A Multisite, Double-blind, Randomized Controlled Trial Comparing Body Composition, Muscle, and Bone Changes to TestosteRone Therapy With or Without Finasteride After Spinal Cord Injury: TRT-SCI Trial
Trial Snapshot
- Phase
- Phase 2
- Status
- Not yet recruiting
- Enrollment
- 300
- Locations
- 4
- Primary Endpoint
- Change in lower limb fat-free mass
Study Overview
Brief Summary
Spinal cord injury (SCI) results in lower limb muscle loss, bone loss, and high fat mass that impede the recovery of physical function, increase bone fracture risk, and worsen health and quality of life. These deficits result from reduced activity after SCI and may be worsened by low testosterone, which is present in many men with SCI. In older men with low testosterone who do not have SCI, testosterone therapy (TRT) is known to increase muscle mass, muscle strength, and bone mineral density, and to reduce body fat. However, it is not known if TRT is effective in men with SCI. The purposes of this study are to determine the effectiveness of TRT in men who have low testosterone and difficulty walking after chronic motor incomplete SCI and to assess whether a process in the body that changes testosterone to dihydrotestosterone (DHT; another hormone that is stronger than testosterone) impacts the effectiveness of TRT in the impaired lower limbs and in other tissues after SCI. The researchers hypothesize that TRT will improve muscle and bone in the impaired limbs of men with chronic incomplete SCI and reduce fat mass, and that finasteride (a drug that blocks that blocks a process that changes testosterone to DHT) will influence prostate symptoms but not the musculoskeletal or body composition benefits produced by TRT.
Detailed Description
There is no known cure for spinal cord injury (SCI) nor for the muscle, bone, or metabolic deficits that impair physical function, increase fracture risk, and worsen health after SCI. These deficits are preceded by the neural insult and impaired motor function and may be impacted by low testosterone, present in many men with SCI. Testosterone therapy (TRT) is known to improve musculoskeletal health, body composition, and physical function in older men with low testosterone who do not have SCI and some of the effects of TRT are known to be mediated by the 5-alpha reductase type II (5AR2) enzyme, which converts testosterone to dihydrotestosterone (DHT; a more potent endogenous metabolite). However, it remains unknown whether TRT improves muscle mass, muscle function, bone mineral density, and body composition / metabolic health in men with low testosterone and ambulatory dysfunction after chronic incomplete SCI, and whether actions of 5AR2 mediates any of the effects of testosterone in the impaired lower limbs and in other tissues with reduced neural input after SCI.
For this study, men with low testosterone and ambulatory dysfunction after chronic motor incomplete SCI will be randomized to receive TRT with or without the 5AR2-inhibitor finasteride or a placebo treatment for 9 months. TRT or placebo injection will be administered every other week; finasteride or placebo will be administered daily. Participants will be assessed at study entry and regularly thereafter. Assessments will include measurements of body composition and bone mineral density by dual energy x-ray absorptiometry (DXA) scans, bone microstructure and strength by high-resolution peripheral quantitative computerized tomography (HR-pQCT) scans, and tests of muscle strength and physical function. Participants will also undergo safety tests, including electrocardiogram (ECG) for cardiac electrophysiology, questionnaires of health status, and blood tests to assess prostate specific antigen (PSA), hematocrit, liver enzymes (AST and ALT), blood lipids, sex hormones, and other markers of health.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Supportive Care
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Veterans eligible for care within the Veterans Health Administration (VHA)
- •Diagnosis of motor incomplete SCI (AIS C-D) for >24-months involving spinal segment lumbar (L)1 or above from trauma, vascular, or orthopedic pathology
- •Low total testosterone (<300 nanograms/decilliter [ng/dL]) and/or low free testosterone (<4.6 ng/dL)
- •Presence of one or more sign of low testosterone, defined as:
- •decreased energy
- •motivation
- •initiative or self-confidence
- •increased fatigue or tiredness
- •reduced sexual desire or activity
- •decreased spontaneous (e.g., morning) erections or erectile dysfunction
- •loss of body hair or reduced shaving
- •feeling sad or blue or having a depressed mood or a persistent low-grade depressive disorder (defined as a score of >3 on the Patient Health Questionnaire [PHQ]-2)
- •hot flashes
- •fatigue or irritability
- •poor concentration or memory
- •mild unexplained (normocytic-normochromic) anemia, defined as hematocrit (HCT) <40%, hemoglobin <13.6 grams/deciliter (g/dL), or red blood cell count <4.5 million/microliter (mcL)
- •sleep disturbances or increased sleepiness
- •reduced muscle bulk, strength, or physical function
- •increased body fat or body mass index
- •Presence of motor impairment, defined as self-selected walking pace ≤1.0 meters/second (m/s) on a 10-meter walk test (10mWT), with or without gait devices or braces and with or without assistance from another person, or as self-selected walking pace >1.0 m/s with reliance on a gait device or brace or with highly compensated movement impairment identified by a trained observer
- •Medically stable condition asymptomatic for bladder infection, major decubiti, cardiopulmonary disease, or other significant condition that will interfere with the study
- •Documented approval from a physician verifying medical status
Exclusion Criteria
- •Involvement in another research study that may influence outcomes
- •Mental state that precludes understanding the protocol
- •Life expectancy <12 months
- •History of or current congenital spinal cord injury (SCI) (e.g., Chiari malformation, myelomeningocele, intraspinal neoplasm, Friedreich's ataxia) or degenerative spinal disorder (e.g., spinocerebellar degeneration) that may complicate procedures
- •Amyotrophic lateral sclerosis, multiple sclerosis, or other neurologic injury / impairment that may complicate procedures
- •Current cancer diagnosis
- •History of prostate or breast cancer
- •Any diagnosed or treated cancer in the past 24 months, except basal or squamous cell carcinoma of the skin that has been successfully treated
- •Any major lower-limb fracture in the past 12 months
- •Unevaluated circulating prostate-specific antigen (PSA) >4.0 nanograms/milliliter (ng/mL) or >3.0 ng/mL in men with prostate cancer risk factors, including agent orange exposure, first degree relative with prostate cancer, or African American background
- •Currently seeking fertility or expected during the study
- •Diagnosed gynecomastia
- •Hematocrit (HCT) >48%
- •Any major cardiovascular event in the last 6 months, defined as:
- •an acute myocardial infarction
- •any cardiac revascularization procedure including stenting
- •angioplasty or coronary artery bypass grafting
- •revascularization of the carotid or middle cerebral artery or procedure to treat critical limb ischemia
- •hospitalization due to unstable angina
- •transient ischemic attack
- •peripheral vascular disease
- •Any angina that is not controlled on a current medical regimen (Canadian class II, III, or IV)
- •Poorly compensated congestive heart failure (New York Heart Association [NYHA] class III or IV)
- •Poorly controlled hypertension when on medication (consistent systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg)
- •Poorly controlled arrhythmia of any type
- •Severe valvular heart disease
- •Baseline electrocardiogram findings such as left bundle branch block or marked abnormality that precludes serial screening for occult ischemic events
- •History of unprovoked deep venous thrombosis, unprovoked pulmonary embolism, history of recurrent deep venous thrombosis or known thrombophilia
- •Major non-cardiovascular surgery (e.g., major abdominal or thoracic procedure) within 90 days before screening or a major surgery scheduled at the time of screening
- •Liver enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) >1.5 times the normal upper limit
- •Severe or end-stage chronic kidney disease defined as eGFR <30 milliliters/minute (mL/min)
- •Diagnosed, but untreated severe obstructive sleep apnea
- •Use of an agent that alters sex-steroid metabolism in the past 90 days, such as: testosterone therapy (TRT), compounded or over-the-counter androgenic hormone or androgen precursor, 5-alpha reductase (5AR) inhibitors, growth hormone, clomiphene, aromatase inhibitors, anti-estrogen or estrogen treatment, or others
- •Use of anti-resorptive or bone anabolic drug therapy in the past 180 days
- •Acute use (>5 days) of any opioid (e.g., oxycodone, hydrocodone) or systemic glucocorticoids >7.5 milligrams (mg)/day prednisone equivalent (e.g., hydrocortisone 30 mg, methylprednisolone 6 mg, or dexamethasone 1.2 mg) in the week before screening, except for men who are taking these for a chronic condition and who are anticipated to continue these for the study duration
- •Known allergy to any TRT component (e.g., cottonseed oil or other)
- •Any other condition, lab abnormality, therapy, medical or psychiatric condition, or reason that might pose a risk to the participant, make participation not in the person's best interest, confound the study results (e.g., inability to comply with study requirements), make the participant unsuitable to receive a study intervention, or interfere with their ability to participate for the full study duration
Arms & Interventions
testosterone, placebo
Testosterone by intramuscular injection (200 mg/q2wk) and placebo pill orally (5 mg/day)
Intervention: testosterone cypionate (Drug)
testosterone, finasteride
Testosterone by intramuscular injection (200 mg/q2wk) and a finasteride pill orally (5 mg/day)
Intervention: testosterone cypionate (Drug)
testosterone, placebo
Testosterone by intramuscular injection (200 mg/q2wk) and placebo pill orally (5 mg/day)
Intervention: placebo pill (Drug)
placebo treatment
Placebo by intramuscular injection (q2wk) and a placebo pill orally (daily)
Intervention: placebo injection (Drug)
placebo treatment
Placebo by intramuscular injection (q2wk) and a placebo pill orally (daily)
Intervention: placebo pill (Drug)
testosterone, finasteride
Testosterone by intramuscular injection (200 mg/q2wk) and a finasteride pill orally (5 mg/day)
Intervention: finasteride (Drug)
Outcomes
Primary Outcomes
Change in lower limb fat-free mass
Time Frame: Baseline, 9 months
Change from baseline in lower limb fat-free mass assessed via dual-energy X-ray absorptiometry (DXA)
Secondary Outcomes
- Change in total body fat-free mass(Baseline, 9 months)
- Change in knee extensor strength(Baseline, 9 months)
- Change in distal femur bone mineral density(Baseline, 9 months)
- Change in visceral adipose tissue (fat) mass(Baseline, 9 months)
- Change in prostate specific antigen (PSA)(Baseline, 3 months, 6 months, 9 months)