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Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors (DEMFOS)

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ClinicalTrials.gov Identifier: NCT04221750
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : March 22, 2021
Sponsor:
Collaborators:
Michael Debakey Veterans Affairs Medical Center
Baylor College of Medicine
Information provided by (Responsible Party):
VA Office of Research and Development

Brief 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 be the most effective strategy for reversing sarcopenic obesity and frailty in older Veterans with obesity.

Condition or disease Intervention/treatment Phase
Frailty Sarcopenic Obesity Aging Behavioral: Lifestyle therapy Drug: Metformin Hydrochloride Drug: Placebo Behavioral: Healthy Lifesylte Phase 3

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 years) Veterans with physical frailty.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Placebo controlled
Primary Purpose: Treatment
Official Title: Lifestyle Intervention Plus Metformin to Treat Frailty in Older Veterans With Obesity
Actual Study Start Date : March 15, 2021
Estimated Primary Completion Date : September 30, 2025
Estimated Study Completion Date : September 30, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lifestyle Therapy plus Metformin
Diet-induced weight loss and Exercise Training plus Metformin 1 gm bid
Behavioral: Lifestyle therapy
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
Other Name: Diet-induced weight loss and exercise training

Drug: Metformin Hydrochloride
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.

Placebo Comparator: Lifestyle Therapy plus Placebo
Diet-induced weight loss and Exercise Training plus Placebo
Behavioral: Lifestyle therapy
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
Other Name: Diet-induced weight loss and exercise training

Drug: Placebo
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.

Active Comparator: Healthy lifestyle plus Metformin
Healthy lifestyle and Metformin 1 gm bid
Drug: Metformin Hydrochloride
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.

Behavioral: Healthy Lifesylte
Group educational sessions that focus on healthy diet, exercise, and social support once a month




Primary Outcome Measures :
  1. Change in the modified Physical Performance Test (PPT) [ Time Frame: 6 months ]
    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; a perfect score would be 36.


Secondary Outcome Measures :
  1. Change in muscle strength [ Time Frame: 6 months ]
    Assessed by biodex dynamometer and1-repetition maximum

  2. Change in dynamic balance [ Time Frame: 6 months ]
    Assessed by the obstacle course

  3. Change in static balance [ Time Frame: 6 months ]
    Assessed by one leg stance

  4. Change in gait speed [ Time Frame: 6 months ]
    Assessed by time need to walk 25 ft

  5. Change in peak aerobic power [ Time Frame: 6 months ]
    Assessed by indirect calorimetry during a graded exercise test

  6. Change in lean body mass [ Time Frame: 6 months ]
    Assessed by dual-energy x-ray absorptiometry (DXA)

  7. Chang in body fat [ Time Frame: 6 months ]
    Assessed by DXA

  8. Change in thigh muscle [ Time Frame: 6 months ]
    Assessed by magnetic resonance imaging (MRI)

  9. Change in thigh fat [ Time Frame: 6 months ]
    Assessed by MRI

  10. Change in muscle quality [ Time Frame: 6 months ]
    Assessed by ratio of skeletal strength per unit of skeletal muscle

  11. Change in bone microarchitecture [ Time Frame: 6 months ]
    Assessed by high-resolution peripheral quantitative computed tomograph (HR-pQCT)

  12. Change in bone strength [ Time Frame: 6 months ]
    Assessed by finite-element analyses

  13. Change in hip, lumbar spine, and wrist bone mineral density (BMD) [ Time Frame: 6 months ]
    Assessed by DXA

  14. Change in wrist and tibial cortical and trabecular BMD [ Time Frame: 6 months ]
    Assessed by HR-pQCT

  15. Change in serum C-telopeptide [ Time Frame: 6 months ]
    Assessed by immunoassay

  16. Change in subjective ability to function [ Time Frame: 6 months ]
    Assessed by Functional Status Questionnaire (score range: 0 to 36 with higher scores indicating better function)

  17. Change in telomere length in skeletal muscles and whole blood [ Time Frame: 6 months ]
    Assessed by Q-PCR

  18. Change in mood [ Time Frame: 6 months ]
    Assessed by geriatric depression scale (score range: 0 to 30, where lower scores indicating better mood)

  19. Change in serum osteocalcin [ Time Frame: 6 months ]
    Assessed by ELISA

  20. Changed in concentration of targeted metabolites [ Time Frame: 6 months ]
    Assessed by liquid chromatography hyphenated with mass spectrometry techniques

  21. Change in serum procollagen type 1 N propeptide [ Time Frame: 6 months ]
    Assessed by radioimmunoassay

  22. Change in serum sclerostin [ Time Frame: 6 months ]
    Assessed by ELISA

  23. Change in serum 25-OH vitamin D [ Time Frame: 6 months ]
    Assessed by immunoassay

  24. Change in serum parathyroid hormone [ Time Frame: 6 months ]
    Assessed by immunoassay

  25. Change in serum Interleukin 6 [ Time Frame: 6 months ]
    Assessed by immunoassay

  26. Change in Tumor necrosis factor [ Time Frame: 6 months ]
    Assessed by immunoassay

  27. Change in high-sensitivity c-reactive protein [ Time Frame: 6 months ]
    Assessed by immunoassay

  28. Change in p16 [ Time Frame: 6 months ]
    Assessed by immunohistochemistry

  29. Change in p21 [ Time Frame: 6 months ]
    Assessed by immmnohistochemistry

  30. Change in satellite cells [ Time Frame: 6 months ]
    Assessed by by immunofluorescence

  31. Change in fiber cross sectional area [ Time Frame: 6 months ]
    Assessed by immunohistochemistry

  32. Change in fiber type-specific response [ Time Frame: 6 months ]
    Assessed by immunofluorescence

  33. Change in gene expression of senescence associated secretory phenotype [ Time Frame: 6 months ]
    Assessed by RT-PCR

  34. Change in protein expression of senescence associated secretory phenotype [ Time Frame: 6 months ]
    Assessed by western blotting

  35. Change in Medical Outcomes 36-Item short form Health survey (SF-36) [ Time Frame: 6 months ]
    Assessed by Physical component summary and mental component summary score (score range 0 to 100, with higher scores indicating better health status)

  36. Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score [ Time Frame: 6 months ]
    Assessed by IWQO-liteL questionnaire

  37. Change in serum adiponectin [ Time Frame: 6 months ]
    Assessed by ELISA

  38. Change in serum leptin [ Time Frame: 6 months ]
    Assessed by ELISA

  39. Change in fasting serum insulin [ Time Frame: 6 months ]
    Assessed by immunoassay

  40. Change in fasting serum glucose [ Time Frame: 6 months ]
    Assessed by glucose oxidase method

  41. Change in blood pressure [ Time Frame: 6 months ]
    Assessed by sphygmonanometry

  42. Change in serum lipids [ Time Frame: 6 months ]
    Assessed by automated enzymatic/colorimetric assays

  43. Change in insulin growth factor 1 [ Time Frame: 6 months ]
    Assessed by immunoassay

  44. Change in Cognitive composite scores [ Time Frame: 6 months ]

    Using cognitive toolbox which yields the following summary scores: Cognitive Function

    Composite Score, Fluid Cognition Composite Score, and Crystallized Cognition Composite Score (score range: -3 to +3 for each with higher scores indicating better cognitive status


  45. Change in habitual physical activity assessed by questionnaires [ Time Frame: 6 months ]
    Using the Stanford physical activity questionnaire (score range: 0 to 40 with higher scores indicating higher physical activity levels)

  46. Change in habitual physical activity measured objectively [ Time Frame: 6 months ]
    Using accelerometers



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   65 Years to 85 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • BMI = or > 30 kg/m2
  • 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

Exclusion Criteria:

  • 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
  • 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, 2-h blood glucose 200 mg/dl in the OGTT, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221750


Contacts
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Contact: Dennis T Villareal, MD (713) 794-7151 Dennis.Villareal@va.gov
Contact: Arjun Paudyal, MS (713) 578-4300

Locations
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United States, Texas
Michael E. DeBakey VA Medical Center, Houston, TX Recruiting
Houston, Texas, United States, 77030
Contact: Dennis T Villareal, MD    713-794-7151    Dennis.Villareal@va.gov   
Principal Investigator: Dennis T Villareal, MD         
Sponsors and Collaborators
VA Office of Research and Development
Michael Debakey Veterans Affairs Medical Center
Baylor College of Medicine
Investigators
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Principal Investigator: Dennis T Villareal, MD Michael E. DeBakey VA Medical Center, Houston, TX
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04221750    
Other Study ID Numbers: ENDA-007-19F
H-46970 ( Other Grant/Funding Number: VA Office of Research and Development )
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: March 22, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description:

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).


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Obesity
Frailty
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Pathologic Processes
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs