Lifestyle Intervention and Testosterone Replacement in Obese Seniors

Study Overview
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Brief Summary
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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
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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.

Official Title
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Testosterone Replacement to Augment Lifestyle Therapy in Obese Older Veterans

Conditions
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Obesity and Hypogonadism

Intervention / Treatment
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* Drug: Testosterone
* Other: Lifestyle Therapy
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Testosterone plus Lifestyle Therapy<br>Testosterone replacement in combination with behavioral diet to induce  10% weight loss + supervised aerobic and exercise training | Drug: Testosterone<br>* Daily testosterone gel applied once daily in the morning to intact skin<br>Other: Lifestyle Therapy<br>* Weekly behavioral diet to induce  10% weight loss in combination with supervised aerobic and exercise training three times a week<br>|
| Placebo Comparator: Placebo plus Lifestyle Therapy<br>Placebo in combination with behavioral diet to induce  10% weight loss and supervised aerobic and exercise training | Other: Lifestyle Therapy<br>* Weekly behavioral diet to induce  10% weight loss in combination with supervised aerobic and exercise training three times a week<br>Drug: Placebo<br>* Placebo gel for testosterone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Physical Performance Test | The primary functional outcome is the modified physical performance test, which includes seven standardized tasks (walking 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 tests) plus two additional tasks (climbing up and down four flights of stairs and performing a 360-degree turn). The score for each task ranges form 0 to 4; a perfect score is 36. Higher scores indicate better physical function. | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Endurance Capacity | Assessed by measuring peak oxygen consumption using indirect calorimetry during a treadmill exercise stress test | Baseline and 6 months | 
| Change in Functional Status | Assessed by the Functional Status Questionnaire. Score range: 0 to 36 with higher scores indicating better functional status Provides information of the participants ability to perform activities of daily living. | Baseline and 6 months | 
| Change in Body Weight | Measured after an overnight fast using calibrated scales | Baseline and 6 months | 
| Change in Lean Body Mass | Assessed by using dual-energy x-ray absorptiometry | Baseline and 6 months | 
| Change in Fat Mass | Assessed by using dual-energy x-ray absorptiometry | Baseline and 6 months | 
| Change in Thigh Muscle Volume | Assessed by using magnetic resonance imaging | Baseline and 6 months | 
| Thigh Fat Volume | Volume of fat in the thigh by measured by magnetic resonance imaging | 6 months | 
| Change in Total Hip Bone Mineral Density | Assessed by using dual-energy x-ray absorptiometry | Baseline and 6 months | 
| Change in Lumbar Spine Bone Mineral Density | As measured by Dual energy x-ray absorptiometry | Baseline and 6 months | 
| Change in Muscle Strength | assessed by total1-repetition maximum (the maximal weight lifted at one time; the totals are the sum of the maximal weights lifted in the biceps curl, bench press, 387 seated row, knee extension, knee flexion, and leg press exercises). | Baseline and 6 months | 
| Change in Static Balance | assessed by one leg limb stance | Baseline and 6 months | 
| Change in Dynamic Balance | Assessed by using the obstacle course | Baseline and 6 months | 
| Change in Gait Speed | Determined by measuring the time needed to walk 25 ft. | Baseline and 6 months | 
| Change in Composite Cognitive Z-score | Test of overall cognitive performance formed by averaging the standardized scores for several domains of cognitive function (attention, memory, executive, language, global). Higher scores indicate better cognitive status. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the baseline scores (units on a scale). Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population | Baseline and 6 months | 
| Change in Modified Mini-mental Exam | Test of global cognition with components for orientation, registration, attention, language, praxis, and immediate and delayed memory. Score ranges from 0 to 100 with higher scores indicate better cognition. | Baseline and 6 months | 
| Stroop Interference | Assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Word List Fluency | Measure of verbal production, semantic memory, and language. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Ray Auditory Verbal Learning Test | The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions: short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Trail A | Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a greater focus on attention). Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Trail B | Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a focus on executive function) Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Symbol Digital Modalities Test | Assesses key neurocognitive functions that underlie many substitution tasks, including attention, visual scanning, and motor speed. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. | Baseline and 6 months | 
| Change in Trabecular Bone Score | The trabecular bone score is a measure of bone texture correlated with bone microarchitecture and a marker for the risk of osteoporosis. Minimum score is 0, there is no maximum value. Higher scores indicate better bone microarchitecture. | Baseline and 6 months | 
| Change in C-terminal Telopeptide | biochemical marker of bone turnover (bone resorption) as measured by immunoassay technique | Baseline and 6 months | 
| Change in N-terminal Propeptide of Type I Procollagen | Biochemical marker of bone turnover (bone formation) as measured by radioimmunoassay technique | Baseline and 6 months | 
| Change in Insulin Growth Factor-1 | Measured by immunoassay methodology | Baseline and 6 months | 
| Change in Trabecular Bone Score (Trabecular Bone Quality) | assessed by trabecular bone score (TBS), a newly developed index for assessing trabecular bone quality and fracture risk. TBS is a bone texture parameter that quantifies cancellous bone microachitecture, which is key in determining bone strength and resistance to fracture, by computing raw data from dual energy x-ray absorptiometry of the lumbar spine. There are no minimum or maximum values. Higher scores mean better outcome. | Baseline and 6 months | 
| Change in Levels of 25-hydroxyvitamin D | assessed by using immunoassay methodology | Baseline and 6 months | 
| Change in Parathyroid Hormone Level | Measured by immunoassay methodology as marker of bone metabolism | Baseline and 6 months | 
| Change in High-sensitivity C-reactive Protein (Inflammatory Marker) | measured in the peripheral blood using immunoassay technique methodology | Baseline and 6 months | 
| Change in Interleukin-6 | Measured from fasting serum using immunoassay technique as marker of inflammation | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Hypogonadism, Frailty