Background: Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a slowly progressive, X-linked motor neuron disease for which there is currently no treatment. It is caused by a mutation in the androgen receptor that results in a polyglutamine repeat expansion. Recent animal studies have demonstrated that decreasing endogenous androgen levels leads to functional improvement and increased survival. Studies have also shown that high levels of 5 alpha-reductase, the enzyme that converts testosterone to the more potent dihydrotestosterone (DHT), are present in the ventral spinal cord, while low levels of this enzyme are found within skeletal muscle. Thus, by selectively decreasing levels of DHT with dutasteride, a 5 alpha-reductase inhibitor, it is hypothesized that there will be a selective protection of motor neurons, without the adverse effects of reducing the anabolic effects of androgen on muscle. Objective: This will be a phase II, double-blind, placebo-controlled trial examining the safety and efficacy of the 5 alpha-reductase inhibitor dutasteride in inhibiting the progression of neurodegeneration in patients with Kennedy's disease. Natural history data will also be obtained from the placebo control arm. Study Population: We aim to enroll 50 men with genetically confirmed Kennedy's disease. Design: Our objective is to examine the safety and efficacy of dutasteride given at a dose of 0.5 mg a day for 2 years in an outpatient setting. This will be a randomized, double-blind, placebo-controlled trial with 25 subjects in each arm. The subjects will be evaluated neurologically and endocrinologically every 6 months at the NIH Clinical Center. In addition to their clinical visits at the NIH, subjects will also be examined by their primary physician after 3, 9, 15, and 21 months of treatment. The primary objective is to examine the effects of dutasteride on inhibiting or reversing the rate of progression of weakness as measured by quantitative muscle testing. Following informed consent, patients will undergo an initial medical history and physical followed by testing of specific neurological and endocrinological measures over a two-day outpatient visit. Patients will provide blood samples for analysis of hormonal levels and extent of muscle damage every three months. In addition, at the initial, one-year, and two-year follow-up visits patients will have nerve conduction studies as well as quantitative and functional strength evaluation. Each patient will be randomized to the treatment or placebo arm and will be given a 3 month supply of the study drug or a matched placebo at each visit. In between clinic visits, the NIH clinical pharmacy will send an additional 3 month supply to each subject until the subsequent visit. Outcome Measures: The primary outcome measure used will be quantitative muscle testing (QMT). Secondary outcome measures include the Adult Myositis Assessment Tool (AMAT), 2-minute walk, a quality of life measure (Medical Outcomes Study 36-item Short Form Version 2, SF-36v2), neurophysiological testing (sensory nerve action potentials, and statistical motor unit number estimation). Changes in hormone levels (testosterone, dihydrotestosterone, androstenedione, estradiol), and creatine kinase levels will also be measured and correlated with changes in strength. Evaluation of disease severity and course as related to CAG repeat length and androgen levels will also be assessed. Future Directions: The results of this phase II study will assist us in developing a multi-center, double-blind, placebo-controlled phase III trial. In addition, natural history data will be obtained from the control arm that will be important in future clinical trials of SBMA.
Inclusion Criteria: - Genetically confirmed SBMA - Neurological symptoms of SBMA - Ability to ambulate 100 feet with or without the use of assistive devices - Willingness to participate in all aspects of trial design and follow-up - Male sex Exclusion Criteria: - Age less than 18 years - Female sex - A history of hypersensitivity to dutasteride or 5 alpha-reductase inhibitors. - Exposure to 5 alpha-reductase inhibitors, anti-androgens, testosterone, or steroids in the preceding 6 months - Patients who are taking potent cytochrome P450 3A4 (CYP3A4) inhibitors for over 4 weeks - Patients with any pre-existing liver disease - Alkaline phosphatase, gamma glutamyl transferase, or direct bilirubin greater than 1.5 times the upper limit of normal - Alanine aminotransferase or aspartate aminotransferase greater than 1.5 times upper limit of normal in subjects with normal creatine kinase levels - Creatinine greater than 1.5 times the upper limit of normal - Platelet count, white blood cell count or hemoglobin below the lower limit of normal - Other clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study