Investigating NMJ Defects in SMA Following Central and Peripheral SMN Restoration

Study Overview
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Brief Summary
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This is an observational study to investigate the improvement of NMJ defects in adult patients with SMA following treatment with Risdiplam. Eligible patients will have received treatment with daily oral Risdiplam after receiving approval through their commercial insurance or drug assistance program. All subjects will be evaluated at one visit. Eligible subjects must have been receiving risdiplam for at least 12 months.

Detailed Description
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This is a proof of concept trial to investigate the impact of FDA approved therapy for adults with SMA on NMJ transmission. The study will enroll genetically confirmed adults with 5 q SMA treated with risdiplam for at least 12 months. Dosing will be weight- based as approved by the FDA (US Prescribing Information). Assessments will include medical history, general physical and neurological examinations, vital signs, and the recording of adverse events. Diagnostic tests will include repetitive nerve stimulation (RNS), motor unit number estimation (MUNE), and decomposition EMG (dEMG). Further evaluations will utilize the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), the modified SMA Functional Rating Scale (SMAFRS), and the Fatigue Severity Scale (FSS). For ambulatory subjects, the assessment will include a six-minute walk test, while for non-ambulatory subjects, the Children's Hospital of Philadelphia Adult/Adolescent Test of Neuromuscular Disorders (CHOP INTEND) will be performed. Handheld dynamometry will be used to measure strength in bilateral shoulder abduction, elbow flexion, elbow extension, hip flexion, hip abduction, hip adduction, knee flexion, and knee extension. The study aims to investigate the impact of Risdiplam on neuromuscular junction (NMJ) function by assessing changes in the percent decrement of the compound muscle action potential amplitude, as measured through 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve. These results will be compared to historical controls. Additionally, the study will evaluate the differences in strength, motor function, and electrophysiological test scores between groups, which will be stratified based on a 10% decrement cutoff. Further analysis will explore the association between these measures and percent decrement among ambulatory and non-ambulatory patients.

Official Title
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Investigating NMJ Defects in SMA Following Central and Peripheral SMN Restoration

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Risdiplam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form Age 18-70 years at time of signing Informed Consent Form Able and willing to provide written informed consent and to comply with the program protocol according to ICH and local regulations Ability to comply with the study protocol, in the investigator's judgment Adequately recovered from any acute illness at the time of screening, and considered clinically well enough to participate, in the opinion of the treating physician Patients with retinopathy of prematurity should have evidence of stable disease Genetic confirmation of 5q SMA documented on standard genetic tests for the disorder Treated with risdiplam for a duration of 12 months or longer Exclusion Criteria: Treatment with an investigational therapy within 180 days prior to initiation of study drug History of established diagnosis of neuromuscular junction disorder Co-morbid conditions that preclude travel or testing Patients who are, in the investigator's opinion, mentally or legally incapacitated to provide an informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Risdiplam|Risdiplam is administered orally once daily and the recommended dosage is determined by age and body weight (see Table 1) [as outlined in the US Prescribing Information for EVRYSDI™(risdiplam)]. Table 1 Adult and Pediatric Dosing Regimen by Age and Body Weight: US Prescribing Information Age and Body Weight (Recommended Daily Dosage): 2 months to less than 2 years of age (0.2 mg/kg); 2 years of age and older weighing less than 20 kg (0.25 mg/kg); 2 years of age and older weighing 20 kg or more (5 mg)|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrement on repetitive nerve stimulation | Change in the percent decrement of the compound muscle action potential amplitude assessed using 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve compared to historical controls. If CMAP amplitude is absent at spinal accessory nerve, SMA, ulnar CMAP will be used to assess NMJ transmission. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six Minute Walk Test (6MWT) Total Distance | The score difference between groups stratified using a 10% decrement cutoff | Baseline | 
| Six Minute Walk Test Difference in Distance Between the First and Final minute | The score difference between groups stratified using a 10% decrement cutoff | Baseline | 
| Modified Spinal Muscular Atrophy Function Rating Scale (SMA-FRS) | The score difference between groups stratified using a 10% decrement cutoff (scale 0-40, higher score is better). | Baseline | 
| Revised Upper Limb Module (RULM) | The score difference between groups stratified using a 10% decrement cutoff (scale 0-37, a higher score is better) | Baseline | 
| Hammersmith Functional Rating Scale (HFMSE) | The score difference between groups stratified using a 10% decrement cutoff (0-66, a higher score is better | Baseline | 
| Fatigue Severity Scale (FSS) | The score difference between groups stratified using a 10% decrement cutoff (9-63, the higher the score the higher the fatigue) | Baseline | 
| Children's Hospital of Philadelphia - Adult Test of Neuromuscular Disorders (CHOP-ATEND) | The score difference between groups stratified using a 10% decrement cutoff analyses (0-52, a higher score is better) | Baseline | 
| Strength Measure using Hand Held Dynamometry | Strength measurements of of bilateral shoulder abduction, elbow flexion, elbow extension, hip flexion, hip abduction, hip adduction, knee flexion and knee extension. The score difference between groups stratified using a 10% decrement cutoff analyses. | Baseline | 
| Ulnar Compound Muscle Action Potential (Ulnar -CMAP) | The difference in amplitudes between groups stratified using a 10% decrement cutoff | Baseline | 
| Motor Unit Number Estimation (MUNE) | Ulnar MUNE using modified multipoint technique. The difference in MUNE score between groups stratified using a 10% decrement cutoff | Baseline |