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

Not yet recruiting

• Conditions: Spinal Muscular Atrophy

• Registration Number: NCT06532474
• Lead Sponsor: St. Jude Children's Research Hospital

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.
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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.
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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2024-07-29
• Study First Submitted QC: 2024-07-29
• Study First Posted: 2024-08-01
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-07
• Last Update Posted: 2024-11-08
• Study Start: 2025-01
• Primary Completion: 2026-05
• Study Completion: 2026-11

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

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

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Measure intramuscular fat fraction in major muscle groups of the lower extremity in patients with SMA types 2 and 3	At baseline and longitudinally at 6 and 12 months	Measurement of thickness of muscle compared to fat on MRI, measured in percentage.
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (phosphocreatine)	At baseline and longitudinally at 6 and 12 months	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.
Feasibility of performing MR functional imaging in SMA patients	At baseline and 6 months	MR functional imaging is considered feasible if ≥ 80% of MRI protocol eligible patients can complete 100% of imaging assessments at baseline and 6 months.
Reliability of performing MR functional imaging in SMA patients	At baseline and 6 months	MR functional imaging is considered reliable if the test-retest reliability is ≥ 0.80 for key imaging biomarkers.
Measure electrophysiological tests of motor neuron function to repetitive nerve stimulation in patients with SMA types 2 and 3	At baseline and longitudinally at 6 and 12 months	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.; ...
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (creatine concentrations)	At baseline and longitudinally at 6 and 12 months	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.

Secondary Outcome Measures

Name	Time	Method
Trough risdiplam drug levels	At baseline and longitudinally at 6 and 12 months	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.
Identify changes in motor function in non-ambulant patients and ambulant patients with SMA types 2 and 3	At baseline and longitudinally at 6 and 12 months	The Hammersmith Functional Motor Scale Expanded (HFMSE) has a score range from 0-66 with lower scores indicating poorer overall motor function.
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 and 12 months	The Revised Upper Limb Module (RULM) has a score range 0-37 with lower scores indicating poorer upper limb motor function.
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 and 12 months	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.
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 4-Stair Climb	At baseline and longitudinally at 6 and 12 months	The 4-Stair Climb (4SC) Test is measured in seconds and assesses lower extremity power and motor function. Longer times indicate lower motor function
Assess myometry, or measurement of muscle strength	At baseline and longitudinally at 6 and 12 months	Myometry measures force in pounds or kilograms and measures the strength of a muscle group. The more force measured indicates more muscle strength.
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 6-Minute Walk	At baseline and longitudinally at 6 and 12 months	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.
Muscle ultrasound thickness and echogenicity of 5 muscles - 2 upper limb and 3 lower limb	At baseline and longitudinally at 6 and 12 months	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.
QOL and disability information - Pediatric Outcomes Data Collection Instrument (PODCI)	At baseline and longitudinally at 6 and 12 months	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.
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 10 Meter Walk/Run	At baseline and longitudinally at 6 and 12 months	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
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Timed Up-and-Go Test	At baseline and longitudinally at 6 and 12 months	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
QOL and disability information - SMA Health Index (SMA-HI)	At baseline and longitudinally at 6 and 12 months	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
Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Supine-to-Stand Test	At baseline and longitudinally at 6 and 12 months	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.
Plasma neurofilament light (NF-L) and phosphorylated heavy chain (pNF-H) levels	At baseline and longitudinally at 6 and 12 months	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.
Blood SMN protein levels	At baseline and longitudinally at 6 and 12 months	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.
Quality of life (QOL) and disability information - Pediatric Quality of Life Inventory (PedsQL)	At baseline and longitudinally at 6 and 12 months	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.

Trial Locations

Locations (1)

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States