kosmac K, Dungan CM, Bamman MM, Peterson CA, Kern PA. Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals. Front Physiol. 2022 Apr 14;13:872745. doi: 10.3389/fphys.2022.872745. eCollection 2022. | |
| 33462708 | Derived | Long DE, Peck BD, Tuggle SC, Villasante Tezanos AG, Windham ST, Bamman MM, Kern PA, Peterson CA, Walton RG. Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin. Geroscience. 2021 Apr;43(2):629-644. doi: 10.1007/s11357-020-00315-9. Epub 2021 Jan 18. |
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Participants may have been excluded prior to randomization to study drug for the following reasons:
Number of individuals consented and further screened for eligibility = 144 Number of participants randomized to drug/placebo = 109 Number of participants completing exercise intervention with drug/placebo use = 94
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin | Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. Metformin: Participants will be randomized to receive metformin in conjunction with their strength training program. |
| FG001 | Placebo, Sugar Pill | Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Metformin | Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. Metformin: Participants will be randomized to receive metformin in conjunction with their strength training program. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Percent Change in Type 2 Myofiber Cross Sectional Area | The ability of metformin to improve the hypertrophic response to resistance training will be determined. Muscle biopsies of the vastus lateralis will be used to quantify myofiber cross-sectional area. The percent change in type 2 myofiber size between week 16 and week 0 was used. | The largest, highest quality pairs of baseline and week 16 mounts were used for quantification of immunohistochemistry (N=30/group) | Posted | Mean | Standard Deviation | Percent change | 16 weeks |
|
Adverse events are reported from the time the subjects sign the consent form until the completion of the study which includes baseline, medication ramp, exercise intervention, and follow up assessments. The total duration of the study for each subject is approximately 1 year.
AEs are reported in real time by close research coordinator and participant interaction. They are graded according to intensity and causality and reported to the IRB in the appropriate amount of time. AEs were grouped according to body system such as musculoskeletal or gastrointestinal and reported together.
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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 | Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. Metformin: Participants will be randomized to receive metformin in conjunction with their strength training program. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea, Diarrhea, Flatulence | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Douglas Long | University of Kentucky | 859-323-5438 | DELONG2@UKY.EDU |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 16, 2018 | Jun 6, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Feb 17, 2014 | Jul 17, 2019 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D006984 | Hypertrophy |
| ID | Term |
|---|---|
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D055070 | Resistance Training |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D005081 | Exercise Therapy |
| D012046 | Rehabilitation |
| D000359 | Aftercare |
| D003266 | Continuity of Patient Care |
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|
| Metformin | Drug | Participants will be randomized to receive metformin in conjunction with their strength training program. |
|
|
| Week 4 and week 16 |
| Percent Change in Total Body Lean Mass by DXA | To determine if metformin improves changes in body composition associated with progressive resistance training. Percent change in total body lean mass in kg was calculated as the difference between week 16 and week 0 from a total body DXA scan. | 16 weeks |
| Insulin Sensitivity | A standard OGTT will be used to determine insulin sensitivity using the Matsuda Index. | 16 weeks |
| Lexington |
| Kentucky |
| 40536 |
| United States |
| 31557380 | Derived | Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, Bush HM, Villasante Tezanos AG, McGwin G, Windham ST, Ovalle F, Bamman MM, Kern PA, Peterson CA. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019 Dec;18(6):e13039. doi: 10.1111/acel.13039. Epub 2019 Sep 26. |
| 30730923 | Derived | Long DE, Villasante Tezanos AG, Wise JN, Kern PA, Bamman MM, Peterson CA, Dennis RA. A guide for using NIH Image J for single slice cross-sectional area and composition analysis of the thigh from computed tomography. PLoS One. 2019 Feb 7;14(2):e0211629. doi: 10.1371/journal.pone.0211629. eCollection 2019. |
| 28441958 | Derived | Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, Kern PA, Bamman MM, Peterson CA. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017 Apr 26;18(1):192. doi: 10.1186/s13063-017-1932-5. |
| BG001 | Placebo, Sugar Pill | Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Data analyzed for those who completed the interventions = 94 | Mean | Inter-Quartile Range | years |
|
| Sex: Female, Male | Data analyzed for those who completed the interventions = 94 | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Data analyzed for those who completed the interventions = 94 | Count of Participants | Participants |
|
| Race (NIH/OMB) | Data analyzed for those who completed the interventions = 94 | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI | Data analyzed for those who completed the interventions = 94 | Mean | Standard Deviation | kg/m^2 |
|
| Short Physical Performance Battery (SPPB) | A physical performance measure based on balance, gait speed, and sit to stand. Total scores are provided as the sum of three subscales; 0-12 total range, 4-12 was required to be included in the study. Balance = 0-4 subscale Gait Speed = 0-4 subscale Sit to stand time = 0-4 subscale Higher scores = better overall performance | Data analyzed for those who completed the interventions = 94 | Mean | Inter-Quartile Range | Scores on a Scale |
|
| Physical Activity Survey for the Elderly (PASE) | Self Reported Physical Activity Score Median and inter-quartile ranges of the total activity score are reported. Total activity score is a sum of various domains including activity reported at home, during sports, housework, caring for other people, and work. The scale range is 0-793; higher scores indicate higher self-reported activity. | Data analyzed for those who completed the interventions = 94 | Median | Inter-Quartile Range | Scores on a Scale |
|
| Short Form-36 Physical Component (SF-36) | Physical Function Component Norm Based Score Median and inter-quartile ranges of the physical function norm based score are reported as there is not a reported maximum. Questions related to physical function are scored 0-100. Physical function score = the average score of physical function questions. A z-score is calculated from the physical function score. The physical function norm based score is calculated from the physical function z-score. Scores above 50 would represent above average physical function where scores below 50 represent below average function. | Data analyzed for those who completed the interventions = 94 | Median | Inter-Quartile Range | Scores on a Scale |
|
| Short Form-36 Mental Component (SF-36) | Mental Component Norm Based Score Median and inter-quartile ranges of the mental health norm based score are reported as there is not a reported maximum. Questions related to mental health are scored 0-100. Mental Health score = the average score of mental health questions. A z-score is calculated from the mental health score. The mental component norm based score is calculated from the mental health z-score. Scores above 50 would represent above average mental health where scores below 50 represent below average mental health. | Data analyzed for those who completed the interventions = 94 | Median | Inter-Quartile Range | Scores on a Scale |
|
| OG001 | Placebo, Sugar Pill | Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. |
|
|
| Secondary | Percent Change in Normal Density Muscle Size by Computed Tomography | The ability of metformin to improve the hypertrophic response at the whole muscle level will be quantified by computed tomography. Percent change in normal density muscle area will be calculated as the difference between week 16 and week 0. | Missing data points include those who, based on femur area, CT positioning at post measure was incorrect = 16. In addition, 1 subject was excluded from analysis as CT data indicated 45% loss of thigh muscle area, which was not consistent with other data for this subject. | Posted | Mean | Standard Deviation | Percent change | 16 weeks |
|
|
|
| Other Pre-specified | Percent Change in Muscle Strength | Determine if metformin treatment augments strength gains in conjunction with progressive resistance training by one repetition maximum assessments. Maximum (1RM) leg extension muscle strength was assessed at week 4 (to account for neurological adaptations during the initial stages of the resistance program) and week 16. The percent change from week 4 to week 16 is reported. | Some participants were not able to complete the procedure on the day of testing, injured etc | Posted | Mean | Standard Deviation | Percent change | Week 4 and week 16 |
|
|
|
| Other Pre-specified | Percent Change in Total Body Lean Mass by DXA | To determine if metformin improves changes in body composition associated with progressive resistance training. Percent change in total body lean mass in kg was calculated as the difference between week 16 and week 0 from a total body DXA scan. | Analysis of lean muscle mass for those who completed the interventions. | Posted | Mean | Standard Deviation | Percent change | 16 weeks |
|
|
|
| Other Pre-specified | Insulin Sensitivity | A standard OGTT will be used to determine insulin sensitivity using the Matsuda Index. | Not Posted | 16 weeks | Participants |
| 0 |
| 54 |
| 0 |
| 54 |
| 17 |
| 54 |
| EG001 | Placebo, Sugar Pill | Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication. Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. | 0 | 55 | 0 | 55 | 6 | 55 |
| Musculoskeletal Pain or Injury | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
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| D005791 |
| Patient Care |
| D013812 | Therapeutics |
| D026741 | Physical Therapy Modalities |
| D064797 | Physical Conditioning, Human |
| D015444 | Exercise |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|