A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With 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 injection.; Small needle prick on the lower back at the location where the IT injection is normally made.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 21.0
Sex: All
Healthy volunteers: No
Keywords: EMBRACE; SMA

Summary:

      The primary objective of Part 1 of this study is to assess the safety and tolerability of
      Nusinersen in participants with SMA who are not eligible to participate in the clinical
      studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). The secondary
      objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in
      participants with SMA. The primary objective of Part 2 of this study is to assess the
      long-term safety and tolerability of Nusinersen in participants with SMA who participated in
      Part 1 and completed their End of Part 1 Evaluation assessments. The secondary objective of
      Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who
      participated in Part 1 and completed their End of Part 1 Evaluation assessments.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound
             heterozygote.

          -  Onset of clinical signs and symptoms consistent with SMA at ≤6 months of age and have
             documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with
             SMA at ≤6 months of age, >7 months of age (211 days) at screening, and have
             documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with
             SMA at >6 months of age, are ≤18 months of age at screening, and have documentation of
             2 or 3 SMN2 copies.

          -  Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is
             planned for study procedures.

          -  Medical care, such as routine immunizations meets and is expected to continue to meet
             guidelines set out in the Consensus Statement for Standard of Care in SMA, in the
             opinion of the Investigator.

          -  Participants with 2 SMN2 copies must reside within approximately 9 hours'
             ground-travel distance from a participating study site for the duration of the study.

        Key Exclusion Criteria:

          -  Meets additional study related criteria.

          -  Any previous exposure to ISIS 396443; previous dosing in this study or previous
             studies with ISIS 396443.

          -  Signs or symptoms of SMA present at birth or within the first week after birth.

          -  Ventilation for ≥16 hours per day continuously for >21 days at screening.

          -  Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous
             system (CNS) catheter at screening.

          -  History of brain or spinal cord disease that would interfere with the LP procedure,
             CSF circulation, or safety assessments.

          -  Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional
             support within 2 months prior to screening, or hospitalization for surgery planned
             during the study.

          -  Clinically significant abnormalities in hematology or clinical chemistry parameters or
             Electrocardiogram (ECG), as assessed by the Investigator.

          -  Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole,
             carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device
             within 30 days prior to screening. Any history of gene therapy, prior antisense
             oligonucleotide (ASO) treatment, or cell transplantation.

        For Part 2 only:

        To be eligible to participate in Part 2 of this study, participants must meet the following
        eligibility criteria at the time of consent to participate in Part 2:

        Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.

        Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study
        and to provide signed and dated informed consent on the Part 2 informed consent form (ICF)
        and authorization to use confidential health information in accordance with national and
        local participant privacy regulations.

        Able to complete all study procedures, measurements, and visits, and parent or legal
        guardian/participant has adequately supportive psychosocial circumstances, in the opinion
        of the Investigator.

        Participants will be excluded from the Part 2 if they meet the following exclusion
        criterion at the time of consent into Part 2 of the study:

        Any significant change in clinical status, including laboratory tests that, in the opinion
        of the Investigator, would make them unsuitable to participate in Part 2. The Investigator
        must reassess the subject's medical fitness for participation and consider any diseases
        that would preclude treatment.

        NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.