Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies
NCT Number: NCT06532474
Status: NOT_YET_RECRUITING
Study Type: OBSERVATIONAL
Conditions: Spinal Muscular Atrophy
Sponsor: St. Jude Children's Research Hospital
Collaborators: Genentech, Inc.
Sex: ALL
Age: CHILD, ADULT
Enrollment: 24
Study Design: Observational Model: |Time Perspective: p
Start Date: 2024-08
Completion Date: 2026-11
Locations: St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, United States

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 evidence for risdiplam effect on skeletal muscle.
* To obtain quality of life and disability data from participants in this study.

Primary Outcome Measures: 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 6 months|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 6 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months
Secondary Outcome Measures: 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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months|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 and 12 months