Testosterone Therapy With or Without Finasteride After Spinal Cord Injury: TRT-SCI Trial

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 funciton 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.

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 L1 or above from trauma, vascular, or orthopedic pathology
• Low total testosterone (<300 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 HCT <40%, hemoglobin <13.6 g/dL, or red blood cell count <4.5 million/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 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 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 PSA >4.0 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
• 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
• stroke
• 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 (AST or ALT) >1.5 times the normal upper limit
• Severe or end-stage chronic kidney disease defined as eGFR <30 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: TRT, compounded or over-the-counter androgenic hormone or androgen precursor, 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 mg/d 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