start date: March 26, 2020
estimated completion: July 4, 2023
last updated: December 17, 2021
phase of development:
Phase 2/Phase 3
size / enrollment: 172
primary outcomes:
- Part B Infantile-onset SMA: Change from Baseline in CHOP INTEND Total Score
The CHOP INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4.
- Baseline up to Day 183
Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.
- Screening up to Day 389
Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
- Screening up to Day 302
Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
- Screening up to Day 302
Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
- Screening up to Day 302
Part A and C: Change from Baseline in Body Length/Height
- Baseline up to Day 302
Part C Infantile-onset SMA: Change from Baseline in Head Circumference
- Baseline up to Day 302
Part C Infantile-onset SMA: Change from Baseline in Chest Circumference
- Baseline up to Day 302
Part C Infantile-onset SMA: Change from Baseline in Arm Circumference
- Baseline up to Day 302
Part A and C Later-onset SMA: Change from Baseline in Ulnar Length
- Baseline up to Day 302
Part A and C: Ratio of Weight for Age
- Baseline up to Day 302
Part A and C: Ratio of Weight for Length
- Baseline up to Day 302
Part C: Ratio of Head-to-chest Circumference
- Baseline up to Day 302
Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
- Baseline up to Day 269
Part A and C: Change from Baseline in Prothrombin Time (PT)
- Baseline up to Day 269
Part A and C: Change from Baseline in International Normalized Ratio (INR)
- Baseline up to Day 269
Part A and C: Change in Urine Total Protein
- Baseline up to Day 302
Part A and C: Change from Baseline in Neurological Examination Outcomes
- Baseline up to Day 302
Part A and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
- Baseline up to Day 302
Part A and C: Percentage of Participants with a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec
- Baseline up to Day 302
secondary outcomes:
- Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders
Day 302
- Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score
Baseline up to Day 302
- Part B Infantile-onset SMA: Time to Death or Permanent Ventilation
Screening up to Day 302
- Part B Infantile-onset SMA: Time to Death (Overall Survival)
Screening up to Day 399
- Part A and B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score
Baseline up to Day 302
- Part A and B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score
Baseline up to Day 302
- Part A and B Later-onset SMA: Total Number of New WHO Motor Milestones
Baseline up to Day 302
- Part A and B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)
Baseline up to Day 302
- Part A and B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL)
Baseline up to Day 302
- Part B: Number of Participants with AEs and SAEs
Screening up to Day 399
- Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
Screening up to Day 302
- Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs
Day 1 up to Day 302
- Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
Screening up to Day 302
- Part B: Change from Baseline in Body Length/Height
Baseline up to Day 302
- Part B Infantile-onset SMA: Change from Baseline in Head Circumference
Baseline up to Day 302
- Part B Infantile-onset SMA: Change from Baseline in Chest Circumference
Baseline up to Day 302
- Part B Infantile-onset SMA: Change from Baseline in Arm Circumference
Baseline up to Day 302
- Part B Later-onset SMA: Change from Baseline in Ulnar Length
Baseline up to Day 302
- Part B: Ratio of Weight for Age
Baseline up to Day 302
- Part B: Ratio of Weight for Length
Baseline up to Day 302
- Part B: Ratio of Head-to-chest Circumference
Baseline up to Day 302
- Part B: Change from Baseline in aPTT
Baseline up to Day 279
- Part B: Change from Baseline in PT
Baseline up to Day 279
- Part B: Change from Baseline in INR
Baseline up to Day 279
- Part B: Change in Urine Total Protein
Baseline up to Day 302
- Part B: Change from Baseline in Neurological Examination Outcomes
Baseline up to Day 302
- Part B: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
Baseline up to Day 302
- Part B: Percentage of Participants with a Postbaseline QTcF of > 500 msec and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec
Baseline up to Day 302
- Part A, B and C: Number of Hospitalizations
Day 1 to Day 302
- Part A, B and C: Duration of Hospitalizations
Day 1 to Day 302
- Part A, B and C: Clinical Global Impression of Change (CGIC)
Day 302
- Part A, B and C: Number of Participants with Serious Respiratory Events
Screening up to Day 399
- Part B Infantile-onset SMA: Percentage of Time on Ventilation
Screening up to Day 302
- Parts A, B and C: Ventilator Use
Screening up to Day 302
- Parts A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
Baseline up to Day 302
- Part C: Change from Baseline in HFMSE Score
Baseline up to Day 302
- Part C: Change from Baseline in RULM Score
Baseline up to Day 302
- Part C: Total Number of New WHO Motor Milestones
Baseline up to Day 302
- Part C: Change from Baseline in ACEND
Baseline up to Day 302
- Part C: Change from Baseline in PedsQL™
Baseline up to Day 302
- Part C: Change from Baseline in CHOP INTEND Total Score
Baseline to up Day 302
- Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score
Baseline up to Day 302
inclusion criteria:
• Eligible Ages: 0 - 120
• Eligible Sexes: all
Key Inclusion Criteria:
Part A, B and C:
- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)
Part A:
Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
Age 2 to ≤ 15 years, inclusive, at the time of informed consent
Part B:
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age > 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
Age 2 to < 10 years at the time of informed consent
Can sit independently but has never had the ability to walk independently
HFMSE score ≥ 10 and ≤ 54 at Screening
Part C:
- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
Part C Cohort 1:
- Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)
Part C Cohort 2:
Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
HFMSE total score ≥4 points at Screening
RULM entry item A score ≥3 points at Screening
Key
exclusion criteria: Criteria:
Part A, B and C:
Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose
Part A:
Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
Medical necessity for a gastric feeding tube
Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Part B:
Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
Medical necessity for a gastric feeding tube
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth
Part C:
Concurrent or previous participation and/or administration of nusinersen in another clinical study
Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening
NOTE: Other protocol defined Inclusion/
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