Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies

Pilot Study Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies

In this observational study, researchers are looking at the effects of spinal muscular atrophy (SMA) drugs on the muscles and nerve cells in patients with SMA.

Primary Objectives

• To evaluate the feasibility and reliability of performing MR functional imaging in exercising muscle in patients with SMA.
• To evaluate patients with SMA types 2 and 3 at baseline and longitudinally at 6 and 12 months

Secondary Objectives

• To describe the MR functional bioenergetics response in the leg muscles in four potential groups of patients with spinal muscular atrophy: untreated, actively treated with nusinersen (Spinraza®) or onasemnogene abeparvovec (Zolgensma®), actively treated with risdiplam (Evrysdi®), and switching from Spinraza or Zolgensma to Evrysdi.
• To identify changes in motor function in patients with SMA types 2 and 3 who initiate treatment with risdiplam.
• To obtain biomarkers in blood, urine, and muscle tissue to provide proof-of-concept support for risdiplam effect on skeletal muscle.
• To obtain quality of life and disability data from participants in this study.

Study Overview

• Status: Recruiting
• Conditions: Spinal Muscular Atrophy

Detailed Description

This is an observational study to demonstrate the feasibility of performing MR functional imaging in exercising muscle in patients with SMA. The participants will be prescribed medication by their treating physician, they will not receive any drug as part of this study.

Participants participating in the ML43225 study, will be put into one of four groups depending on their type of SMA and the drugs they may or may not be taking. They will be asked to come to clinic 3 times over one year. Each visit will include magnetic resonance (MR) studies, a muscle ultrasound, a nerve test, muscle function testing, lung function testing, blood work, vital signs, and participants will be asked about their quality of life and daily life activities. After participants have completed the 3 required visits, they will be taken off study.

• Study Type: Observational
• Enrollment (Estimated): 24

Contacts and Locations

• Study Contact: Name: Jean Laboe, RN; Phone Number: 901-595-1693; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital
      • Principal Investigator: Richard Finkel, MD
      • Contact: Jean Laboe, RN; Phone Number: 901-595-1693; Email: referralinfo@stjude.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Those who meet the Eligibility criteria and consent to enrollment on the study.

Description

Inclusion Criteria:

• Genetic confirmation of SMA with homozygous deletion of SMN1 or compound heterozygous deletion/mutation of SMN1
• Two, three, or four copies of SMN2
• Age 5 to 20 years
• Non-ambulatory participants: maximum function sitting or standing with support, never walked independently, still able to sit independently for 5 seconds at screening, with active ankle plantar flexion strength of at least 3 N with hand-held myometry and capable of performing repetitive maximal plantar flexion effort for 120 seconds. HFMSE score at screening between 10 and 45 points.
• Ambulatory participants: minimum function of independent walking, able to walk unassisted a minimum of 100 meters at screening, ankle plantar flexion strength of at least 10 N with hand-held myometry and capable of performing repetitive maximal plantar flexion for 120 seconds. HFMSE score at screening between 40 and 60.

• SMN-directed therapy inclusion:

  • Current Evrysdi prescription

    • Must have Evrysdi prescription through their treating physician but have not yet initiated treatment OR

  • Current Spinraza or Zolgensma prescription

    • For patients on Spinraza, must have been taking Spinraza for at least 12 months at screening (4 loading and 2 maintenance doses) and following the FDA-recommended dosing schedule
    • For patients on Zolgensma, must have been dosed at least one year prior to screening
    • Must have Spinraza or Zolgensma prescription through their treating physician OR

  • Changing from Spinraza or Zolgensma to Evrysdi

    • For patients on Spinraza, must have been taking Spinraza for at least 12 months at screening (4 loading and 2 maintenance doses) and following the FDA-recommended dosing schedule
    • For patients on Zolgensma, must have been dosed at least one year prior to screening
    • Must have voluntarily decided to switch therapies based on discussion with their treating physician
    • Must have Evrysdi prescription through their treating physician but have not yet initiated treatment OR
  • Have never received any SMN-directed therapies

Exclusion Criteria:

• Labs at screening that are abnormal and identified as clinically significant by the PI: CBC, and CMP, liver function tests (over twice the upper limit of normal), PT/PTT, urine protein of 2+ or greater.
• Inability to perform reliably the motor function testing or the exercise testing in the MR scanner.
• Treatment with a possible SMA-enhancing or mitochondrial-enhancing medication, unless discontinued within 3 months prior to screening: oral albuterol, hydroxyurea, phenylbutryate, valproic acid, creatine, l-carnitine, or other mitochondrial type supplement (riboflavin, lipoic acid, etc.). A daily multivitamin and Vitamin D supplement and intermittent inhaled albuterol are permitted if the dosage is unchanged during the study.
• Need for routine non-invasive ventilation support.
• Non-oral nutritional support, e.g., gastrostomy tube feeding.
• Any ferrous metal implants (e.g., spinal rods) that preclude testing in a MR scanner.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Cohort 1; Current Evrysdi prescription
Cohort 2; Current Spinraza or Zolgensma prescription
Cohort 3; Changing from Spinraza or Zolgensma to Evrysdi
Cohort 4; Have never received any SMN-directed therapies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of performing MR functional imaging in SMA patients	MR functional imaging is considered feasible if ≥ 80% of MRI protocol eligible patients can complete 100% of imaging assessments at baseline and 6 months.	At baseline and at 6 months (+/- 14 days)
Reliability of performing MR functional imaging in SMA patients	MR functional imaging is considered reliable if the test-retest reliability is ≥ 0.80 for key imaging biomarkers.	At baseline and at 6 months (+/- 14 days)
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (phosphocreatine)	Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure phosphocreatine within the gastrocnemius-soleus leg muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (creatine concentrations)	Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure creatine concentrations within the gastrocnemius-soleus leg muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Measure intramuscular fat fraction in major muscle groups of the lower extremity in patients with SMA types 2 and 3	Measurement of thickness of muscle compared to fat on MRI, measured in percentage.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Measure electrophysiological tests of motor neuron function to repetitive nerve stimulation in patients with SMA types 2 and 3	Electrophysiological testing: Compound motor action potential (CMAP, measured in millivolts), motor unit number estimate (MUNE, average 200-400 for most limb muscles), and repetitive stimulation at 3 Hz - right ulnar to abductor digiti minimus and right fibular/peroneal nerve to tibialis anterior muscle. A decrease of more than 40% in the amplitude of CMAP is considered abnormal.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify changes in motor function in non-ambulant patients and ambulant patients with SMA types 2 and 3	The Hammersmith Functional Motor Scale Expanded (HFMSE) has a score range from 0-66 with lower scores indicating poorer overall motor function.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in non-ambulant patients with SMA types 2 and 3 - Revised Upper Limb Module	The Revised Upper Limb Module (RULM) has a score range 0-37 with lower scores indicating poorer upper limb motor function.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in non-ambulant patients with SMA types 2 and 3 - Block and Box Test	The Block and Box Test (BBT) is a measure of gross manual dexterity and is scored by counting the number of blocks carried from one compartment to another. Higher scores are indicative of better manual dexterity.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 6-Minute Walk	The 6-Minute Walk (6MW) Test measures how far someone can walk in six minutes, a higher score indicates better exercise tolerance score. A low score correlates with lower function.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 10 Meter Walk/Run	The 10 Meter Walk/Run (10MW) Test is measured in seconds and assesses walking speed over a short distance. Longer times indicate lower motor function	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 4-Stair Climb	The 4-Stair Climb (4SC) Test is measured in seconds and assesses lower extremity power and motor function. Longer times indicate lower motor function	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Supine-to-Stand Test	The Supine-to-Stand (STS) Test is measured in seconds and assesses the ability to move from laying on your back to standing up straight. Longer times indicate lower motor function.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Timed Up-and-Go Test	The Timed Up-and-Go (TUG) Test is measured in seconds and assesses the ability to stand up from sitting in a chair, walk 10 feet, turn around, walk back, and sit down. Longer times indicate lower motor function	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Assess myometry, or measurement of muscle strength	Myometry measures force in pounds or kilograms and measures the strength of a muscle group. The more force measured indicates more muscle strength.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Muscle ultrasound thickness and echogenicity of 5 muscles - 2 upper limb and 3 lower limb	Muscle thickness is measured in centimeters and echogenicity is measured in gray-scale value. Muscle thickness and echogenicity are related to muscle strength, physical function, muscle mass, and quality of muscle.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Plasma neurofilament light (NF-L) and phosphorylated heavy chain (pNF-H) levels	The NF-L and pNF-H levels are measured in nanograms per milliliter from blood samples and can be an indicator of nerve cell damage. Higher values normally mean more nerve damage is occurring.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Blood SMN protein levels	SMN protein levels are measured in nanograms per milliliter from blood samples. Higher values indicate more SMN protein production which is normally deficit in people with SMA.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Pyruvic acid (mg/dL)	This parameters has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. A normal blood pyruvic acid level is between 0.3 and 1.5 milligrams per deciliter (mg/dL). Elevated pyruvic acid in glycolysis usually indicates a disruption in the normal metabolic pathway.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Lactic Acid (millimoles per liter)	This parameter has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. Normally, blood lactate levels are between 1-2 mmol/L when not exercising. Elevated lactic acid during glycolysis indicates that the body is primarily relying on anaerobic glycolysis, meaning it is breaking down glucose for energy without sufficient oxygen, leading to a buildup of lactate as a byproduct.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Lactate dehydrogenase (LDH) (units per liter (U/L)	This parameters has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. Normal LDH levels in children vary by age. Normal adult range is 140-280 U/L. An elevated level of lactate dehydrogenase (LDH) in glycolysis indicates an increased rate of anaerobic metabolism.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Trough risdiplam drug levels	Trough risdiplam drug level is measured in nanograms per milliliter from blood samples and indicates the concentration of risdiplam in someone's blood stream. Higher values mean someone has more risdiplam exposure. This will only be tested on participants who are taking the drug risdiplam.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Quality of life (QOL) and disability information - Pediatric Quality of Life Inventory (PedsQL)	The Pediatric Quality of Life Inventory (PedsQL) is a 23-item questionnaire measuring health-related quality of life in children and adolescents aged 2-18. Higher scores indicate better quality of life.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
QOL and disability information - Pediatric Outcomes Data Collection Instrument (PODCI)	The Pediatric Outcomes Data Collection Instrument (PODCI) is an 83-86 item questionnaire that measures the health-related quality of life for children and adolescents with musculoskeletal disorders aged 2-18. Higher scores indicate better quality of life.	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
QOL and disability information - SMA Health Index (SMA-HI)	The SMA Health Index (SMA-HI) is a 107 item questionnaire that measures a patient's perception of disease burden in 15 areas of health related to SMA. Higher scores indicate more SMA disease burden	At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Richard Finkel, MD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• Clinical Trials Open at St. Jude
• Description St. Jude Children's Research Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: July 29, 2024
• First Submitted That Met QC Criteria: July 29, 2024
• First Posted (Actual): August 1, 2024

Study Record Updates

• Last Update Posted (Estimated): November 4, 2025
• Last Update Submitted That Met QC Criteria: November 3, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy (SMA); Spinraza; Zolgensma; SMA drugs; Responses of Skeletal Muscle; SMN-directed therapies; Eyrysdi
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy, Spinal
• Other Study ID Numbers: ML43225

Drug and device information, study documents

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