Clinical Trial: Dutasteride to Treat Spinal and Bulbar Muscular Atrophy (SBMA)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase II Clinical Trial to Examine the Efficacy and Safety of Dutasteride in Patients With Kennedy's Disease (Spinal and Bulbar Muscular Atrophy

Brief Summary:

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

    Detailed Summary:

    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 neu
    Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

    Current Primary Outcome: Muscle Strength Change From Baseline [ Time Frame: 0, 12, and 24 months ]

    Quantitative muscle assessment (QMA) was done with a fixed frame dynamometer, a strain gauge tensiometer, and a computer-aided acquisition system. Maximal voluntary isometric muscle contractions were measured twice, the average was calculated, and the results were summed over 22 muscle groups (11 on each side). The total force was scaled for body weight and expressed as percent change from baseline. Measurements were performed at 0, 12, and 24 months. The calculated percent changes at 12 and 24 months are shown.


    Original Primary Outcome:

    Current Secondary Outcome:

    • Creatine Kinase, Change From Baseline [ Time Frame: 0, 12, and 24 months ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      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 ]
      Sexual function was rated using the International Index of Erectile Function (IIEF). The total IIEF s

      Original Secondary Outcome:

      Information By: National Institutes of Health Clinical Center (CC)

      Dates:
      Date Received: March 15, 2006
      Date Started: March 2006
      Date Completion:
      Last Updated: January 25, 2011
      Last Verified: January 2011