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

Phase 2

Completed

Conditions: Spinal Muscular Atrophy

Interventions: Drug: Nusinersen

Registration Number: NCT02386553

Lead Sponsor: Biogen

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nusinersen	Nusinersen	Nusinersen administered as an intrathecal injection

Primary Outcome Measures

Name	Time	Method
Time to Death or Respiratory Intervention	Screening up to Day 2891	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.

Secondary Outcome Measures

Name	Time	Method
Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA)	At 13 and 24 months of age	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
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE)	Day 700	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.
Percentage of Participants Alive	Up to 8 years of age
Change From Baseline in Head to Chest Circumference Ratio	Baseline, Day 2891	Negative change from baseline indicates reduction in head-to-chest circumference ratio.
Change From Baseline in Vital Signs (Heart Rate)	Baseline, Day 2891	Negative change from baseline indicates reduction in heart rate.
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria	Baseline up to Day 2891	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.
Change From Baseline in Arm Circumference	Baseline, Day 2891
Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale	Baseline, Day 2891	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.
Change From Baseline in Head Circumference	Baseline, Day 2891
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)	Baseline, Day 2160	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.
Change From Baseline in Weight for Age	Baseline, Day 2891	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.
Change From Baseline in Weight for Length	Baseline, Day 1849	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.
Change From Baseline in Vital Signs (Temperature)	Baseline, Day 2891	Negative change from baseline indicates reduction in temperature.
Change From Baseline in Chest Circumference	Baseline, Day 2891
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From the signing of the informed consent form (ICF) up to the end of the study (up to Day 2891)	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.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)	Baseline up to Day 2891	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.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)	Baseline up to Day 2891	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.
Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]	Baseline up to Day 2891	aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]	Baseline up to Day 2891	PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)	Baseline up to Day 2891	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.
Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]	Baseline up to Day 2891	INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Change From Baseline in Vital Signs (Blood Pressure)	Baseline, Day 2891
Change From Baseline in Vital Signs (Respiratory Rate)	Baseline, Day 2891	Negative change from baseline indicates reduction in respiratory rate.
Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities	Baseline up to Day 2891	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.
Cerebrospinal Fluid (CSF) Concentration of Nusinersen	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	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
Number of Participants With Neurological Examination Abnormalities Reported as AEs	From the signing of the ICF up to the end of the study (up to Day 2891)	Participants with abnormalities in neurological examinations recorded as AEs were reported.

Trial Locations

Locations (21): David Geffen School of Medicine
🇺🇸
Los Angeles, California, United States
University of California Davis Health System
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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
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David Geffen School of Medicine
🇺🇸Los Angeles, California, United States