A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (ENDEAR)

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 Infantile-onset Spinal Muscular Atrophy

The primary objective of the study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally (IT) to participants with infantile-onset with infantile-onset spinal muscular atrophy (SMA). The secondary objective of the study is to examine the safety and tolerability of nusinersen administered intrathecally to participants with infantile-onset SMA.

Study Overview

• Status: Terminated
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Procedure: Sham procedure; Drug: nusinersen

Detailed Description

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
• Enrollment (Actual): 122
• Phase: Phase 3

Expanded Access

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

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Sydney Children's Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital, Children's Neuroscience Centre
• Belgium
  • Brussels, Belgium, 15 - 1020
    • Hôpital Universitaire des Enfants Reine Fabiola (Huderf)
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • British Columbia Children's Hospital/UBC
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for sick children
• France
  • Paris, France, 75012
    • Institut de Myologie
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen
• Italy
  • Genova, Italy, 16148
    • Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative
  • Rome, Italy, 00153
    • Pediatric Neurology Unit, Catholic University
• Japan
  • Tokyo, Japan, 162-8666
    • Tokyo Women's Medical University
  • Hyogo
    • Nishinomiya, Hyogo, Japan, 663-8131
      • Hyogo College of Medicine
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebrón
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz, Pediatric Neurology Department
• Sweden
  • Gothenburg, Sweden
    • University of Gothenburg, The Queen Silvia Children's Hospital
• Turkey
  • Ankara, Turkey, 06230
    • Hacettepe Children's Hospital
• United Kingdom
  • London, United Kingdom, WC1N 1EH
    • UCL Institute of Child Health/Great Ormond Street
  • Newcastle, United Kingdom, NE1 3BZ
    • MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Doernbecher Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia - Neurology
  • Texas
    • Dallas, Texas, United States, 75235
      • UT Southwestern Medical Center/Children's Medical Center Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Primary Children's Medical Center (University of Utah)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Be born (gestational age) between 37 and 42 weeks
• Be medically diagnosed with spinal muscular atrophy (SMA)
• Have Survival Motor Neuron2 (SMN2) Copy number = 2
• Body weight equal to or greater than 3rd percentile for age using appropriate country-specific guidelines
• Be able to follow all study procedures
• Reside within approximately 9 hours ground-travel distance from a participating study center, for the duration of the study

Key Exclusion Criteria:

• Hypoxemia (oxygen [O2] saturation awake less than 96% or O2 saturation asleep less than 96%, without ventilation support) during screening evaluation
• 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 participant unsuitable for participation in the study
• Participant's parent or legal guardian is not willing to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: nusinersen	Drug: nusinersen; Administered by intrathecal (IT) injection as specified in the treatment arm.; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS SMNRx; IONIS-SMN Rx
Sham Comparator: Sham procedure	Procedure: Sham procedure; Small needle prick on the lower back at the location where the IT injection is normally made

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Motor Milestones Responders	The definition of a motor milestones responder was based on improvement in the motor milestones categories in Section 2 of the Hammersmith Infant Neurological Examination (HINE), with the exclusion of voluntary grasp, as follows: (i) subject demonstrates ≥ 2-point increase in the motor milestones category of ability to kick or achievement of maximal score on that category (touching toes), or a 1-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and (ii) among the motor milestone categories, with the exclusion of voluntary grasp, there are more categories where there is improvement as defined in (i) than worsening. (For the category of ability to kick, worsening is defined as ≥ 2-point decrease or decrease to the lowest possible score of no kicking. For the other categories, worsening is defined as ≥ 1-point decrease.) The lowest possible score for the HINE is 0 (zero), and the highest possible score for the HINE is 28.	assessed at the later of the Day 183, Day 302, or Day 394 study visits
Time to Death or Permanent Ventilation	Estimated proportion of participants who died or required permanent ventilation by a given study day, based on the Kaplan-Meier product-limit method. Time to death or permanent ventilation was defined as either tracheostomy or ≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event. This endpoint was adjudicated by a blinded, independent group of experienced clinicians, the Event Adjudication Committee (EAC), based on review of clinical study data and supporting information. Results are based on all available data.	Day 91, Day 182, Day 273, Day 364, Day 394

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders	A participants was considered a CHOP-INTEND responder if the change from baseline in CHOP-INTEND total score is ≥ 4 points based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Results are based on all available data.	assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
Summary of Time to Death	Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.	Day 91, Day 182, Day 273, Day 364, Day 394
Percentage of Participants Not Requiring Permanent Ventilation		Up to Day 394
Percentage of Compound Muscular Action Potential (CMAP) Responders	CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A participant was defined as a CMAP responder if the CMAP amplitude at the peroneal nerve was increasing to or maintained at ≥ 1 mV (comparing to the baseline) based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. Results are based on all available data.	assessed at the later of the Day 183, Day 302, or Day 394 study visits
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration	Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants below the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.	Day 91, Day 182, Day 273, Day 364, Day 394
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration	Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants above the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.	Day 91, Day 182, Day 273, Day 364, Day 394
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs	AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the participant (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.	Screening through Day 394 (± 7 days) or early termination
Number of Participants With AEs Corresponding to Changes in Hematology Values		up to Day 394 (± 7 days) or early termination
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values		up to Day 394 (± 7 days) or early termination
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline		up to Day 394 (± 7 days) or early termination
Summary of Shifts in 12-lead Electrocardiogram (ECG) Results	Shift to 'abnormal, not clinically significant' includes 'unknown' or 'normal' to 'abnormal, not clinically significant'. Shift to 'abnormal, clinically significant' includes 'unknown' or 'normal' to 'abnormal, clinically significant'.	up to Day 394 (± 7 days) or early termination
Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values		up to Day 394 (± 7 days) or early termination

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
• Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, Pivneva I, Wu EQ, Arjunji R, Feltner D, Sproule DM. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019 May;36(5):1164-1176. doi: 10.1007/s12325-019-00923-8. Epub 2019 Mar 16.
• Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.
• 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.

Helpful Links

• Cure SMA
• Muscular Dystrophy Association
• National Organization for Rare Diseases
• Clinical Study Report (CSR) Synopsis - a results summary

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2014
• Primary Completion (Actual): November 21, 2016
• Study Completion (Actual): November 21, 2016

Study Registration Dates

• First Submitted: July 14, 2014
• First Submitted That Met QC Criteria: July 15, 2014
• First Posted (Estimate): July 17, 2014

Study Record Updates

• Last Update Posted (Actual): February 17, 2021
• Last Update Submitted That Met QC Criteria: February 12, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443; IONIS-SMNRx; IONIS-SMN Rx; Spinraza; ISIS-SMN Rx; ENDEAR
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: ISIS 396443-CS3B; 2013-004422-29 (EudraCT Number)