Dutasteride to Treat Spinal and Bulbar Muscular Atrophy (SBMA)

• Creatine Kinase, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Serum creatine kinase was determined in venous blood samples analyzed at the Department of Laboratory Medicine of the NIH Clinical Center.
• Manual Muscle Testing, Change From Baseline. [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Manual muscle testing was performed using a modified Medical Research Council (MRC) scale (0=worst, 5=best); the average muscle score was based on 22 muscle groups.
• Adult Myopathy Assessment Tool, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  The Adult Myopathy Assessment Tool rates physical function and muscle endurance, with higher scores indicating better performance; it includes 7 timed functional tasks and 6 endurance tasks (0=worst, 45=best).
• Timed 2-minute Walk, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  The subjects did the 2-minute walk in a 50-foot (15.2-meter) corridor three times, and the average distance was calculated. The subjects were allowed to use an assistive device and rest between the trials.
• Swallow Score Average, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Modified barium swallow studies were done at 0, 12, and 24 months. Twenty-five domains were assessed, and six were chosen for final analysis based on the abnormal findings in subjects evaluated at baseline: vallecular pooling and repeated-swallow, each assessed with thin liquids, purees, and solids (rated 1-4, abnormal to normal).
• Bulbar Rating Scale, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  The Bulbar Rating Scale includes eight domains each rated on a 1-4 scale, abnormal to normal. The original 8-32 point scale was transformed to a 0-100% scale to represent the responses as percentages.
• Sensory Nerve Action Potential Average, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Nerve conduction studies were done on four sensory nerves (median, ulnar, radial, sural), and the amplitudes of the evoked responses were averaged. Loss of amplitude indicates impairment of conduction.
• Median Compound Muscle Action Potential, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Nerve conduction studies were done on the median motor nerve, and the compound muscle action potential amplitude was determined. Loss of amplitude indicates impairment of conduction.
• Peroneal Compound Muscle Action Potential, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Nerve conduction studies were done on the peroneal nerve, and the compound muscle action potential amplitude was determined. Loss of amplitude indicates impairment of conduction.
• Motor Unit Nerve Estimation, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Motor unit number estimation (MUNE) was done with a statistical MUNE program, on the abductor pollicis brevis. All subjects were evaluated on the right side unless severe atrophy produced very low compound muscle action potentials; in this case, the left side was investigated or the abductor digiti minimi was substituted. A decrease in MUNE indicates a loss of motor units.
• Activities of Daily Living, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Subjects rated their daily activity with a modified 9-question Activities of Daily Living (ADL) questionnaire (0-4, fully impaired to normal).
• Medical Outcomes Study 36-item Short Form Version 2 (SF-36v2) Physical Component Summary, Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Subjects completed the Medical Outcomes Study Short Form Version 2 (SF-36v2), in which they rated their physical quality of life over the preceding 4 weeks. Raw SF-36v2 scores were converted to norm-based scales and component summaries using the scoring code provided by QualityMetric (mean=50, standard deviation (SD)=10).
• Medical Outcomes Study 36-item Short Form Version 2 (SF-36v2) Mental Component Summary, Percent Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Subjects completed the Medical Outcomes Study Short Form Version 2 (SF-36v2), in which they rated their mental quality of life over the preceding 4 weeks. Raw SF-36v2 scores were converted to norm-based scales and component summaries using the scoring code provided by QualityMetric (mean=50, standard deviation (SD)=10), and percent change in the norm-based scale was calculated.
• International Index for Erectile Function (IIEF), Change From Baseline [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  Sexual function was rated using the International Index of Erectile Function (IIEF). The total IIEF score (5-75, worst-best) was reported as the percent maximum (0-100%).

This study will determine if the drug dutasteride can improve weakness, mobility, functioning, nerve function, and quality of life in patients with spinal and bulbar muscular atrophy (SBMA). Patients with this inherited disease have an abnormal androgen receptor protein. The male hormones testosterone and dihydrotestosterone (DHT) bind to this abnormal receptor, causing damage to nerve cells that innervate muscle and leading to weakness. Dutasteride decreases DHT production. Lowering DHT levels may decrease the harmful effects of DHT to the nerves and improve strength in people with SBMA.

Males 18 years of age and older with SBMA who have neurological symptoms and can walk 100 feet (with or without assistive devices) may be eligible for this study. Candidates are screened with a blood test and a review of their medical records and genetic studies.

Participants undergo the following procedures:

• Blood and urine tests, history and physical examination, assessment of muscle strength
• Quality-of-life questionnaire
• Tests to assess functional abilities, such walking up steps, keeping the head up while lying down, and other measures
• Nerve conduction study and motor unit number estimation to assess nerve damage. A probe placed on the skin delivers small electrical impulses and wires taped to the skin record the impulses.
• Quantitative muscle testing to measure strength. The subject pushes and pulls levers attached to a gauge. Strength is recorded by a computer.
• Medication. Participants are divided into two groups. One group is given the study drug, dutasteride; the other receives a placebo (sugar pill). All participants take their assigned medication once a day for 24 months.
• Follow-up evaluations. Every 6 months for 2 years, participants return to NIH to repeat the tests described above to determine the effects of the dutasteride. Nerve and quantitative muscle testing is not done at the 6- and 18-month visits.
• In addition to their follow-up appointments here at the NIH every 6 months, participants will also have blood tests and a physical examination performed after 3, 9, 15 and 21 months of treatment by the patient's local physician.

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.

• Kennedy's Disease
• Spinal and Bulbar Muscular Atrophy

• Drug: Dutasteride
  Dutasteride 0.5 mg/day
  Other Name: Avodart
• Drug: Placebo
  Matched placebo

• Active Comparator: Dutasteride
  Dutasteride 0.5 mg/day
  Intervention: Drug: Dutasteride
• Placebo Comparator: Placebo
  Matched placebo
  Intervention: Drug: Placebo

• Rhodes LE, Freeman BK, Auh S, Kokkinis AD, La Pean A, Chen C, Lehky TJ, Shrader JA, Levy EW, Harris-Love M, Di Prospero NA, Fischbeck KH. Clinical features of spinal and bulbar muscular atrophy. Brain. 2009 Dec;132(Pt 12):3242-51.
• Fernández-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE, Levy EW, Solomon BI, Harris-Love MO, La Pean A, Schindler AB, Chen C, Di Prospero NA, Fischbeck KH. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb;10(2):140-7. Epub 2011 Jan 6.

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