A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)

A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Later-onset Spinal Muscular Atrophy

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.

This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc.

In August 2016, sponsorship of the trial was transferred to Biogen.

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.