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 : February 17, 2021
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|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 no longer available outside the clinical trial. More info ...
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||122 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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|
Administered by intrathecal (IT) injection as specified in the treatment arm.
|Sham Comparator: Sham procedure||
Procedure: Sham procedure
Small needle prick on the lower back at the location where the IT injection is normally made
- 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.
- 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 ]
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, Learn About Clinical Studies.
|Ages Eligible for Study:||up to 210 Days (Child)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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.
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
|Study Director:||Medical Director||Biogen|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Other Study ID Numbers:||
2013-004422-29 ( EudraCT Number )
|First Posted:||July 17, 2014 Key Record Dates|
|Results First Posted:||July 28, 2017|
|Last Update Posted:||February 17, 2021|
|Last Verified:||February 2021|
Spinal Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease