Investigating NMJ Defects in SMA Following Central and Peripheral SMN Restoration

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Risdiplam

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 18

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll genetically confirmed adults with 5 q SMA with electrodiagnostic evidence of NMJ defects treated with risdiplam for a duration of 12 months or longer.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bakri Elsheikh
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Bakri Elsheikh, MBBS, Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2021
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: January 21, 2022
• First Submitted That Met QC Criteria: January 21, 2022
• First Posted (Actual): February 2, 2022

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 20, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy, Spinal; Physiological Effects of Drugs; Peripheral Nervous System Agents; Neuromuscular Agents; Risdiplam
• Other Study ID Numbers: 2021H0158; ML43109 (Other Identifier: Genentech, Inc.)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No