Clinical trial NCT06532474: Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies
Official title: Pilot Study Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy (SMA)
SMA drugs
Responses of Skeletal Muscle
SMN-directed therapies
Eyrysdi
Spinraza
Zolgensma
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2024-08-01
Enrollment: 24
Sex: ALL
Minimum age (years): 5
Maximum age (years): 20
Standard ages: CHILD
ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Those who meet the Eligibility criteria and consent to enrollment on the study.

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Feasibility of performing MR functional imaging in SMA patients
timeFrame: At baseline and at 6 months (+/- 14 days)
measure: Reliability of performing MR functional imaging in SMA patients
timeFrame: At baseline and at 6 months (+/- 14 days)
measure: Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (phosphocreatine)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (creatine concentrations)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Measure intramuscular fat fraction in major muscle groups of the lower extremity in patients with SMA types 2 and 3
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Measure electrophysiological tests of motor neuron function to repetitive nerve stimulation in patients with SMA types 2 and 3
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Secondary outcomes:
measure: Identify changes in motor function in non-ambulant patients and ambulant patients with SMA types 2 and 3
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in non-ambulant patients with SMA types 2 and 3 - Revised Upper Limb Module
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in non-ambulant patients with SMA types 2 and 3 - Block and Box Test
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 6-Minute Walk
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 10 Meter Walk/Run
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in ambulant patients with SMA types 2 and 3 - 4-Stair Climb
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Supine-to-Stand Test
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Timed Up-and-Go Test
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Assess myometry, or measurement of muscle strength
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Muscle ultrasound thickness and echogenicity of 5 muscles - 2 upper limb and 3 lower limb
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Plasma neurofilament light (NF-L) and phosphorylated heavy chain (pNF-H) levels
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Blood SMN protein levels
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Pyruvic acid (mg/dL)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Lactic Acid (millimoles per liter)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Lactate dehydrogenase (LDH) (units per liter (U/L)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Trough risdiplam drug levels
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: Quality of life (QOL) and disability information - Pediatric Quality of Life Inventory (PedsQL)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: QOL and disability information - Pediatric Outcomes Data Collection Instrument (PODCI)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
measure: QOL and disability information - SMA Health Index (SMA-HI)
timeFrame: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Other outcomes:
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Richard Finkel, MD
role: PRINCIPAL_INVESTIGATOR
References: