Spinal and Bulbar Muscular Atrophy Clinical Trial
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)
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04944940 -
Clinical, Molecular and Imaging Biomarkers in Spinal and Bulbar Muscular Atrophy (SBMA)
|
||
Recruiting |
NCT03555578 -
Specified Drug-Use Survey of Leuprorelin Acetate Injection Kit 11.25 mg "All-Case Investigation: Spinal and Bulbar Muscular Atrophy (SBMA)"
|
||
Recruiting |
NCT06411912 -
A Study of NIDO-361 in Patients With SBMA
|
Phase 2 | |
Completed |
NCT02156141 -
High Intensity Training in Patients With Spinal and Bulbar Muscular Atrophy
|
N/A | |
Completed |
NCT02024932 -
Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy
|
Phase 2 | |
Active, not recruiting |
NCT05517603 -
A Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of AJ201 In Patients
|
Phase 1/Phase 2 | |
Recruiting |
NCT06169046 -
A Placebo-controlled Study of Clenbuterol in Spinal and Bulbar Muscular Atrophy
|
Phase 2 |