FrailtyPhase 3DEMFOSNCT04221750
Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors
A Phase 3 study testing Lifestyle therapy, Metformin Hydrochloride and Healthy Lifestyle in people with Frailty and Sarcopenic Obesity, run by VA Office of Research and Development at 1 site in United States.
Trial summary
The continuing increase in prevalence of obesity in older adults including many older Veterans has become a major health concern. The clinical trial will test the central hypothesis that a multicomponent intervention consisting of lifestyle therapy (diet-induced weight loss and exercise training) plus metformin will… Read more about this study
- Who is it for?
- Ages 65 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- Frailty, Sarcopenic Obesity, Aging
- What is being tested?
- Lifestyle therapy, Metformin Hydrochloride and Healthy Lifestyle
- Type of treatment
- Pill or oral medicine, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 114 participants
- Where
- 1 siteUnited States
- Study dates
- 14 May 2021to 31 Jul 2025
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 to 85 years
- All sexes
- Healthy volunteers accepted
- Older adult
Who may be able to join
- Age 65 - 85 years
- BMI = or > 30 kg/m2
- Mild to moderate frailty (score of 18 to 31 in the modified Physical Performance Test)
- Stable body weight (plus/minus 2 kg) during the past 6 months
- Sedentary (regular exercise <1 h/wk or <2 x/wk for the last 6 months)
- Willing to provide informed consent
Who cannot join
- Any major chronic diseases, or any condition that would interfere with exercise or dietary restriction, or use of metformin, in which exercise, dietary restrictions, or metformin are contraindicated, or that would interfere with interpretation of results
- Cardiopulmonary disease (e.g. recent MI, unstable angina, stroke) or unstable disease (e.g., NYHA Class III or IV congestive heart failure, severe pulmonary disease requiring steroid pills or the use of supplemental oxygen) that would contraindicate exercise or dietary restriction
- Severe orthopedic (e.g. awaiting joint replacement) and/or neuromuscular (e.g. multiple sclerosis, active rheumatoid arthritis) disease or impairments that would contraindicate participation in exercise
- Renal impairment as defined by an estimated glomerular filtration rate (eGFR of less than 30 mL/min/1.73 m2) in which metformin is contraindicated
- Other significant co-morbid disease that would impair ability to participate in the exercise intervention (e.g. severe psychiatric disorder [e.g. bipolar, schizophrenia], excess alcohol use [>14 drinks per week])
- Severe visual or hearing impairments that would interfere with following directions
Show all 19Show fewer
- Significant cognitive impairment, defined as a known diagnosis of dementia or positive screening test for dementia using the Mini-Mental State Exam (i.e. MMSE score <24)69
- Uncontrolled hypertension (BP>160/90 mm Hg)
- History of malignancy during the past 5 years (except non-melanoma skin cancers)
- Current use of bone acting drugs (e.g. use of estrogen, or androgen containing compound,raloxifene, calcitonin, parathyroid hormone during the past year or bisphosphonates during the last two years)
- Osteoporosis (T-score -2.5 and below on hip or spine scan) or history of fragility fractures
- Known history of diabetes mellitus or any of the following:
- Fasting blood glucose of 126 mg/dl, or HbA1c of 6.5% or >
- Terminal illness with life expectancy less than 12 months, as determined by a physician
- Use of any drugs or natural products designed to induce weight loss within past three months
- History of excessive alcohol consumption (e.g. 8 or more drinks a week for women and 15 or more drinks a week for men)
- Positive exercise stress test for ischemia or any indication for early termination of exercise stress testing
- Taking metformin or any other glucose lowering drug
- Lives outside of the study site or is planning to move out of the area in the next 2 years
Trial locations and contacts
1 site in 1 country.
United States1 site
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, 77030-4211
About this study
Official title: Lifestyle Intervention Plus Metformin to Treat Frailty in Older Veterans With Obesity
The continuing increase in prevalence of obesity in older adults including many older Veterans has become a major health concern. The clinical trial will test the central hypothesis that a multicomponent intervention consisting of lifestyle therapy (diet-induced weight loss and exercise training) plus metformin will be the most effective strategy for reversing sarcopenic obesity and frailty in older Veterans with obesity.
Read the detailed description
The growing prevalence of obesity in older adults including many older Veterans, has become a major concern in the US already strained health care system in general and in the VA in particular. In older adults, obesity exacerbates the age-related decline in physical function resulting in frailty, decrease in quality of life, loss of independence, and increase in nursing home admissions. The investigators' group demonstrated that weight loss from lifestyle therapy improves physical function and ameliorates frailty but the improvement was modest at best and most obese older adults remained frail. More importantly, there are concerns that the weight-loss induced loss of muscle and bone mass could worsen underlying age-related sarcopenia and osteopenia in the subset of frail obese elderly. Metformin, a biguanide, is a widely available drug used as first line treatment of type 2 diabetes. Animal studies suggest that metformin improves health span and increases lifespan, hence may represent a novel intervention for frailty. Because metformin reduces cellular senescence and senescence-associated phenotype (SASP), it is believed to retard accelerated aging most especially in older adults with obesity. The objective is to conduct a head-head comparative efficacy, placebo controlled, randomized controlled trial to test the hypothesis that lifestyle therapy + metformin for six months will be more effective than lifestyle therapy alone or metformin alone in improving physical function and preventing the weight loss-induced reduction in muscle and bone mass in obese (BMI > 30 kg/m2) older (age 65 - 85 years) Veterans with physical frailty.
- Conditions
- Frailty, Sarcopenic Obesity, Aging
- Being tested
- Lifestyle therapy, Metformin Hydrochloride, Placebo, Healthy Lifestyle
- Medical subject headings
- Frailty
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lifestyle therapyBehavioural
Also called Diet-induced weight loss and exercise training
Weight management program, in which participants are prescribed a balanced diet that provides and energy deficit of 500 to 750 kcal per day to induced ~10% weight loss plus Supervised combined aerobic and resistance exercise training three times weekly
Metformin HydrochlorideDrug
Given orally starting at 500 mg (one tablet) taken orally once a day with meals. After a week, the dose of metformin will be increased to 1000 mg (two tablets) daily. After another week, the dose of metformin will be increased to 1500 mg (three tablets) daily.
PlaceboDrug
Given orally starting at 500 mg (one tablet) taken orally once a day with meals. After a week, the dose of placebo will be increased to 1000 mg (two tablets) daily. After another week, the dose of placebo will be increased to 1500 mg (three tablets) daily.
Healthy LifestyleBehavioural
Group educational sessions that focus on healthy diet, exercise, and social support once a month
| Study group | Role | What they receive |
|---|---|---|
| Lifestyle Therapy plus Metformin | Experimental | Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily Receives: Behavioral: Lifestyle therapy; Drug: Metformin Hydrochloride |
| Lifestyle Therapy plus Placebo | Placebo comparator | Diet-induced weight loss and Exercise Training plus Placebo Receives: Behavioral: Lifestyle therapy; Drug: Placebo |
| Healthy lifestyle plus Metformin | Active comparator | Healthy lifestyle and Metformin 1500 mg daily Receives: Drug: Metformin Hydrochloride; Behavioral: Healthy Lifestyle |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in the Modified Physical Performance Test (PPT)
The Physical Performance Test includes seven standardized tasks (walking 15.2 m [50 ft], putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and performing a progressive Romberg test) plus two additional tasks (going up and down four flights of stairs and making a 360-degree turn). The score for each task ranges from 0 to 4, with higher scores indicating better physical performance; lowest score is 0 and a perfect score would be 36.
Measured: 6 months
Secondary outcomes (26)
Change in Muscle Strength
Knee extension muscle strength measured using a Biodex dynamometer
Measured: 6 months
Change in Gait Speed
Gait speed was calculated from the time required to walk 4 meters at the participant's usual walking pace and expressed in meters per minute.
Measured: 6 months
Change in Peak Aerobic Power
Assessed by indirect calorimetry during a graded exercise test
Measured: 6 months
Change in Lean Body Mass
Assessed by dual-energy x-ray absorptiometry (DXA)
Measured: 6 months
Change in Body Fat
Assessed by using dual energy x-ray absorptiometry
Measured: 6 months
Change in Thigh Muscle
Assessed by magnetic resonance imaging (MRI)
Measured: 6 months
Change in Distal Tibia Bone Microarchitecture: Cortical Thickness
Assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia
Measured: 6 months
Change in Bone Strength
Assessed as distal tibia failure load estimated using finite-element analysis of HR-pQCT scans.
Measured: 6 months
Change in Bone Mineral Density (BMD) at the Total Hip
Assessed by dual-energy X-ray absorptiometry (DXA) at the total hip site
Measured: 6 months
Change in Bone Mineral Density at the Lumbar Spine
Assessed by dual-energy X-ray absorptiometry (DXA) at the lumbar spine site
Measured: 6 months
Change in Serum C-telopeptide
Bone resorption marker assessed by electrochemiluminescence immunoassay. Values represent least-squares mean ratios of 6-month to baseline C-telopeptide derived from mixed-effects models (exp[post - pre]).
Measured: 6 months
Change in Mood
Assessed by geriatric depression scale (score range: 0 to 30, where lower scores indicating better mood)
Measured: 6 months
Change in Serum Procollagen Type 1 N Propeptide
Bone formation marker assessed in fasting serum samples by radioimmunoassay (RIA). Values represent least-squares mean ratios of 6-month to baseline procollagen type 1 N propeptide derived from mixed-effects models (exp[post - pre]).
Measured: 6 months
Change in Serum 25-OH Vitamin D
Measured by automated immunoassay
Measured: 6 months
Change in Serum Parathyroid Hormone
Assessed by Beckman Coulter immunoassay
Measured: 6 months
Change in High-sensitivity C-reactive Protein
Assessed by immunoturbidimetric assay. CRP was log-transformed prior to analysis. Values represent least-squares mean ratios of 6-month to baseline CRP derived from mixed-effects models (exp[post - pre]).
Measured: 6 months
Change in Medical Outcomes 36-Item Short Form Health Survey (SF-36)
Assessed by Physical component summary component summary score (score range 0 to 100, with higher scores indicating better health status)
Measured: 6 months
Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) Score
Assessed by Impact of Weight on Quality of Life-Lite (IWQOL-lite) questionnaire. Score ranges from 0 to 100, with higher scores indicating better weight-related quality of life.
Measured: 6 months
Change in Serum Adiponectin
Assessed by enzyme linked immunosorbent assay (ELISA)
Measured: 6 months
Change in Serum Leptin
Assessed by radioimmunoassay
Measured: 6 months
Change in Fasting Serum Insulin
Assessed by chemiluminescent immunoassay
Measured: 6 months
Change in Fasting Serum Glucose
Assessed by glucose oxidase method
Measured: 6 months
Change in Systolic Blood Pressure
Seated systolic blood pressure assessed using an oscillometric blood pressure monitor.
Measured: 6 months
Change in Serum Lipids: Triglycerides
Assessed by automated enzymatic/colorimetric assays: triglycerides are reported.
Measured: 6 months
Change in Serum Insulin Growth Factor 1
Measured using an automated immunochemiluminometric assay (ICMA)
Measured: 6 months
Change in Cognitive Function Composite Score
Global cognitive function was assessed using the NIH Toolbox Cognition Battery Total Cognition Composite Score, a standardized measure of overall cognitive performance. Age-Corrected Standard Scores were used. These scores are standardized relative to individuals of the same age, with a normative mean of 100 and a standard deviation of 15. Higher scores indicate better cognitive performance.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2020
- Study start14 May 2021
- Primary completion31 Jul 2025
- Study completion31 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for FrailtyStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 114 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Collaborators
- Michael E. DeBakey VA Medical Center, Baylor College of Medicine
- Responsible party
- Sponsor
- Investigators
- Dennis T Villareal, MD, Principal investigator, Michael E. DeBakey VA Medical Center, Houston, TX
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04221750
- Sponsor's protocol ID
- ENDA-007-19F
- Other IDs
- H-46970
- Acronym
- DEMFOS
- Status last verified
- Aug 2026
- First submitted
- 2 Jan 2020
- Last updated
- 14 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Publications from this research will be made available to the public through the National Library of Medicine PubMed Central website within one year after the date of publication (guidance is provided on the ORD website). MEDVAMC will not provide unrestricted, open public access to large scale health related datasets because of re-identification concerns and the obligation to protect Veterans' private information. However, controlled public access will be provided to the greatest extent possible under specific DUAs or other written agreements, and open access will be provided to the final datasets underlying peer-reviewed publications (aggregated data that can be released with privacy and confidentiality risks).
Publications
Nava MLD, Viola V, Aguilar M, Bryant MS, Nambi V, Armamento-Villareal R, Qualls C, Villareal DT. Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial. Lancet Healthy Longev. 2027 Jul 1:100883. doi: 10.1016/j.lanhl.2026.100883. Online ahead of print.
PubMed 42532077