A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
Condition: Spinal Muscular Atrophy
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy
Intervention: Nusinersen; Sham procedure
Intervention description: Administered by intrathecal (IT) lumbar puncture (LP) injection; Small needle prick on the lower back at the location where the IT injection is normally made
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 126.0
Sex: All
Minimum age: 2 Years
Maximum age: 12 Years
Healthy volunteers: No
Keywords: Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS-SMN Rx; ISIS 396443; CHERISH; IONIS-SMNRx; IONIS-SMN Rx

Summary:

      The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS
      396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy
      (SMA). The secondary objective is to examine the safety and tolerability of nusinersen
      administered intrathecally to participants with later-onset SMA.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Parent or guardian has signed informed consent and, if indicated per participant's age
             and institutional guidelines, participant has signed informed assent

          -  Be medically diagnosed with Spinal Muscular Atrophy (SMA)

          -  Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months
             of age

          -  Be able to sit independently, but has never had the ability to walk independently

          -  Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than
             or equal to 10 and less than or equal to 54 at Screening

          -  Be able to complete all study procedures, measurements and visits and parent or
             guardian and subject has adequately supportive psychosocial circumstances, in the
             opinion of the Investigator

          -  Have an estimated life expectancy of greater than 2 years from Screening, in the
             opinion of the Investigator

          -  Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use
             is planned for study procedures

          -  For subjects who have reached reproductive maturity, satisfy study contraceptive
             requirements

        Key Exclusion Criteria:

          -  Respiratory insufficiency, defined by the medical necessity for invasive or
             non-invasive ventilation for greater than 6 hours during a 24 hour period, at
             Screening

          -  Medical necessity for a gastric feeding tube, where the majority of feeds are given by
             this route, as assessed by the Site Investigator

          -  Severe contractures or severe scoliosis evident on X-ray examination at Screening

          -  Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event,
             or nutritional support within 2 months of Screening or planned during the duration of
             the study

          -  Presence of an untreated or inadequately treated active infection requiring systemic
             antiviral or antimicrobial therapy at any time during the screening period

          -  History of brain or spinal cord disease, including tumors, or abnormalities by
             magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with
             the LP procedures or cerebrospinal fluid (CSF) circulation

          -  Presence of an implanted shunt for the drainage of CSF or an implanted central nervous
             system (CNS) catheter

          -  History of bacterial meningitis

          -  Dosing with IONIS-SMN Rx in any previous clinical study

          -  Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts
             the subject's ability to perform any of the outcome measure testing required in the
             protocol and from which the subject has not fully recovered or achieved a stable
             baseline

          -  Clinically significant abnormalities in hematology or clinical chemistry parameters or
             electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit
             that would render the subject unsuitable for inclusion

          -  Treatment with another investigational drug (e.g., oral albuterol or salbutamol,
             riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or
             device within 1-month of Screening or 5 half-lives of study agent, whichever is
             longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any
             history of gene therapy, antisense oligonucleotide therapy, or cell transplantation.

          -  Ongoing medical condition that according to the Site Investigator would interfere with
             the conduct and assessments of the study. Examples are medical disability (e.g.,
             wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of
             safety or would compromise the ability of the subject to undergo study procedures.

        NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.