Lifestyle Intervention and Testosterone Replacement in Obese Seniors (LITROS)

• ClinicalTrials.gov Identifier: NCT02367105
• Recruitment Status: Completed
• First Posted: February 20, 2015
• Results First Posted: August 31, 2020
• Last Update Posted: July 26, 2022
• Sponsor: VA Office of Research and Development
• Collaborators: Michael E. DeBakey VA Medical Center; Baylor College of Medicine; Biomedical Research Institute of New Mexico
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Obesity and Hypogonadism	Drug: Testosterone; Other: Lifestyle Therapy; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Testosterone Replacement to Augment Lifestyle Therapy in Obese Older Veterans
• Actual Study Start Date: February 1, 2015
• Actual Primary Completion Date: July 31, 2019
• Actual Study Completion Date: December 31, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Testosterone plus Lifestyle Therapy; Testosterone replacement in combination with behavioral diet to induce ~10% weight loss + supervised aerobic and exercise training	Drug: Testosterone; Daily testosterone gel applied once daily in the morning to intact skin; Other: Lifestyle Therapy; Weekly behavioral diet to induce ~10% weight loss in combination with supervised aerobic and exercise training three times a week
Placebo Comparator: Placebo plus Lifestyle Therapy; Placebo in combination with behavioral diet to induce ~10% weight loss and supervised aerobic and exercise training	Other: Lifestyle Therapy; Weekly behavioral diet to induce ~10% weight loss in combination with supervised aerobic and exercise training three times a week; Drug: Placebo; Placebo gel for testosterone

Outcome Measures

Primary Outcome Measures :

1. Change in the Physical Performance Test [ Time Frame: Baseline and 6 months ]
   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.

Secondary Outcome Measures :

1. Change in Endurance Capacity [ Time Frame: Baseline and 6 months ]
   Assessed by measuring peak oxygen consumption using indirect calorimetry during a treadmill exercise stress test
2. Change in Functional Status [ Time Frame: Baseline and 6 months ]

   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.

3. Change in Body Weight [ Time Frame: Baseline and 6 months ]
   Measured after an overnight fast using calibrated scales
4. Change in Lean Body Mass [ Time Frame: Baseline and 6 months ]
   Assessed by using dual-energy x-ray absorptiometry
5. Change in Fat Mass [ Time Frame: Baseline and 6 months ]
   Assessed by using dual-energy x-ray absorptiometry
6. Change in Thigh Muscle Volume [ Time Frame: Baseline and 6 months ]
   Assessed by using magnetic resonance imaging
7. Thigh Fat Volume [ Time Frame: 6 months ]
   Volume of fat in the thigh by measured by magnetic resonance imaging
8. Change in Total Hip Bone Mineral Density [ Time Frame: Baseline and 6 months ]
   Assessed by using dual-energy x-ray absorptiometry
9. Change in Lumbar Spine Bone Mineral Density [ Time Frame: Baseline and 6 months ]
   As measured by Dual energy x-ray absorptiometry
10. Change in Muscle Strength [ Time Frame: Baseline and 6 months ]
    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).
11. Change in Static Balance [ Time Frame: Baseline and 6 months ]
    assessed by one leg limb stance
12. Change in Dynamic Balance [ Time Frame: Baseline and 6 months ]
    Assessed by using the obstacle course
13. Change in Gait Speed [ Time Frame: Baseline and 6 months ]
    Determined by measuring the time needed to walk 25 ft.
14. Change in Composite Cognitive Z-score [ Time Frame: Baseline and 6 months ]

    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

15. Change in Modified Mini-mental Exam [ Time Frame: Baseline and 6 months ]
    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.
16. Stroop Interference [ Time Frame: Baseline and 6 months ]

    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.

17. Change in Word List Fluency [ Time Frame: Baseline and 6 months ]
    Measure of verbal production, semantic memory, and language. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
18. Change in Ray Auditory Verbal Learning Test [ Time Frame: Baseline and 6 months ]

    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.

19. Change in Trail A [ Time Frame: Baseline and 6 months ]

    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.

20. Change in Trail B [ Time Frame: Baseline and 6 months ]

    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.

21. Change in Symbol Digital Modalities Test [ Time Frame: Baseline and 6 months ]

    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.

22. Change in Trabecular Bone Score [ Time Frame: Baseline and 6 months ]

    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.

23. Change in C-terminal Telopeptide [ Time Frame: Baseline and 6 months ]
    biochemical marker of bone turnover (bone resorption) as measured by immunoassay technique
24. Change in N-terminal Propeptide of Type I Procollagen [ Time Frame: Baseline and 6 months ]
    Biochemical marker of bone turnover (bone formation) as measured by radioimmunoassay technique
25. Change in Insulin Growth Factor-1 [ Time Frame: Baseline and 6 months ]
    Measured by immunoassay methodology
26. Change in Trabecular Bone Score (Trabecular Bone Quality) [ Time Frame: Baseline and 6 months ]

    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.

27. Change in Levels of 25-hydroxyvitamin D [ Time Frame: Baseline and 6 months ]
    assessed by using immunoassay methodology
28. Change in Parathyroid Hormone Level [ Time Frame: Baseline and 6 months ]
    Measured by immunoassay methodology as marker of bone metabolism
29. Change in High-sensitivity C-reactive Protein (Inflammatory Marker) [ Time Frame: Baseline and 6 months ]
    measured in the peripheral blood using immunoassay technique methodology
30. Change in Interleukin-6 [ Time Frame: Baseline and 6 months ]
    Measured from fasting serum using immunoassay technique as marker of inflammation

Other Outcome Measures:

1. Change in Total Testosterone Levels [ Time Frame: Baseline and 6 months ]
   as measured in the peripheral blood by liquid chromatography/mass spectrometry
2. Change in Estradiol [ Time Frame: Baseline and 6 months ]
   As measured by LC-MS/MS
3. Change in Hematocrit [ Time Frame: Baseline and 6 months ]
   the ratio of the volume of red blood cells to the total volume of blood.
4. Change in Prostate Specific Antigen [ Time Frame: Baseline and 6 months ]
   blood test to screen for prostate cancer
5. Change in Short Form Health Survey (SF-36) Quality of Life Physical Component [ Time Frame: Baseline and 6 months ]
   Using Short Form-36 of Life Questionnaire Physical Component subscale. Minimum score is 0, Maximum score is 100. Higher scores indicate better outcome.
6. Change in International Prostate Symptom Score [ Time Frame: Baseline and 6 months ]
   Using the International Prostate Symptom Scoring (IPS); Minimum score is 0, Maximum score is 35. Higher scores mean worse outcome.
7. Change in Triglyceride Levels [ Time Frame: Baseline and 6 months ]
   Blood samples obtained in the fasting state as part of measurements of lipid profile
8. Change in HDL-cholesterol [ Time Frame: Baseline and 6 months ]
   Blood samples obtained in the fasting state as part of measurements of lipid profile
9. Change in Waist Circumference [ Time Frame: Baseline and 6 months ]
   Waist circumference as measured horizontally at the midpoint between the highest point of the iliac crest and the lowest portion of the 12th rib in the standing position.
10. Change in Glucose [ Time Frame: Baseline and 6 months ]
    Measured in the blood after overnight fast
11. Change in Mood [ Time Frame: Baseline and 6 months ]
    Using Yesavage Depression Scale Lower scores indicate better mood (range 0 to 30).
12. Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network [ Time Frame: Baseline and 6 months ]
    Functional connectivity was measured with seeds of the DMN (medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]). Correlation coefficients representing the degree of connectivity between hypothesized regions were Fisher transformed. An a priori threshold of p<.001 at the voxel level and p<.05, FDR corrected for multiple comparisons across the whole brain, at the cluster level were used to determine significant connectivity.
13. Change in Skeletal Muscle Growth Factor (MYOD1) [ Time Frame: Baseline and 6 months ]
    Assessed by using RNA-seq quantification of gene expression in skeletal muscles obtained during muscle biopsies.
14. Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density) [ Time Frame: Baseline and 6 months ]
    assessed by quantitative computed tomography at 4% distal tibia using the following thresholds: 180 mg/cm3 and 45% of the area

Eligibility Criteria

• Ages Eligible for Study: 65 Years to 85 Years (Older Adult)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Male
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, Texas

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, United States, 77030

Sponsors and Collaborators

VA Office of Research and Development

Michael E. DeBakey VA Medical Center

Baylor College of Medicine

Biomedical Research Institute of New Mexico

Investigators

• Principal Investigator: Dennis T Villareal, MD; Michael E. DeBakey VA Medical Center, Houston, TX

  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:

Study Protocol and Statistical Analysis Plan  [PDF] June 11, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02367105
• Other Study ID Numbers: ENDA-034-12F; CX000906 ( Other Grant/Funding Number: VA CSRD )
• First Posted: February 20, 2015
• Results First Posted: August 31, 2020
• Last Update Posted: July 26, 2022
• Last Verified: January 2022

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).

• 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

Keywords provided by VA Office of Research and Development:

Obesity; Hypogonadism; Frailty

Additional relevant MeSH terms:

Hypogonadism; Gonadal Disorders; Endocrine System Diseases; Testosterone; Androgens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs