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

This study has been 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)
Sponsor:
Information provided by (Responsible Party):
Biogen
ClinicalTrials.gov Identifier:
NCT02193074
First received: July 14, 2014
Last updated: June 29, 2017
Last verified: June 2017
  Purpose
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 Intervention Phase
Spinal Muscular Atrophy Drug: nusinersen Procedure: Sham procedure Phase 3

Access to an investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Biogen:

Primary Outcome Measures:
  • 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.


  • 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:
  • 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.

  • 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.

  • Percentage of Participants Not Requiring Permanent Ventilation [ Time Frame: Up to Day 394 ]
  • 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.

  • 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.

  • 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.

  • 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.

  • Number of Participants With AEs Corresponding to Changes in Hematology Values [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  • Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  • Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline [ Time Frame: up to Day 394 (± 7 days) or early termination ]
  • 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'.

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

Enrollment: 122
Actual Study Start Date: August 19, 2014
Study Completion Date: November 21, 2016
Primary Completion Date: November 21, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02193074

  Show 31 Study Locations
Sponsors and Collaborators
Biogen
Investigators
Study Director: Medical Director Biogen
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02193074     History of Changes
Other Study ID Numbers: ISIS 396443-CS3B
2013-004422-29 ( EudraCT Number )
Study First Received: July 14, 2014
Results First Received: May 16, 2017
Last Updated: June 29, 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:
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

ClinicalTrials.gov processed this record on August 16, 2017