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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02193074
Registration number
NCT02193074
Ethics application status
Date submitted
14/07/2014
Date registered
17/07/2014
Date last updated
17/02/2021
Titles & IDs
Public title
A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
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Scientific 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
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Secondary ID [1]
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2013-004422-29
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Secondary ID [2]
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ISIS 396443-CS3B
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Universal Trial Number (UTN)
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Trial acronym
ENDEAR
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Spinal Muscular Atrophy
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Neurological
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Other neurological disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - nusinersen
Treatment: Surgery - Sham procedure
Experimental: nusinersen -
Sham comparator: Sham procedure -
Treatment: Drugs: nusinersen
Administered by intrathecal (IT) injection as specified in the treatment arm.
Treatment: Surgery: Sham procedure
Small needle prick on the lower back at the location where the IT injection is normally made
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Treatment: Surgery
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Motor Milestones Responders
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Assessment method [1]
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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.
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Timepoint [1]
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assessed at the later of the Day 183, Day 302, or Day 394 study visits
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Primary outcome [2]
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Time to Death or Permanent Ventilation
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Assessment method [2]
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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.
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Timepoint [2]
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Day 91, Day 182, Day 273, Day 364, Day 394
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Secondary outcome [1]
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Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders
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Assessment method [1]
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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.
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Timepoint [1]
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assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
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Secondary outcome [2]
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Summary of Time to Death
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Assessment method [2]
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Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
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Timepoint [2]
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Day 91, Day 182, Day 273, Day 364, Day 394
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Secondary outcome [3]
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Percentage of Participants Not Requiring Permanent Ventilation
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Assessment method [3]
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Timepoint [3]
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Up to Day 394
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Secondary outcome [4]
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Percentage of Compound Muscular Action Potential (CMAP) Responders
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Assessment method [4]
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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.
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Timepoint [4]
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assessed at the later of the Day 183, Day 302, or Day 394 study visits
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Secondary outcome [5]
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Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration
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Assessment method [5]
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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.
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Timepoint [5]
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Day 91, Day 182, Day 273, Day 364, Day 394
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Secondary outcome [6]
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Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration
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Assessment method [6]
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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.
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Timepoint [6]
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Day 91, Day 182, Day 273, Day 364, Day 394
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Secondary outcome [7]
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Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs
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Assessment method [7]
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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.
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Timepoint [7]
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Screening through Day 394 (± 7 days) or early termination
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Secondary outcome [8]
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Number of Participants With AEs Corresponding to Changes in Hematology Values
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Assessment method [8]
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Timepoint [8]
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up to Day 394 (± 7 days) or early termination
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Secondary outcome [9]
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Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
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Assessment method [9]
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Timepoint [9]
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up to Day 394 (± 7 days) or early termination
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Secondary outcome [10]
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Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
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Assessment method [10]
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Timepoint [10]
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up to Day 394 (± 7 days) or early termination
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Secondary outcome [11]
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Summary of Shifts in 12-lead Electrocardiogram (ECG) Results
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Assessment method [11]
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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'.
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Timepoint [11]
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up to Day 394 (± 7 days) or early termination
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Secondary outcome [12]
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Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
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Assessment method [12]
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Timepoint [12]
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up to Day 394 (± 7 days) or early termination
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Eligibility
Key inclusion criteria
Key
* 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
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Minimum age
No limit
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Maximum age
210
Days
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Stopped early
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/08/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
21/11/2016
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Sample size
Target
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Accrual to date
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Final
122
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Sydney Children's Hospital - Sydney
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Recruitment hospital [2]
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Royal Children's Hospital, Children's Neuroscience Centre - Parkville
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Recruitment postcode(s) [1]
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2031 - Sydney
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Recruitment postcode(s) [2]
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3052 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Colorado
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Country [3]
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United States of America
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State/province [3]
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Florida
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Country [4]
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United States of America
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Illinois
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Country [5]
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United States of America
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State/province [5]
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Massachusetts
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Country [6]
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United States of America
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State/province [6]
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Missouri
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Country [7]
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United States of America
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State/province [7]
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New York
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Country [8]
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United States of America
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State/province [8]
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North Carolina
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Country [9]
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United States of America
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State/province [9]
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Oregon
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United States of America
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Pennsylvania
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United States of America
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Texas
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United States of America
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Utah
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Belgium
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State/province [13]
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Brussels
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Canada
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British Columbia
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Canada
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State/province [15]
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Ontario
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France
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State/province [16]
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Paris
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Germany
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Essen
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Germany
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Freiburg
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Country [19]
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Italy
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State/province [19]
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Genova
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Italy
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Rome
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Japan
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Hyogo
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Japan
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Tokyo
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Korea, Republic of
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Seoul
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Spain
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Barcelona
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Spain
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Madrid
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Sweden
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Gothenburg
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Turkey
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Ankara
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United Kingdom
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London
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Country [29]
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United Kingdom
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State/province [29]
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Newcastle
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Biogen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT02193074
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Trial related presentations / 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.
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Public notes
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Contacts
Principal investigator
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Medical Director
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Address
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Biogen
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Contact person for public queries
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT02193074
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