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

NCT06532474 | Recruiting

• 1 other identifier: ML43225
• Study Type: observational
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Spinal Muscular Atrophy

Keywords

Spinal Muscular Atrophy (SMA); SMA drugs; Responses of Skeletal Muscle; SMN-directed therapies; Eyrysdi; Spinraza; Zolgensma

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (19)

• Identify changes in motor function in non-ambulant patients and ambulant patients with SMA types 2 and 3

  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

  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

  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

  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

  At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)

Study Arms (4)

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

Eligibility Criteria

• Age: 5 Years - 20 Years
• Sex: all
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Genentech, Inc.: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

RECRUITING

Related Links

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

Biospecimen

Retention: SAMPLES WITH DNA

blood and urine

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Study Officials

• Richard Finkel, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jean Laboe, RN

CONTACT

901-595-1693; referralinfo@stjude.org

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2024
• First Posted: August 1, 2024
• Study Start: October 29, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): March 1, 2027
• Last Updated: November 4, 2025

Record last verified: 2025-11

Locations

US (1)