Clinical, Molecular and Imaging Biomarkers in Spinal and Bulbar Muscular Atrophy (SBMA)

Study Overview
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Brief Summary
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Background: SBMA is an inherited chronic disease. It affects males in mid to late adulthood. It causes slowly progressive weakness of muscles and hand tremors. Researchers want to learn more about the effects of SBMA. Objective: To identify measurements that change over time in SBMA, including tests of muscle strength and function, as well as measurements of muscle and fat size. Eligibility: Men over the age of 18 both with and without a history of SBMA. Design: Participants will have a medical history, physical exam, and blood and urine tests. They will have neuromuscular ultrasound. They will have a lumbar puncture to obtain spinal fluid. For this, a needle will be inserted into the spinal canal in the lower back. Participants will have muscle strength and function tests. These tests may include pushing, pulling, rising from a chair and sitting back down, and/or walking. During these tests, they may wear an accelerometer (activity tracker) on their wrist. Participants will get an activity tracker to wear on their wrist for 10 days at home every 3 months. Participants with SBMA will also have lower limb magnetic resonance imaging (MRI) and optional whole-body MRI. They will have lung function tests. They will have speech and swallow tests. They will complete questionnaires. They may have optional body scans to measure bone density and lean body mass. They may have optional muscle biopsies. For biopsies, a needle will be used to take a small piece of muscle from the leg. Participants with SBMA will have 5 study visits over 2 years (every 6 months). Participants without SBMA will have 1 study visit.

Detailed Description
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Study Description: Spinal and bulbar muscular atrophy (SBMA) is an inherited form of motor neuron disease caused by a CAG-repeat expansion in the androgen receptor gene on the X chromosome for which there is no treatment currently. Biomarkers will be collected from participants with SBMA during this study to understand the natural history and progression of the disease. Objectives: The main objective of this study is to develop clinical, molecular and imaging outcome parameters that correlate with disease progression and severity and that predict clinical decline. These biomarkers and outcome measures can serve as potential tools for the evaluation of efficacy in future therapeutic studies in SBMA. Endpoints: The studies performed under this protocol are exploratory. However, the following measures may be used to characterize baseline status and disease progression over the course of the study: Muscle strength by manual and quantitative myometry Distance traveled in meters on the 6-minute walk test Activity levels as measured by an accelerometer Global disability measured by the SBMAFRS questionnaire Fatigue as measured by the Fatigue Severity Scale Breathing function measured by pulmonary function test Swallow and speech function measured by questionnaires, tongue muscle strength, digital audio recordings for analysis of voice and speech, and barium swallow Skeletal muscle MRI measurement of muscle volume and fat fraction Whole body MRI measurement of body muscle fat fraction, muscle fat infiltration, and liver. Skeletal muscle ultrasound measurement of muscle thickness, echogenicity and elasticity Nerve ultrasound measurement of nerve cross sectional area and anterior posterior diameter Laboratory studies from blood, serum, urine, and CSF Muscle biopsy assessment of androgen receptor levels and function Study Population: There will be a total of up to 70 male participants in this study. The target number of completers is 25 male participants with genetically confirmed SBMA and 25 healthy male participants who are age (plus or minus 5 years) and sex matched to the SBMA participants. Description of Sites/Facilities Enrolling Participants: NIH Clinical Center Study Duration: 48 months for data collection and analysis Participant Duration: SBMA participants will be seen for a baseline visit followed by a visit every six months for a total of 5 visits (about 29 months). Healthy volunteers will have a single visit.

Official Title
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An Observational Study to Assess Clinical, Molecular and Imaging Biomarkers in Spinal and Bulbar Muscular Atrophy (SBMA)

Conditions
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Spinal and Bulbar Muscular Atrophy, Kennedys Disease, Motor Neuron Disease

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Some restrictions are placed on participation in the study because we aim to identify disease biomarkers specific to those with early t intermediate stages of disease who would be potential candidates for future therapeutic studies. In order to be eligible to participate in the SBMA cohort, an individual must meet all of the following criteria: Stated willingness to comply with all study procedures and availability for the duration of the study Male, above the age of 18 years Genetically confirmed SBMA Ability of subject to understand and the willingness to sign a written informed consent document Ability of subject to travel to the NIH Clinical Center. Note: an SBMA patient who meets both of the additional following criteria will be offered an optional whole body MRI at subsequent follow-up visits: Spinal bulbar muscular atrophy functional rating of < 50 (and > 35). On initial whole body MRI, subject has evidence of muscle fat replacement such that the total volume of disease affected muscles (i.e., muscles with at least 10% muscle fat infiltration and no more than 50% muscle fat fraction) is at least: 500ml if only 1 muscle is eligible or 250ml if more than one muscle meets the criteria In order to be eligible to participate in this study in the Healthy Control cohort, an individual must meet all of the following criteria: Stated willingness to comply with all study procedures and availability to travel to the NIH for the duration of the study Male, above the age of 18 years No history of SBMA or other neuromuscular disorder No history of facial palsy Ability of subject to understand and the willingness to sign a written informed consent document Ability of subject to travel to the NIH Clinical Center. EXCLUSION CRITERIA: SBMA is a disease that affects males and manifests in adulthood. Thus, woman and children are not included in this study. This study will not include individuals who lack consent capacity. An SBMA patient who meets any of the following criteria will be excluded from participation in this study: Contraindications to MRI such as a contraindicated non-removable metal device (i.e., pacemaker, defibrillator, insulin pump, metal clips, non-removable jewelry) or claustrophobia. Non ambulatory PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants) INR greater than or equal to 1.5, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction History of a bleeding disorder Use of anticoagulants Use of androgen reducing agents within the past two years Note: An SBMA patient who meets any of the following criteria will be excluded from the lumbar puncture procedure: PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants) INR greater than or equal to 1.5, thrombocytopenia (less than 70,000), or abnormal bleeding time or platelet dysfunction History of a bleeding disorder Use of anticoagulants Note: An SBMA patient who meets any of the following criteria will be excluded from the muscle biopsy procedure: Advanced wasting of tibialis anterior that precludes needle muscle biopsy (in order to ensure that a sample taken would be of muscle and not just fat and fascia) Use of aspirin or non-steroidal anti-inflammatory agents 3 days prior to the procedure Note: An SBMA patient who meets any of the following criteria will be excluded from the whole body MRI: Patient has a history of prior treatment with androgen reducing agents including LHRH agonists or antagonists, androgen receptor antagonists and selective androgen receptor modifiers. Patient is unable to complete the study assessments of QMT or timed walk tests. Patient anticipates making major lifestyle changes during the observation period relating to diet and exercise. A Healthy Control participant who meets any of the following criteria will be excluded from the study: PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants) INR greater than or equal to 1.5, thrombocytopenia (less than 70,000), or abnormal bleeding time or platelet dysfunction History of a bleeding disorder Use of anticoagulants

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Volunteers<br>Healthy male participants who are age and sex matched to the SBMA participants | |
| Patients with Spinal and bulbar muscular atrophy (SBMA)<br>Male participants with genetically confirmed SBMA | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease progression as measured by clinical and molecular tests | Clinical measurements include MRI, DEXA, physical function, swallow, and pulmonary testing. Molecular measurements include serum and plasma biomarkers, muscle analysis, and urine testing. | Baseline to visits every 6 months to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Natural History, Motor Neuron Disease, Spinal and Bulbar Muscular Atrophy, Kennedys disease, Androgen Receptor, Natural History Study