Pilot Study Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Feasibility of performing MR functional imaging in SMA patients
研究概览
简要总结
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 muscles in five potential groups of patients with spinal muscular atrophy: untreated, actively treated with nusinersen (Spinraza®) or onasemnogene abeparvovec (Zolgensma®), actively treated with risdiplam (Evrysdi®), switching from Spinraza or Zolgensma to Evrysdi and initiating combination therapy of Spinraza or Zolgensma with 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.
详细描述
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 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 5 Years 至 20 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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, 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, HFMSE score at screening between 40 and
- •SMN-directed therapy inclusion:
- •Current Evrysdi prescription (Group 1)
- •Must have Evrysdi prescription through their treating physician
- •If initiating combined therapy using Evrysdi with Spinraza or Zolgensma, must have not started Evrysdi treatment OR
- •Current Spinraza or Zolgensma prescription (Group 2)
- •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 (Group 3)
- •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 (Group 4)
排除标准
- •Any chronic medical condition, planned surgery, or treatment with a medication which would impact safety or participation of the study at the investigator's discretion
- •Inability to perform reliably the motor function testing or the exercise testing in the MR scanner.
- •Fat fraction > 35% in calf or bicep at screening MRI
- •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.
结局指标
主要结局
Feasibility of performing MR functional imaging in SMA patients
时间窗: At baseline and at 6 months (+/- 14 days)
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
时间窗: At baseline and at 6 months (+/- 14 days)
MR functional imaging is considered reliable if the test-retest reliability is ≥ 0.80 for key imaging biomarkers.
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (phosphocreatine)
时间窗: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure phosphocreatine within the muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.
Measure intramuscular fat fraction in major muscle groups of the lower extremity in patients with SMA types 2 and 3
时间窗: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Measurement of thickness of muscle compared to fat on MRI, measured in percentage.
Measure electrophysiological tests of motor neuron function to repetitive nerve stimulation in patients with SMA types 2 and 3
时间窗: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
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.
Compare skeletal muscle oxidative phosphorylation bioenergetics in patients with SMA types 2 and 3 (creatine concentrations)
时间窗: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure creatine concentrations within the muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.
Measure intramuscular fat fraction in major muscle extremity in patients with SMA types 2 and 3
时间窗: At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days)
Measurement of thickness of muscle compared to fat on MRI, measured in percentage.
次要结局
- Trough risdiplam drug levels(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)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- QOL and disability information - Pediatric Outcomes Data Collection Instrument (PODCI)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- QOL and disability information - SMA Health Index (SMA-HI)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- 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 ambulant patients with SMA types 2 and 3 - 4-Stair Climb(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))
- Identify changes in motor function in ambulant patients with SMA types 2 and 3 - Supine-to-Stand 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 - Timed Up-and-Go Test(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- Assess myometry, or measurement of 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(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(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- Blood SMN protein levels(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- Pyruvic acid (mg/dL)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- Lactic Acid (millimoles per liter)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))
- Lactate dehydrogenase (LDH) (units per liter (U/L)(At baseline and longitudinally at 6 (+/- 14 days) and 12 months (+/- 14 days))