A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Biogen25 enrolled

Overview

The primary objective of the study is to examine the efficacy of multiple doses of Nusinersen administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA). Secondary objectives of this study are to examine the effects of Nusinersen in infants with genetically diagnosed and presymptomatic SMA.

Study Type

INTERVENTIONAL

Allocation

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Spinal Muscular Atrophy

Interventions

NusinersenDRUG

Solution for intrathecal injection

Eligibility

Sex: ALLMin age: 0 WeeksMax age: 6 Weeks

Medical Language ↔ Plain English

Key Inclusion Criteria: * Age ≤ 6 weeks at first dose. * Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation. * Genetic documentation of 2 or 3 copies of survival motor neuron 2 (SMN2). * Ulnar compound muscle action potential (CMAP) ≥ 1 mV at Baseline. * Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins. * Meet additional study related criteria. Key Exclusion Criteria: * Hypoxemia (oxygen saturation \<96% awake or asleep without any supplemental oxygen or respiratory support). * Any clinical signs or symptoms at Screening or immediately prior to the first dosing (Day 1) that are, in the opinion of the Investigator, strongly suggestive of SMA. * Clinically significant abnormalities in hematology or clinical chemistry parameters. * Treatment with an investigational drug given for the treatment of SMA biological agent, or device. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation. * Meet additional study related criteria. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Locations (21)

David Geffen School of Medicine

Los Angeles, California, United States

Outcomes

Primary Outcomes

Time to Death or Respiratory Intervention

The time was the age of the participant at the first occurrence of either a respiratory intervention or death. Respiratory intervention was defined as invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy.

Time frame: Screening up to Day 2891

Secondary Outcomes

Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA)

A participant was considered having clinically manifested SMA if any of the following occurred: * 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

Time frame: At 13 and 24 months of age

Percentage of Participants Alive

Time frame: Up to 8 years of age

Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE)

HINE is evaluated in infants between 2-24 months of age. It's a simple, standardized instrument including 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of HINE (HINE-2) was assessed, which evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform task and score of 2, 3, or 4 indicating full milestone development. Total score is calculated by summing item scores to give maximum possible score of 26. Higher score indicates good neurological function.

Data from ClinicalTrials.gov

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University of California Davis Health System

Sacramento, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Hospital, Orlando

Orlando, Florida, United States

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

Chicago, Illinois, United States

The Johns Hopkins Hospital

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Columbia University

New York, New York, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Utah

Salt Lake City, Utah, United States

...and 11 more locations

Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria

The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone.

Time frame: Baseline up to Day 2891

Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale

The CHOP-INTEND test was designed to evaluate the motor skills of infants with signiﬁcant motor weakness. Participants who were ≥2 years were continued to be assessed until a CHOP INTEND maximum score of 64 was achieved. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, ﬁve were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with higher scores indicating greater muscle strength and function. Total score was calculated as the sum of scores for each item. Total score ranged from 0 (worst possible score) and 64 (best possible score). CHOP-INTEND assessments were discontinued once participants achieved a maximum score of 64, so the number of participants with available data points decreased over time.

Time frame: Baseline, Day 2891

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)

The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. 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 and ranged from 0 to 66. Higher scores indicate increased motor function. Baseline was defined as the time of first HFMSE score after Day 700.

Time frame: Baseline, Day 2160

Change From Baseline in Weight for Age

The World Health Organization (WHO) child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child. Negative change from baseline indicates low weight for age percentile.

Time frame: Baseline, Day 2891

Change From Baseline in Weight for Length

The WHO child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child.

Time frame: Baseline, Day 1849

Change From Baseline in Head Circumference

Time frame: Baseline, Day 2891

Change From Baseline in Chest Circumference

Time frame: Baseline, Day 2891

Change From Baseline in Head to Chest Circumference Ratio

Negative change from baseline indicates reduction in head-to-chest circumference ratio.

Time frame: Baseline, Day 2891

Change From Baseline in Arm Circumference

Time frame: Baseline, Day 2891

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

AE was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect.

Time frame: From the signing of the informed consent form (ICF) up to the end of the study (up to Day 2891)

Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Hematology parameters included hemoglobin, hematocrit, erythrocytes, platelets, leukocytes, neutrophils, eosinophils, basophils, lymphocytes, and monocytes count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values.

Time frame: Baseline up to Day 2891

Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

Blood chemistry parameters included bilirubin (direct and indirect), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, creatinine, sodium, potassium, chloride, protein, albumin, calcium, phosphate, glucose, cystatin C, creatine kinase. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values.

Time frame: Baseline up to Day 2891

Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

Urinalysis included assessments of specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, erythrocytes, leukocytes, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values.

Time frame: Baseline up to Day 2891

Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]

aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Time frame: Baseline up to Day 2891

Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]

PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Time frame: Baseline up to Day 2891

Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]

INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Time frame: Baseline up to Day 2891

Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities

Clinical significance of abnormalities in ECG was determined based on the investigator's discretion. Shift to abnormal indicated values that were normal or unknown at baseline and shifted to abnormal values post-baseline.

Time frame: Baseline up to Day 2891

Change From Baseline in Vital Signs (Temperature)

Negative change from baseline indicates reduction in temperature.

Time frame: Baseline, Day 2891

Change From Baseline in Vital Signs (Blood Pressure)

Time frame: Baseline, Day 2891

Change From Baseline in Vital Signs (Heart Rate)

Negative change from baseline indicates reduction in heart rate.

Time frame: Baseline, Day 2891

Change From Baseline in Vital Signs (Respiratory Rate)

Negative change from baseline indicates reduction in respiratory rate.

Time frame: Baseline, Day 2891

Number of Participants With Neurological Examination Abnormalities Reported as AEs

Participants with abnormalities in neurological examinations recorded as AEs were reported.

Time frame: From the signing of the ICF up to the end of the study (up to Day 2891)

Cerebrospinal Fluid (CSF) Concentration of Nusinersen

Time frame: Predose on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801

Plasma Concentration of Nusinersen

Time frame: Predose on Days 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801 and 4-hour post-dose on Day 1