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

An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

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 Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Nusinersen

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
• Germany
  • Baden-Wurttemberg
    • Freiburg im Breisgau, Baden-Wurttemberg, Germany, 79106
      • Universitaetsklinikum Freiburg
• Italy
  • Milan, Italy, 20162
    • Fondazione Serena Onlus - Centro Clinico Nemo
  • Lazio
    • Rome, Lazio, Italy, 165
      • Ospedale Pediatrico Bambino Gesu
• Qatar
  • Doha, Qatar, 3050
    • Hamad General Hospital
• Taiwan
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 6230
    • Hacettepe University Medical Faculty
  • Istanbul, Turkey (Türkiye), 31755
    • Yeditepe University Medical School Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine
    • Sacramento, California, United States, 95817
      • University Of California Davis Health System
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital, Orlando
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nusinersen; Nusinersen administered as an intrathecal injection	Drug: Nusinersen; Solution for intrathecal injection; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS SMNRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Screening up to Day 2891

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At 13 and 24 months of age
Percentage of Participants Alive		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.	Day 700
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.	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.	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.	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.	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.	Baseline, Day 1849
Change From Baseline in Head Circumference		Baseline, Day 2891
Change From Baseline in Chest Circumference		Baseline, Day 2891
Change From Baseline in Head to Chest Circumference Ratio	Negative change from baseline indicates reduction in head-to-chest circumference ratio.	Baseline, Day 2891
Change From Baseline in Arm Circumference		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.	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.	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.	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.	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.	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.	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.	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.	Baseline up to Day 2891
Change From Baseline in Vital Signs (Temperature)	Negative change from baseline indicates reduction in temperature.	Baseline, Day 2891
Change From Baseline in Vital Signs (Blood Pressure)		Baseline, Day 2891
Change From Baseline in Vital Signs (Heart Rate)	Negative change from baseline indicates reduction in heart rate.	Baseline, Day 2891
Change From Baseline in Vital Signs (Respiratory Rate)	Negative change from baseline indicates reduction in respiratory rate.	Baseline, Day 2891
Number of Participants With Neurological Examination Abnormalities Reported as AEs	Participants with abnormalities in neurological examinations recorded as AEs were reported.	From the signing of the ICF up to the end of the study (up to Day 2891)
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

Collaborators and Investigators

• Sponsor: Biogen
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

General Publications

• Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.
• Crawford TO, Swoboda KJ, De Vivo DC, Bertini E, Hwu WL, Finkel RS, Kirschner J, Kuntz NL, Nazario AN, Parsons JA, Pechmann A, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Zhu C, Raynaud S, Lago TR, Paradis AD, Foster R, Chin R, Berger Z; NURTURE Study Group. Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle Nerve. 2023 Aug;68(2):157-170. doi: 10.1002/mus.27853. Epub 2023 Jul 6.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2015
• Primary Completion (Actual): December 17, 2024
• Study Completion (Actual): December 17, 2024

Study Registration Dates

• First Submitted: February 27, 2015
• First Submitted That Met QC Criteria: March 6, 2015
• First Posted (Estimated): March 12, 2015

Study Record Updates

• Last Update Posted (Estimated): October 20, 2025
• Last Update Submitted That Met QC Criteria: October 3, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: NURTURE
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy, Spinal; nusinersen
• Other Study ID Numbers: 232SM201; 2014-002098-12 (EudraCT Number)

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No