Principal Investigator: Russell Butterfield
Keywords: Spinal Muscular Atrophy , SMA , Infant Department: Pediatric Administration
IRB Number: 00078916 Co Investigator: Ai Sakonju
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, Movement Disorders, Spinal Muscular Atrophy
Recruitment Status: Recruiting

Contact Information

Nicole Rausch

Brief Summary

6.1. Objectives
6.1.1. Primary Objective
The primary objective of the study is to examine the efficacy of multiple doses of ISIS 396443 administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic SMA.

6.1.2. Secondary Objectives
Secondary objectives of this study are to examine the effects of ISIS 396443 in infants with genetically diagnosed and presymptomatic SMA on the following:

  • Development of clinically manifested SMA as determined by a composite of clinical features seen in subjects with SMA
  • Growth and function
  • Safety, tolerability, and PK

6.2. Endpoints
6.2.1. Primary Endpoint
The primary endpoint of the study is the time to death or respiratory intervention (invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy).

6.2.2. Secondary Endpoints
The secondary efficacy endpoints of this study are as follows (all assessed at approximately 13 and 24 months of age, unless otherwise noted):

  • Proportion of subjects developing clinically manifested SMA as defined by any of the following:
    • Age-adjusted weight <5th percentile or decrease of ≥2 major weight growth curve percentiles (3rd, 5th, 10th, 25th, or 50th) or a percutaneous gastric tube placement for nutritional support
    • Failure to achieve the ability to sit without support 
    • Failure to achieve standing with assistance
    • Failure to achieve hands-and-knees crawling
    • Failure to achieve walking with assistance by 24 months of age
    • Failure to achieve standing alone by 24 months of age
    • Failure to achieve walking alone by 24 months of age
  • Proportion of subjects alive
  • Attainment of motor milestones assessed as part of the Hammersmith Infant Neurological Examination (HINE) (Section 2)
  • Attainment of motor milestones as assessed by World Health Organization (WHO) criteria
  • Change from Baseline in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale
  • Change from Baseline in HFMSE
  • Change from Baseline in growth parameters: weight for age/length, head circumference, chest circumference, head to chest circumference ratio, and arm circumference

The secondary safety endpoints of this study are as follows:

  • Incidence of adverse events (AEs) and/or serious adverse events (SAEs)
  • Change from Baseline in clinical laboratory parameters, electrocardiograms (ECGs), and vital signs
  • Neurological examinations

The secondary PK endpoint of this study is CSF and plasma ISIS 396443 concentrations.

6.2.3. Exploratory Endpoints
The exploratory endpoints of this study are as follows:

  • Change from Baseline in CMAP
  • Change from Baseline in 6-Minute Walk Test (6MWT)
  • Change from Baseline in the Peabody Developmental Motor Scale 2 (PDMS-2)
  • Measures of respiratory events: respiratory infections, hospitalizations for respiratory events, noninvasive and invasive ventilator use, and oxygen saturation
  • Proportion of subjects who develop thoracoabdominal asynchrony measured by Respiratory Plethysmography (RP)
  • Time to death or permanent ventilation (≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event OR tracheostomy)
  • Time to death or ventilation (≥6 hours ventilation/day continuously for 1 or more days OR tracheostomy)
  • Change from Baseline in CSF SMN protein concentrations
  • Change from Baseline in cognitive assessments
  • Change from Baseline and maintenance in body composition and bone density (as assessed by dual-energy X-ray absorptiometry [DEXA])
  • Proportion of subjects who develop signs and symptoms of dysphagia
  • Change from Baseline in the quality of life questionnaires

Inclusion Criteria

8.1. Inclusion Criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at Screening or at the timepoint specified in the individual eligibility criterion listed:

1. Ability of parent(s) or guardian(s) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local subject privacy regulations.
2. Age ≤6 weeks at first dose.
3. Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation.
4. Genetic documentation of 2 or 3 copies of SMN2.
5. Ulnar CMAP ≥1 mV at Baseline.
6. Receiving adequate nutrition and hydration (without gastrostomy) in the opinion of the Investigator.
7. Body weight ≥3rd percentile for age using appropriate country-specific guidelines.
8. Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins.
9. Able to complete all study procedures, measurements, and visits and parent(s) or guardian(s)/subject has adequately supportive psychosocial circumstances in the opinion of the Investigator.

Exclusion Criteria

8.2. Exclusion Criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at Screening or at the timepoint specified in the individual criterion listed:

1. Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support, or for altitudes >1000 m, oxygen saturation of <92% awake or asleep without any supplemental oxygen or respiratory support).
2. Any clinical signs or symptoms at Screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA.

3. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening Period.
4. History of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments.
5. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
6. History of bacterial meningitis or viral encephalitis.
7. Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Investigator, at Screening that would render the subject unsuitable for inclusion.
8. Treatment with an investigational drug given for the treatment of SMA (e.g., albuterol/ salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, etc.), biological agent, or device. Any history of gene therapy, prior ASO treatment, or cell transplantation.
9. Diagnosis of neonatal Respiratory Distress Syndrome requiring surfactant replacement therapy or invasive ventilatory support.
10. The subject’s parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study or is unable to or does not agree to comply with study requirements.
11. Ongoing medical condition that, according to the Investigator, would interfere with the conduct and assessments of the study. Examples are medical disability that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures.
12. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject unsuitable for enrollment.