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

Biogen126 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

126

Conditions

Spinal Muscular Atrophy

Interventions

NusinersenDRUG

Administered by intrathecal (IT) lumbar puncture (LP) injection

Sham procedurePROCEDURE

Small needle prick on the lower back at the location where the IT injection is normally made

Eligibility

Sex: ALLMin age: 2 YearsMax age: 12 Years

Medical Language ↔ Plain English

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.

Locations (24)

Outcomes

Primary Outcomes

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15

The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.

Time frame: Baseline and Month 15

Secondary Outcomes

Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15

Time frame: Baseline and Month 15

Proportion of Participants That Achieved Any New Motor Milestone at Month 15

New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.

Data from ClinicalTrials.gov

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UCLA Clinical and Translational Research Center

Los Angeles, California, United States

Lucile Packard Children's Hospital at Stanford

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Hospital

Orlando, Florida, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Columbia University Medical Center

New York, New York, United States

Oregon Health & Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia - Neurology

Philadelphia, Pennsylvania, United States

...and 14 more locations

Time frame: Month 15

Number of New Motor Milestones Achieved Per Participant

New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.

Time frame: Month 15

Change From Baseline in Revised Upper Limb Module (RULM) Test

The RULM Test is used in patients with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test has a total of 20 items with an entry item that serves as functional class identification and does not contribute to the total score. The remaining 19 scorable items reflect different functional domains and are graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.

Time frame: Baseline and Month 15

Proportion of Participants That Achieved Standing Alone

If the participant was unable to achieve standing alone at Baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.

Time frame: Month 15

Proportion of Participants That Achieved Walking With Assistance

If the participant was unable to achieve walking with assistance at baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.

Time frame: Month 15

Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)

AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death; an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.