Starting a Testosterone and Exercise Program After Hip Injury

Study Overview
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Brief Summary
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This study is a randomized controlled double-blinded multi-center clinical trial enrolling female hip fracture patients who are 65 and older. It will compare the effects of six months of supervised exercise training combined with daily topical testosterone gel, to six months of supervised exercise and inactive gel, and to Enhanced Usual Care. Out of nine participants, 4 will receive topical testosterone gel and a supervised exercise training program; 4 will receive topical inactive gel and a supervised exercise training program; and 1 will receive a home exercise program. All participants will receive nutritional counseling, and calcium and vitamin D supplements.

Detailed Description
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Hip fractures are common among older women and can have a devastating impact on their ability to remain independent. A clinically important functional decline and failure to recover following a hip fracture has been documented as late as a year after the fracture, even among women who were functioning at high levels before the event. Age-associated androgen deficiency in women contributes to deficits in muscle mass, strength and power that are common in this patient population before the fracture, and are exacerbated afterward. A pilot study of testosterone (T) supplementation in elderly female hip fracture patients has demonstrated the feasibility of T treatment in this population, and showed gains in lean body mass (LBM) and muscle strength with active drug, compared to placebo. The benefits of exercise in restoring muscle strength and physical function after a hip fracture have been documented. However, it remains unclear whether T treatment can augment the effects of exercise on mobility and patient-reported function after hip fracture. The STEP-HI study is a 3-group, multi-center, randomized, placebo-controlled, double-blinded, parallel group clinical trial in older female hip fracture patients. Between 120 and 168 female hip fracture patients, age 65 years and older, will be enrolled from multiple clinical sites, using objective screening criteria for T deficiency (serum total testosterone level < 60 ng/dL) and physical frailty (Modified Physical Performance Test (PPT) Score of 12-28). The trial will compare the effects of Enhanced Usual Care with home exercises and no gel treatment (EUC), supervised exercise training (EX) with inactive (placebo) gel (EX+P), and EX combined with T therapy (EX+T), to ascertain the incremental impact of adding T to EX in older adult women with a recent hip fracture. The study team will carefully monitor testosterone levels, adverse events, biochemical parameters, and factors related to adherence to the interventions. Information from this study has the potential to alter treatment of hip fracture in older women, a problem that contributes to significant morbidity and mortality, and has a large public health impact. The STEP-HI study is highly aligned with NIA's mission of identifying interventions that target common geriatric conditions and improve treatment options for older adults with multiple morbidities or risk factors.

Official Title
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Combining Testosterone Therapy and Exercise to Improve Function Post Hip Fracture

Conditions
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Hip Fracture, Frailty, Sarcopenia

Intervention / Treatment
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* Drug: Testosterone
* Drug: Placebo gel
* Behavioral: Supervised exercise training
* Behavioral: Home exercise program
* Behavioral: Health Education Modules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female 65 years and older. Surgical repair of a non-pathologic fracture of the proximal femur (Including: femoral neck or intracapsular, intertrochanteric, and subtrochanteric fractures) with a surgical repair date that is within 24 weeks at randomization. If a revision of such a fracture is performed due to failure of the repair, that surgery revision date may be used to calculate the time frame for the screening and randomization dates. Community-dwelling or in assisted living prior to the hip fracture event. Functional impairment at the time of screening, defined as a modified Physical Performance Score (mPPT) of 12-28. Serum total testosterone level <60 ng/dL. Exclusion Criteria: Cognitive impairment or dementia of severity sufficient to interfere with ability to fully participate in the study or provide one's own informed consent, or a score of 11 or greater on the Short Blessed Test of Orientation, Memory and Concentration. Residence too far from research center (specific distance to be determined by each site) or planned travel greater than 2 weeks within the next 9 months. Anticipated to be permanently living in a nursing home at the time of randomization. Use of progestin or androgen containing compound within the previous 6 months. Treatment with systemic corticosteroids (daily dose > 5 mg prednisone or equivalent) for at least 90 days within the previous 12 months. Visual or hearing impairments that interfere with following directions for research procedures. Active or unstable cardiopulmonary disease (recent myocardial infarction, unstable angina, class III or IV Congestive Heart Failure) within prior 6 months, which would limit full participation in the study. Respiratory disease requiring chronic continuous oxygen therapy, or oxygen therapy during walking or exercise, which would limit full participation in this study. History of idiopathic deep venous thrombosis or pulmonary embolus (i.e., not related to period or immobilization or surgery), any pulmonary embolus less than 12 weeks prior to the first screening visit, recurrent or multiple venous thrombi; history of a hypercoagulable state such as Factor V Leiden thrombophilia. Musculoskeletal or neurological conditions that limit participation in this study, could be made worse by exercise training, or not expected to improve with exercise. Lower extremity amputation other than toes. Severe lower extremity pain or ulceration that could limit full participation in this study. History of: a) Breast, ovarian, endometrial or cervical cancer with diagnosis within the previous 10 years; b) Breast, ovarian, endometrial, or cervical cancer of Stage 2 or higher. History of HIV or active viral hepatitis. End Stage Renal Disease on dialysis or Glomerular Filtration Rate (GFR)<15 ml/min. Allergy to gel components. Recent history of alcohol or substance abuse, or current alcohol intake of ≥ 10 drinks/week. Planned joint surgery during the intervention period. Participation in another research study that in the site investigator's judgement could interfere or conflict with STEP-HI research assessments or interventions. Current use of aldactone, flutamide or leflunomide. Geriatric Depression Scale (GDS) score ≥ 12 at the screening assessment. Uncontrolled hypertension, defined as a systolic BP > 160 mmHg or diastolic BP > 95 mmHg, on at least two occasions. Elevated liver transaminase or alkaline phosphatase levels ≥ 2.5 times above normal range. Erythrocytosis defined as hematocrit > 51% (all sites but University of Utah) or ≥ 52% at University of Colorado - Denver and University of Utah sites. Severe anemia defined as Hgb < 7gm/dL. Uncontrolled diabetes defined as HgbA1C > 10%. Untreated or unstable thyroid disease, with serum Thyroid-stimulating Hormone (TSH) level ≥ 10 milli-international units per liter (mIU/L) or TSH level ≤ 0.4 mIU/L. Levels outside of the given range require site physician documentation addressing treatment or absence of thyroid disease and approval by the Central Coordinating Center (CCC). Site investigator's judgement that the participant would not be able to complete research procedures or interventions.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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Female

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise + Testosterone (EX + T)<br>Supervised exercise training 2 times per week and topical testosterone 1% gel (12.5 mg per pump depression) daily, both for six months duration. | Drug: Testosterone<br>* Topical testosterone gel 1%<br>* Other names: T;Behavioral: Supervised exercise training<br>* Multicomponent exercise program focused primarily on progressive resistance exercise training<br>* Other names: EX;|
| Placebo Comparator: Exercise + Placebo (EX + P)<br>Supervised exercise training 2 times per week and placebo gel daily, both for six months duration. | Drug: Placebo gel<br>* Inactive skin gel<br>* Other names: P;Behavioral: Supervised exercise training<br>* Multicomponent exercise program focused primarily on progressive resistance exercise training<br>* Other names: EX;|
| Other: Enhanced Usual Care (EUC)<br>Home exercise program 3 times per week and monthly health education modules, both for six months duration. | Behavioral: Home exercise program<br>* Flexibility exercises performed at home 3 times per week and reviewed by study staff once a month.<br>* Other names: EUC;Behavioral: Health Education Modules<br>* 30-40 minute presentations conducted by study staff for participants focused on health concerns unrelated to exercise.<br>* Other names: EUC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in six minute walk distance at 6 months | Distance that the individual can walk on a specified track, within six minutes | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Lean Body Mass at 6 months | Total lean body mass measured by dual x-ray absorptiometry (DXA) | Baseline and 6 months | 
| Change in Appendicular Lean Body Mass at 6 months | Lean body mass of the arms and legs, measures by dual x-ray absorptiometry (DXA) | Baseline and 6 months | 
| Change in 1-repetition maximum (1-RM) leg press strength at 6 months | 1-repetition maximum strength for leg press | Baseline and 6 months | 
| Change in Total Modified Physical Performance Test (mPPT) Score at 6 months | 9 objective physical performance tasks | Baseline and 6 months | 
| Change in Short Physical Performance Battery (SPPB) Score at 6 months | 3 objective physical performance tasks (Chair rise, Progressive Romberg, Walking speed for an 8 ft course) | Baseline and 6 months | 
| Change in Older Adult Resources and Services Activities of Daily Living (ADL) Questionnaire (OARS) ADL Total Score at 6 months | Standardized self-report questions regarding performance of activities of daily living | Baseline and 6 months | 
| Change in Functional Status Questionnaire (FSQ) Total Score at 6 months | Standardized self-report questions regarding performance of activities of daily living | Baseline and 6 months | 
| Change in Hip Rating Questionnaire Total Score at 6 months | Standardized questions regarding quality of life and function as related to the hip fracture event | Baseline and 6 months | 
| Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health score at 6 months | Standardized questions regarding quality of life | Baseline and 6 months | 
| Change in Bone Mineral Density (BMD) of the non-fractured proximal femur at 6 months | Bone mineral density measured by dual x-ray absorptiometry (DXA) | Baseline and 6 months |