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

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ClinicalTrials.gov Identifier: NCT02193074
Recruitment Status : Terminated (After a positive interim analysis, the decision was made to terminate the study early to allow for participants to enroll into an open label study)
First Posted : July 17, 2014
Results First Posted : July 28, 2017
Last Update Posted : July 28, 2017
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Drug: nusinersen Procedure: Sham procedure Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 19, 2014
Actual Primary Completion Date : November 21, 2016
Actual Study Completion Date : November 21, 2016


Arm Intervention/treatment
Experimental: nusinersen Drug: nusinersen
Administered by intrathecal (IT) injection as specified in the treatment arm.
Other Names:
  • ISIS 396443
  • BIIB058
  • Spinraza
  • IONIS-SMN Rx
  • ISIS SMNRx

Sham Comparator: Sham procedure Procedure: Sham procedure
Small needle prick on the lower back at the location where the IT injection is normally made




Primary Outcome Measures :
  1. Percentage of Motor Milestones Responders [ Time Frame: assessed at the later of the Day 183, Day 302, or Day 394 study visits ]

    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.


  2. Time to Death or Permanent Ventilation [ Time Frame: Day 91, Day 182, Day 273, Day 364, Day 394 ]
    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.


Secondary Outcome Measures :
  1. Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders [ Time Frame: assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits ]
    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.

  2. Summary of Time to Death [ Time Frame: Day 91, Day 182, Day 273, Day 364, Day 394 ]
    Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.

  3. Percentage of Participants Not Requiring Permanent Ventilation [ Time Frame: Up to Day 394 ]
  4. Percentage of Compound Muscular Action Potential (CMAP) Responders [ Time Frame: assessed at the later of the Day 183, Day 302, or Day 394 study visits ]
    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.

  5. Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration [ Time Frame: Day 91, Day 182, Day 273, Day 364, Day 394 ]
    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.

  6. Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration [ Time Frame: Day 91, Day 182, Day 273, Day 364, Day 394 ]
    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.

  7. Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs [ Time Frame: Screening through Day 394 (± 7 days) or early termination ]
    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.

  8. Number of Participants With AEs Corresponding to Changes in Hematology Values [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  9. Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  10. Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  11. Summary of Shifts in 12-lead Electrocardiogram (ECG) Results [ Time Frame: up to Day 394 (± 7 days) or early termination ]
    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'.

  12. Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values [ Time Frame: up to Day 394 (± 7 days) or early termination ]


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 210 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02193074


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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02193074     History of Changes
Other Study ID Numbers: ISIS 396443-CS3B
2013-004422-29 ( EudraCT Number )
First Posted: July 17, 2014    Key Record Dates
Results First Posted: July 28, 2017
Last Update Posted: July 28, 2017
Last Verified: June 2017

Keywords provided by Biogen:
Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS-SMN Rx
ISIS 396443
IONIS-SMNRx
IONIS-SMN Rx
Spinraza
ENDEAR

Additional relevant MeSH terms:
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Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases