Clinical trial NCT02367105: Lifestyle Intervention and Testosterone Replacement in Obese Seniors
Official title: Testosterone Replacement to Augment Lifestyle Therapy in Obese Older Veterans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity and Hypogonadism
Keywords: Obesity
Hypogonadism
Frailty
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Michael E. DeBakey VA Medical Center
name: Baylor College of Medicine
name: Biomedical Research Institute of New Mexico
First posted: 2015-02-20
Enrollment: 83
Sex: MALE
Minimum age (years): 65
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The prevalence of obesity in Veterans is greater than in the general population, and even more so among users of the VA Health Care System. In addition, the population of obese older Veterans is rapidly increasing as more baby boomers become senior citizens. In older Veterans, obesity exacerbates the age- related decline in physical function and causes frailty which predisposes to admission to a VA chronic care facility. However, the optimal clinical approach to obesity in older adults is controversial because of the concern that weight loss therapy could be harmful by aggravating the age-related loss of muscle mass and bone mass. In fact, the MOVE (Managing Overweight/Obese Veterans) program does not have any guidelines for eligible Veterans if they are 70 or older. It is possible that the addition of testosterone replacement to lifestyle therapy will preserve muscle mass and bone mass and reverse frailty in obese older Veterans and thus prevent their loss of independence and decrease demand for VA health care services.

Detailed description: Obesity is not only highly prevalent among Americans, but even more so among Veterans using VA medical facilities. Failure to assist Veterans in managing weight and sedentary lifestyle affects current treatment and increases future demand for VA health care services. Decreased muscle mass with aging and the need to carry extra mass due to obesity make it particularly difficult for obese older Veterans to function independently and results in frailty leading to increased nursing home admissions and increased morbidity and mortality. Data from preliminary studies showed that lifestyle therapy resulting in weight loss in this understudied population improves physical function and ameliorates frailty. However, this improvement in physical function is modest at best and most obese older adults remain physically frail. More importantly, there are concerns that lifestyle therapy may exacerbate underlying sarcopenia and osteopenia from weight loss- induced loss of lean body mass and bone mineral density (BMD). As a result, most geriatricians are reluctant to recommend lifestyle therapy that includes weight loss in obese frail elderly patients although the combination of weight loss and exercise is recommended as part of standard care for obese patients in general. Thus, it is not surprising that among Veterans, the MOVE (Managing Overweight/Obese Veterans) program does not have any guidelines for eligible Veterans if they are 70 or older. In addition to overeating and lack of exercise, age-related decline in anabolic hormone (i.e. testosterone) may contribute to sarcopenia and osteopenia, which in turn is exacerbated by obesity. Indeed, preliminary studies discovered that obese older men had markedly low levels of serum testosterone at baseline which remained low throughout the duration of lifestyle therapy. Because testosterone replacement therapy has been shown to increase muscle mass and BMD, it is therefore likely that concomitant testosterone replacement during lifestyle therapy in obese older adults would preserve lean body mass and BMD, and reverse frailty. Accordingly, the optimal management to the problem of sarcopenic obesity and frailty might require a comprehensive approach of a combination of lifestyle intervention and the correction of anabolic hormone deficiency. Therefore, the primary goal of this proposal is to conduct a randomized, comparative efficacy, double-blind, placebo-controlled (for testosterone) trial of the effects of 1) lifestyle therapy (1% diet-induced weight loss and exercise training) + testosterone replacement therapy versus 2) lifestyle therapy without testosterone replacement (testosterone placebo) in obese (BMI e 30 kg/m2) older (age e 65 yrs) male Veterans. The investigators hypothesize that 1) lifestyle therapy + testosterone replacement will cause a greater improvement in physical function than lifestyle therapy without concomitant testosterone replacement; 2) lifestyle therapy + testosterone replacement will cause a greater preservation of fat-free mass and thigh muscle volume than lifestyle therapy without testosterone replacement, 3) lifestyle therapy + testosterone replacement will cause a greater preservation in BMD and bone quality than lifestyle therapy without testosterone replacement, and 4) lifestyle therapy + testosterone replacement will cause a greater reduction in intramuscular proinflammatory cytokines than lifestyle therapy without testosterone replacement. The overarching hypothesis across aims is that a multifactorial intervention by means of lifestyle therapy plus testosterone replacement will be the most effective approach for reversing sarcopenic obesity and frailty in obese older male adults, as mediated by their additive effects in suppressing chronic inflammation, and stimulating muscle and bone anabolism. Obesity in older adults, including many aging Veterans, is a major public health problem. In fact, the public health success that has occurred in recent years could be in danger if lifestyles of older adults are neglected. The novel health outcomes and mechanistic-based data generated from this proposed randomized clinical trial (RCT) will have important ramifications for the standard of care for this rapidly increasing segment of the aging Veteran population.

Eligibility criteria: Inclusion Criteria:

Subjects will be

* older (65-85 yr)
* obese (BMI 30 kg/m2 or greater) Veteran men with low testosterone (less than 300 mg/dL) as defined by the Endocrine Society
* mild to moderately frail
* must have stable weight (\~not less than or more than 2 kg) during the last 6 months
* sedentary (regular exercise less than 1 h/week or less than 2x/week for the last 6 months)

Exclusion Criteria:

* Any major chronic diseases, or any condition that would interfere with exercise or dietary restriction, in which exercise or dietary restriction are contraindicated, or that would interfere with interpretation of results.
* Examples include, but are not limited to:

  * cardiopulmonary disease (e.g. recent myocardial infarction (MI), unstable angina, stroke etc) or unstable disease (e.g. CHF)
  * severe orthopedic/musculoskeletal or neuromuscular impairments
  * visual or hearing impairments
  * cognitive impairment (Mini Mental State Exam Score less than 24)
  * current use of bone active drugs
  * uncontrolled diabetes (i.e. fasting blood glucose more than 140 mg/dl and/or HbA1c greater than 9.5%).
* Any contraindications to testosterone supplementation

  * history of prostate or breast cancer
  * history of testicular disease
  * untreated sleep apnea
  * hematocrit more than 50%
  * prostate-related findings of palpable nodule on exam, a serum PSA of 4.0 ng/ml or greater
  * International Prostate Symptom Sore more than 19
  * history of venous thromboembolism
* Osteoporosis or a BMD T-score of -2.5 in the lumbar spine or total hip as well as those patients with a history of osteoporosis-related fracture (spine, hip, or wrist)

Primary outcomes:
measure: Change in the Physical Performance Test
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Change in Endurance Capacity
timeFrame: Baseline and 6 months
measure: Change in Functional Status
timeFrame: Baseline and 6 months
measure: Change in Body Weight
timeFrame: Baseline and 6 months
measure: Change in Lean Body Mass
timeFrame: Baseline and 6 months
measure: Change in Fat Mass
timeFrame: Baseline and 6 months
measure: Change in Thigh Muscle Volume
timeFrame: Baseline and 6 months
measure: Thigh Fat Volume
timeFrame: 6 months
measure: Change in Total Hip Bone Mineral Density
timeFrame: Baseline and 6 months
measure: Change in Lumbar Spine Bone Mineral Density
timeFrame: Baseline and 6 months
measure: Change in Muscle Strength
timeFrame: Baseline and 6 months
measure: Change in Static Balance
timeFrame: Baseline and 6 months
measure: Change in Dynamic Balance
timeFrame: Baseline and 6 months
measure: Change in Gait Speed
timeFrame: Baseline and 6 months
measure: Change in Composite Cognitive Z-score
timeFrame: Baseline and 6 months
measure: Change in Modified Mini-mental Exam
timeFrame: Baseline and 6 months
measure: Stroop Interference
timeFrame: Baseline and 6 months
measure: Change in Word List Fluency
timeFrame: Baseline and 6 months
measure: Change in Ray Auditory Verbal Learning Test
timeFrame: Baseline and 6 months
measure: Change in Trail A
timeFrame: Baseline and 6 months
measure: Change in Trail B
timeFrame: Baseline and 6 months
measure: Change in Symbol Digital Modalities Test
timeFrame: Baseline and 6 months
measure: Change in Trabecular Bone Score
timeFrame: Baseline and 6 months
measure: Change in C-terminal Telopeptide
timeFrame: Baseline and 6 months
measure: Change in N-terminal Propeptide of Type I Procollagen
timeFrame: Baseline and 6 months
measure: Change in Insulin Growth Factor-1
timeFrame: Baseline and 6 months
measure: Change in Trabecular Bone Score (Trabecular Bone Quality)
timeFrame: Baseline and 6 months
measure: Change in Levels of 25-hydroxyvitamin D
timeFrame: Baseline and 6 months
measure: Change in Parathyroid Hormone Level
timeFrame: Baseline and 6 months
measure: Change in High-sensitivity C-reactive Protein (Inflammatory Marker)
timeFrame: Baseline and 6 months
measure: Change in Interleukin-6
timeFrame: Baseline and 6 months
Other outcomes:
measure: Change in Total Testosterone Levels
timeFrame: Baseline and 6 months
measure: Change in Estradiol
timeFrame: Baseline and 6 months
measure: Change in Hematocrit
timeFrame: Baseline and 6 months
measure: Change in Prostate Specific Antigen
timeFrame: Baseline and 6 months
measure: Change in Short Form Health Survey (SF-36) Quality of Life Physical Component
timeFrame: Baseline and 6 months
measure: Change in International Prostate Symptom Score
timeFrame: Baseline and 6 months
measure: Change in Triglyceride Levels
timeFrame: Baseline and 6 months
measure: Change in HDL-cholesterol
timeFrame: Baseline and 6 months
measure: Change in Waist Circumference
timeFrame: Baseline and 6 months
measure: Change in Glucose
timeFrame: Baseline and 6 months
measure: Change in Mood
timeFrame: Baseline and 6 months
measure: Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network
timeFrame: Baseline and 6 months
measure: Change in Skeletal Muscle Growth Factor (MYOD1)
timeFrame: Baseline and 6 months
measure: Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density)
timeFrame: Baseline and 6 months
Locations:
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
Study officials:
affiliation: Michael E. DeBakey VA Medical Center, Houston, TX
name: Dennis T Villareal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gregori G, Celli A, Barnouin Y, Paudyal A, Armamento-Villareal R, Napoli N, Qualls C, Villareal DT. Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial. Am J Clin Nutr. 2021 Nov 8;114(5):1590-1599. doi: 10.1093/ajcn/nqab253.