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Trial record 33 of 119 for:    "Progressive Muscular Atrophy"

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

Tracking Information
First Submitted Date  ICMJE July 14, 2014
First Posted Date  ICMJE July 17, 2014
Results First Submitted Date  ICMJE May 16, 2017
Results First Posted Date  ICMJE July 28, 2017
Last Update Posted Date July 28, 2017
Actual Study Start Date  ICMJE August 19, 2014
Actual Primary Completion Date November 21, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 29, 2017)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 15, 2014)
Time to death or permanent ventilation [ Time Frame: Up to 13 months ]
Change History Complete list of historical versions of study NCT02193074 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 29, 2017)
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2014)
  • Change from baseline in CHOP INTEND [ Time Frame: At 13 months ]
  • Change from baseline in motor milestones [ Time Frame: At 13 months ]
  • Percent of subjects not requiring permanent ventilation [ Time Frame: Up to 13 months ]
  • Survival rate [ Time Frame: Up to 13 months ]
  • Time to death or permanent ventilation in the subgroups of subjects below the study median disease duration [ Time Frame: Up to 13 months ]
  • Time to death or permanent ventilation in the subgroups of subjects above the study median disease duration [ Time Frame: Up to 13 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE
  • Drug: nusinersen
    Administered by intrathecal (IT) injection as specified in the treatment arm.
    Other Names:
    • ISIS 396443
    • BIIB058
    • Spinraza
    • IONIS-SMN Rx
    • ISIS SMNRx
  • Procedure: Sham procedure
    Small needle prick on the lower back at the location where the IT injection is normally made
Study Arms  ICMJE
  • Experimental: nusinersen
    Intervention: Drug: nusinersen
  • Sham Comparator: Sham procedure
    Intervention: Procedure: Sham procedure
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 24, 2017)
122
Original Estimated Enrollment  ICMJE
 (submitted: July 15, 2014)
111
Actual Study Completion Date  ICMJE November 21, 2016
Actual Primary Completion Date November 21, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 210 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
Removed Location Countries Hong Kong,   Taiwan
 
Administrative Information
NCT Number  ICMJE NCT02193074
Other Study ID Numbers  ICMJE ISIS 396443-CS3B
2013-004422-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP