Starting a Testosterone and Exercise Program After Hip Injury

Phase 3

Completed

Conditions: Sarcopenia
Frailty
Hip Fracture

Interventions: Drug: Testosterone
Behavioral: Home exercise program
Drug: Placebo gel
Behavioral: Supervised exercise training
Behavioral: Health Education Modules

Registration Number: NCT02938923

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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. The randomization protocol is that for every nine participants randomized, 4 will be assigned to the topical testosterone gel and supervised exercise training group; 4 will be assigned to topical inactive gel and supervised exercise training group; and 1 will be assigned to the enhanced usual care group. All participants will receive nutritional counseling, and calcium and vitamin D supplements.

Detailed Description: 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 randomized from multiple clinical sites in the USA, 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 primary study aim is to compare 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 129

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Exercise + Testosterone (EX + T)	Testosterone	Supervised exercise training 2 times per week and topical testosterone 1% gel (12.5 mg per pump depression) daily, both for six months duration.
Exercise + Testosterone (EX + T)	Supervised exercise training	Supervised exercise training 2 times per week and topical testosterone 1% gel (12.5 mg per pump depression) daily, both for six months duration.
Exercise + Placebo (EX + P)	Supervised exercise training	Supervised exercise training 2 times per week and placebo gel daily, both for six months duration.
Enhanced Usual Care (EUC)	Home exercise program	Home exercise program 3 times per week and monthly health education modules, both for six months duration.
Enhanced Usual Care (EUC)	Health Education Modules	Home exercise program 3 times per week and monthly health education modules, both for six months duration.
Exercise + Placebo (EX + P)	Placebo gel	Supervised exercise training 2 times per week and placebo gel daily, both for six months duration.

Primary Outcome Measures

Name	Time	Method
Change in Six Minute Walk Distance	Baseline to 6 months	Walking endurance was measured using a 6-Minute Walk Distance. Participants were asked to walk back and forth on a measured path marked clearly at both ends for turning purposes, while being told when each minute has passed, and receiving verbal encouragement every 60 seconds. Total distance was measured in meters with higher distances equating to higher walking endurance. Each individual participant distance from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more improvement in walking distance. In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.

Secondary Outcome Measures

Name	Time	Method
Change in Total Lean Body Mass	Baseline to 6 months	Total lean body mass measured by dual x-ray absorptiometry (DXA). Baseline DXA scans were completed prior to the first administration of study drug. All scans were completed prior to exercise or 1-RM measurements if scheduled for the same day. DXA scans were reviewed for quality control, proper positioning, and artifacts centrally. Each individual participant measure from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more gains in total lean body mass. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline. DXA was not performed at 3 months.
Change in Appendicular Lean Body Mass	Baseline to 6 months	Lean body mass of the arms and legs, measured by dual x-ray absorptiometry (DXA). Baseline DXA scans were completed prior to the first administration of study drug. All scans were completed prior to exercise or 1-RM measurements if scheduled for the same day. DXA scans were reviewed for quality control, proper positioning, and artifacts centrally. Each individual participant measure from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more gains in appendicular lean body mass. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline. DXA was not performed at 3 months.
Change in 1-repetition Maximum (1-RM) Leg Press Strength	Baseline to 6 months	Muscle strength measured as the maximal amount of weight that the participant was able to lift for one repetition (1-RM). The 1-RM is defined as the greatest resistance that could be overcome through a defined range of motion using proper techniques. Subjects were asked to move against progressively heavier resistance loads until a repetition failure was achieved. Each individual participant measure from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent the increased ability to lift more weight. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Total Modified Physical Performance Test (mPPT) Score	Baseline to 6 months	A modified version of the Physical Performance Test (mPPT) was used to measure physical function. Participants were asked to complete 9 standardized tasks (book lift, putting on a lab coat, picking up a penny from the floor, standing balance, standing up five times from a 16-inch chair, 50 foot walk including a turn, 360 degree turn, stair climb for 10 steps, and climbing 2 additional flights of steps) for a total score ranging from 0 (significant impairment) to 36 (excellent functioning). Each individual participant score from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more improvement in physical functioning.
Change in Short Physical Performance Battery (SPPB) Score	Baseline to 6 months	The Short Physical Performance Battery (SPPB) is a well validated objective physical performance measure used to identify risk for disability. The SPPB consists of: chair rise, progressive Romberg balance, and 4 meter gait speed. Each task was scored (0-4) with a total range of 0-12. Participants who score 0 are unable to complete the tasks and participants with higher scores are considered to have higher functional mobility. Each individual participant score from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more improvement in physical performance. In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Older Adult Resources and Services (OARS) Activities of Daily Living (ADL) Questionnaire	Baseline to 6 months	The OARS Multidimensional Functional Assessment Questionnaire Activities of Daily Living (ADL) is a standardized, valid and reliable, self-report questionnaire used to determine the effect of services on the functional status of older adults by asking respondents about their ability to perform ADLS on 2 subscales: Basic (BADL) and Instrumental (IADL). Both subscales are scored from 0 (significant impairment) to 14 (excellent functioning). The individual participant score from Baseline was subtracted from Month 6 to represent change over the length of the study. Higher positive values represent more improvement in functioning. In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Functional Status Questionnaire (FSQ) Total Score	Baseline to 6 months	The Functional Status Questionnaire (FSQ) is a self-reported measure asking about the amount of difficulty a participant experienced when performing daily tasks in the previous 4 weeks. There are a total of 6 subscales, but only the basic ADL and Intermediate ADL were used in the STEP-HI study for a total of 9 items. Scores range from 0 (high amount of difficulty completing tasks) to 36 (no difficulty completing tasks). Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Hip Rating Questionnaire Total Score	Baseline to 6 months	The Hip Rating Questionnaire (HRQ) Standardized is a 14-item scale with weighted questions regarding quality of life (pain level and ability to walk) and function (ability to use stairs, put on socks/shoes, use public transportation, bathe, shop, do housework, and get in and out of a chair/bed) related to the hip fracture event. The scale scores range from 16 to 100. Higher scores are associated with less pain, higher function, and better quality of life. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health	Baseline to 6 months	Patient-Reported Outcomes Measurement Information System (PROMIS®) Global Health instrument is a 10 item self report questionnaire used to measure overall quality of life using 2 summary scores: Physical and Mental Health. Each summary score is standardized to the general population, with the average T-score for the US population being 50 and standard deviation of 10. Each individual participant T-score from Baseline was subtracted from Month 6 T-score to represent change over the length of the study. Higher scores represent larger increases in Physical and Mental Health. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), statistical contracts were evaluated to determine if there was significant between-group differences in the change from baseline to 3 months and additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline.
Change in Bone Mineral Density (BMD) of the Non-fractured Proximal Femur	Baseline to 6 months	Bone mineral density (BMD) measured by dual x-ray absorptiometry (DXA) of the non-fractured proximal femur in participants without hardware in the contralateral hip. Baseline DXA scans were completed prior to the first administration of study drug. All scans were completed prior to exercise or 1-RM measurements if scheduled for the same day. DXA scans were reviewed for quality control, proper positioning, and artifacts centrally. Per the protocol: In addition to the primary analysis (unadjusted baseline to 6 month comparison), additional analysis of covariance were performed to adjust for baseline values and covariates that differed across groups at baseline. DXA was not performed at 3 months.

Trial Locations

Locations (8): University of Maryland School of Medicine/Johns Hopkins University
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Baltimore, Maryland, United States
HebrewSenior Life Harvard Medical School
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Roslindale, Massachusetts, United States
Washington University School of Medicine in St. Louis
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Saint Louis, Missouri, United States
University of Texas Medical Branch at Galveston (UTMB)
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Galveston, Texas, United States
University of Pittsburgh Medical Center
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Pittsburgh, Pennsylvania, United States
University of Colorado, Denver
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Aurora, Colorado, United States
University of Connecticut Heath - UConn Health
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Farmington, Connecticut, United States
University of Utah
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Salt Lake City, Utah, United States