Clinical trial NCT05518773: Mechanisms and Treatment of Exercise Intolerance and Persistent Fatigue in Spinal Muscular Atrophy
Official title: Mechanisms and Treatment of Exercise Intolerance and Persistent Fatigue in Spinal Muscular Atrophy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Spinal Muscular Atrophy
Keywords: spinal muscular atrophy
neuromuscular disease
risdiplam
nusinersen
aerobic capacity
oxygen uptake
fatigue
near infrared spectroscopy
muscle ultrasound
exercise tolerance
six minute walk test
mitochondria mitophagy
mitochondria
exercise
cycle ergometry
SMA
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2022-08-29
Enrollment: 34
Sex: ALL
Minimum age (years): 8
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study sample will include 34 ambulatory SMA patients, 17 currently treated with nusinersen, and 17 currently treated with risdiplam.

Brief summary: This study will focus on the pathophysiological underpinnings of reduced exercise capacity and fatigue in ambulatory patients with spinal muscular atrophy (SMA). There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to survival motor neuron (SMN) protein deficiency. This is an observational, single visit study including 34 ambulatory SMA patients treated with SMN repletion therapies (risdiplam or nusinersen) for at least 6 months at enrollment.

Detailed description: SMN depletion affects muscle mitochondria and thus muscle function as a result. The relationship between these and their effect(s) on fatigue in the context of SMN repletion treatment has not been evaluated. If muscle function is vulnerable to SMN insufficiency, treatment strategies targeting muscle in addition to the central nervous system (motor neurons) may ameliorate fatigue and improve exercise capacity, thereby improving quality of life and bringing SMA treatments closer to a cure. This project explores such an idea by comparing the effects of the two different SMN repletion modalities in patients. This is an observational cross-sectional study involving ambulatory SMA children and adults treated for at least 6 months with SMN repletion therapy, either (1) systemically with risdiplam, or (2) intrathecally (central nervous system-only), with nusinersen.

Eligibility criteria: Inclusion Criteria:

* Genetic confirmation of SMA with laboratory documentation of homozygous deletion of survival motor neuron (SMN1) exon 7;
* At least 8 years of age at time of signing Informed Consent Form (or assent)
* Children or adults currently receiving treatment, for at least 6 months, with SMN repletion therapy, either with

  (1) risdiplam, or (2) nusinersen
* Able to walk independently at least 25 meters
* Able to tread a stationary cycle ergometer.

Exclusion Criteria:

* Unable to walk 25 meters independently.
* Use of investigational medications intended for the treatment of SMA within 30 days prior to study entry.
* The presence of any contraindication to exercise according the American College of Sports Medicine (ACSM) criteria.

Primary outcomes:
measure: Peak oxygen uptake
timeFrame: Baseline
Secondary outcomes:
measure: NIRS derived index of muscle oxygen extraction
timeFrame: Baseline
measure: Distance walked during the Six Minute Walk Test (6MWT)
timeFrame: Baseline
measure: Leg muscle composition
timeFrame: Baseline
Other outcomes:
measure: Relationship of muscle quality and function
timeFrame: Baseline
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Jacqueline Montes, PT, EdD
role: PRINCIPAL_INVESTIGATOR
References: