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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Spinal Muscular Atrophy
Interventions Drug: nusinersen
Procedure: Sham procedure
Enrollment 122
Recruitment Details  
Pre-assignment Details Of the 149 participants screened, 27 were screening failures. A total of 122 participants enrolled and were randomized; 1 participant withdrew prior to receiving treatment.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302. Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Period Title: Overall Study
Started 41 [1] 80 [1]
Completed During Follow-Up Period 11 26
Completed Due to Early Study Termination 13 39
Completed 24 65
Not Completed 17 15
Reason Not Completed
Withdrawal by Subject             1             2
Adverse Event             16             13
[1]
Randomized and received double-blind treatment.
Arm/Group Title Control Nusinersen Total
Hide Arm/Group Description Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302. Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302. Total of all reporting groups
Overall Number of Baseline Participants 41 80 121
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 41 participants 80 participants 121 participants
Age at Screening 164.7  (48.54) 147.2  (46.85) 153.1  (47.95)
Age at First Dose 180.5  (50.92) 163.4  (49.57) 169.2  (50.48)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 80 participants 121 participants
Female
24
  58.5%
43
  53.8%
67
  55.4%
Male
17
  41.5%
37
  46.3%
54
  44.6%
1.Primary Outcome
Title Percentage of Motor Milestones Responders
Hide Description

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 Frame assessed at the later of the Day 183, Day 302, or Day 394 study visits
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 37 73
Measure Type: Number
Unit of Measure: percentage of participants
0 51
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentages
Estimated Value 50.68
Confidence Interval (2-Sided) 95%
31.81 to 66.48
Estimation Comments exact unconditional confidence interval
2.Primary Outcome
Title Time to Death or Permanent Ventilation
Hide Description 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.
Time Frame Day 91, Day 182, Day 273, Day 364, Day 394
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died or required permanent ventilation.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 28 31
Measure Type: Number
Unit of Measure: proportion of participants
By Day 91 (13 weeks/3 months) 0.268 0.240
By Day 182 (26 weeks/6 months) 0.605 0.294
By Day 273 (39 weeks/9 months) 0.702 0.404
By Day 364 (52 weeks/12 months) 0.735 0.447
By Day 394 (13 months) 0.735 0.447
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0046
Comments [Not Specified]
Method Log Rank
Comments Based on log-rank test stratified by disease duration.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0164
Comments [Not Specified]
Method Cox proportional hazards model
Comments Based on Cox proportional hazards model adjusted for each subject’s disease duration at screening.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.530
Confidence Interval (2-Sided) 95%
0.3156 to 0.8902
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders
Hide Description 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.
Time Frame assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 37 73
Measure Type: Number
Unit of Measure: percentage of participants
3 71
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter DIfference in percentages
Estimated Value 68.53
Confidence Interval (2-Sided) 95%
51.27 to 81.99
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Summary of Time to Death
Hide Description Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
Time Frame Day 91, Day 182, Day 273, Day 364, Day 394
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died. Results are based on all available data.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 16 13
Measure Type: Number
Unit of Measure: proportion of particiants
by Day 91 0.195 0.101
by Day 182 0.348 0.141
by Day 273 0.382 0.173
by Day 364 0.419 0.173
by Day 394 0.419 0.173
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0041
Comments [Not Specified]
Method Log Rank
Comments Based on log-rank test stratified by disease duration (primary analysis).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0082
Comments [Not Specified]
Method Cox proportional hazards
Comments Based on Cox proportional hazards model adjusted for each subject’s disease duration at screening (sensitivity analysis).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.372
Confidence Interval (2-Sided) 95%
0.1787 to 0.7745
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants Not Requiring Permanent Ventilation
Hide Description [Not Specified]
Time Frame Up to Day 394
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: percentage of participants
68 77
6.Secondary Outcome
Title Percentage of Compound Muscular Action Potential (CMAP) Responders
Hide Description 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 Frame assessed at the later of the Day 183, Day 302, or Day 394 study visits
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 37 73
Measure Type: Number
Unit of Measure: percentage of participants
5 36
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentages
Estimated Value 30.21
Confidence Interval (2-Sided) 95%
10.35 to 48.09
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration
Hide Description 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 Frame Day 91, Day 182, Day 273, Day 364, Day 394
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were below the study median disease duration.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 21 39
Measure Type: Number
Unit of Measure: proportion of participants
by Day 91 0.238 0.128
by Day 182 0.546 0.128
by Day 273 0.697 0.228
by Day 364 0.773 0.271
by Day 394 0.773 0.271
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments [Not Specified]
Method Cox proportional hazards
Comments Based on Cox proportional hazards model adjusted for each subject’s disease duration at screening.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.240
Confidence Interval (2-Sided) 95%
0.1002 to 0.5753
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration
Hide Description 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.
Time Frame Day 91, Day 182, Day 273, Day 364, Day 394
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were above the study median disease duration.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 20 41
Measure Type: Number
Unit of Measure: proportion of participants
by Day 91 0.300 0.350
by Day 182 0.670 0.462
by Day 273 0.725 0.584
by Day 364 0.725 0.625
by Day 394 0.725 0.625
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3953
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Control, Nusinersen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6268
Comments [Not Specified]
Method Cox proportional hazards
Comments Based on Cox proportional hazards model adjusted for each subject’s disease duration at screening.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.844
Confidence Interval (2-Sided) 95%
0.4270 to 1.6698
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs
Hide Description 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.
Time Frame Screening through Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: participants
Any event 40 77
Moderate or severe event 39 70
Severe event 33 45
Possibly related or related event 6 9
Related event 0 0
Serious event 39 61
Related serious event 0 0
Treatment discontinuation due to an event 16 13
10.Secondary Outcome
Title Number of Participants With AEs Corresponding to Changes in Hematology Values
Hide Description [Not Specified]
Time Frame up to Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: participants
Anemia 1 1
Neutrophil count increased 0 1
Leukocytosis 1 0
11.Secondary Outcome
Title Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
Hide Description [Not Specified]
Time Frame up to Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: participants
Blood potassium decreased 0 2
Liver function test abnormal 0 1
Alanine aminotransferase increased 0 1
Aspartate aminotransferase increased 0 1
Blood chloride decreased 0 1
Blood iron decreased 0 1
Blood sodium decreased 0 1
C-reactive protein increased 1 2
Hypokalemia 3 2
Hypoglycemia 2 0
Hyperglycemia 1 0
Transaminases increased 1 0
12.Secondary Outcome
Title Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
Hide Description [Not Specified]
Time Frame up to Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and had an assessment.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: participants
Systolic blood pressure <90 mmHg 36 74
Systolic blood pressure >140 mmHg 4 4
Systolic blood pressure >160 mmHg 0 0
Diastolic blood pressure <50 mmHg 26 71
Diastolic blood pressure >90 mmHg 13 12
Diastolic blood pressure >100 mmHg 3 0
Pulse rate <60 bpm 0 0
Pulse rate >100 bpm 41 80
Temperature >38.0 C 7 6
Temperature <36.0 C 21 45
Respiratory rate <12 breaths/min 0 0
Respiratory rate >20 breaths/min 41 80
Body weight ≥7% decrease from BL 1 4
Body weight ≥7% increase from BL 33 67
13.Secondary Outcome
Title Summary of Shifts in 12-lead Electrocardiogram (ECG) Results
Hide Description 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’.
Time Frame up to Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and whose baseline value was not abnormal and who had at least one post-baseline value.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 34 65
Measure Type: Number
Unit of Measure: participants
Shift to abnormal, not clinically significant 5 17
Shift to abnormal, clinically significant 0 8
From unknown to abnormal, clinically significant 0 0
14.Secondary Outcome
Title Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
Hide Description [Not Specified]
Time Frame up to Day 394 (± 7 days) or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.
Arm/Group Title Control Nusinersen
Hide Arm/Group Description:
Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Number of Participants Analyzed 41 80
Measure Type: Number
Unit of Measure: participants
0 0
Time Frame Screening through Day 394 (± 7 days) or early termination
Adverse Event Reporting Description Treatment-emergent events are presented.
 
Arm/Group Title Control Nusinersen
Hide Arm/Group Description Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302. Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
All-Cause Mortality
Control Nusinersen
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Control Nusinersen
Affected / at Risk (%) Affected / at Risk (%)
Total   39/41 (95.12%)   61/80 (76.25%) 
Cardiac disorders     
Cardiac arrest  1  2/41 (4.88%)  2/80 (2.50%) 
Cardio-respiratory arrest  1  5/41 (12.20%)  5/80 (6.25%) 
Cyanosis  1  1/41 (2.44%)  1/80 (1.25%) 
Sinus tachycardia  1  0/41 (0.00%)  1/80 (1.25%) 
Gastrointestinal disorders     
Dysphagia  1  1/41 (2.44%)  2/80 (2.50%) 
Gastric haemorrhage  1  0/41 (0.00%)  1/80 (1.25%) 
Gastrointestinal haemorrhage  1  1/41 (2.44%)  0/80 (0.00%) 
Retching  1  1/41 (2.44%)  0/80 (0.00%) 
Salivary hypersecretion  1  1/41 (2.44%)  0/80 (0.00%) 
Vomiting  1  1/41 (2.44%)  3/80 (3.75%) 
General disorders     
Death  1  1/41 (2.44%)  1/80 (1.25%) 
General physical health deterioration  1  0/41 (0.00%)  1/80 (1.25%) 
Pyrexia  1  0/41 (0.00%)  4/80 (5.00%) 
Surgical failure  1  0/41 (0.00%)  1/80 (1.25%) 
Infections and infestations     
Bronchiolitis  1  1/41 (2.44%)  4/80 (5.00%) 
Bronchitis  1  0/41 (0.00%)  4/80 (5.00%) 
Bronchitis viral  1  0/41 (0.00%)  3/80 (3.75%) 
Candida sepsis  1  1/41 (2.44%)  0/80 (0.00%) 
Corona virus infection  1  1/41 (2.44%)  0/80 (0.00%) 
Ear infection  1  0/41 (0.00%)  1/80 (1.25%) 
Gastroenteritis rotavirus  1  0/41 (0.00%)  1/80 (1.25%) 
Lower respiratory tract infection  1  0/41 (0.00%)  4/80 (5.00%) 
Lower respiratory tract infection viral  1  0/41 (0.00%)  1/80 (1.25%) 
Lung infection  1  0/41 (0.00%)  1/80 (1.25%) 
Moraxella infection  1  0/41 (0.00%)  1/80 (1.25%) 
Nasopharyngitis  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia  1  5/41 (12.20%)  19/80 (23.75%) 
Pneumonia bacterial  1  2/41 (4.88%)  3/80 (3.75%) 
Pneumonia influenzal  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia moraxella  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia parainfluenzae viral  1  1/41 (2.44%)  1/80 (1.25%) 
Pneumonia pneumococcal  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia pseudomonal  1  1/41 (2.44%)  0/80 (0.00%) 
Pneumonia respiratory syncytial viral  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia viral  1  2/41 (4.88%)  6/80 (7.50%) 
Pyelonephritis  1  0/41 (0.00%)  1/80 (1.25%) 
Respiratory syncytial virus bronchiolitis  1  3/41 (7.32%)  4/80 (5.00%) 
Respiratory tract infection  1  1/41 (2.44%)  6/80 (7.50%) 
Respiratory tract infection viral  1  1/41 (2.44%)  1/80 (1.25%) 
Rhinovirus infection  1  2/41 (4.88%)  7/80 (8.75%) 
Sepsis  1  0/41 (0.00%)  1/80 (1.25%) 
Staphylococcal sepsis  1  0/41 (0.00%)  1/80 (1.25%) 
Stoma site abscess  1  0/41 (0.00%)  1/80 (1.25%) 
Systemic infection  1  1/41 (2.44%)  0/80 (0.00%) 
Upper respiratory tract infection  1  0/41 (0.00%)  4/80 (5.00%) 
Urinary tract infection  1  0/41 (0.00%)  3/80 (3.75%) 
Viral infection  1  1/41 (2.44%)  5/80 (6.25%) 
Viral upper respiratory tract infection  1  6/41 (14.63%)  3/80 (3.75%) 
Injury, poisoning and procedural complications     
Delayed recovery from anaesthesia  1  0/41 (0.00%)  1/80 (1.25%) 
Feeding tube complication  1  0/41 (0.00%)  1/80 (1.25%) 
Femur fracture  1  1/41 (2.44%)  0/80 (0.00%) 
Head injury  1  1/41 (2.44%)  0/80 (0.00%) 
Tracheal haemorrhage  1  1/41 (2.44%)  0/80 (0.00%) 
Tracheal obstruction  1  1/41 (2.44%)  0/80 (0.00%) 
Vaccination complication  1  0/41 (0.00%)  1/80 (1.25%) 
Investigations     
Body temperature increased  1  1/41 (2.44%)  0/80 (0.00%) 
Heart rate decreased  1  1/41 (2.44%)  0/80 (0.00%) 
Medical observation  1  0/41 (0.00%)  2/80 (2.50%) 
Oxygen saturation decreased  1  2/41 (4.88%)  1/80 (1.25%) 
Respirovirus test positive  1  1/41 (2.44%)  0/80 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  1/41 (2.44%)  1/80 (1.25%) 
Failure to thrive  1  1/41 (2.44%)  1/80 (1.25%) 
Feeding disorder of infancy or early childhood  1  2/41 (4.88%)  2/80 (2.50%) 
Feeding intolerance  1  0/41 (0.00%)  2/80 (2.50%) 
Weight gain poor  1  2/41 (4.88%)  3/80 (3.75%) 
Nervous system disorders     
Brain injury  1  0/41 (0.00%)  1/80 (1.25%) 
Hypoxic-ischaemic encephalopathy  1  0/41 (0.00%)  1/80 (1.25%) 
Psychiatric disorders     
Agitation  1  1/41 (2.44%)  0/80 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/41 (2.44%)  1/80 (1.25%) 
Acute respiratory failure  1  9/41 (21.95%)  11/80 (13.75%) 
Apnoea  1  2/41 (4.88%)  2/80 (2.50%) 
Apparent life threatening event  1  2/41 (4.88%)  0/80 (0.00%) 
Aspiration  1  1/41 (2.44%)  3/80 (3.75%) 
Atelectasis  1  4/41 (9.76%)  14/80 (17.50%) 
Bronchial secretion retention  1  5/41 (12.20%)  1/80 (1.25%) 
Chronic respiratory failure  1  0/41 (0.00%)  1/80 (1.25%) 
Dyspnoea  1  2/41 (4.88%)  4/80 (5.00%) 
Hypercapnia  1  0/41 (0.00%)  1/80 (1.25%) 
Hypoventilation  1  0/41 (0.00%)  1/80 (1.25%) 
Hypoxia  1  1/41 (2.44%)  4/80 (5.00%) 
Increased bronchial secretion  1  0/41 (0.00%)  1/80 (1.25%) 
Lung disorder  1  1/41 (2.44%)  1/80 (1.25%) 
Obstructive airways disorder  1  0/41 (0.00%)  1/80 (1.25%) 
Pneumonia aspiration  1  5/41 (12.20%)  8/80 (10.00%) 
Respiratory arrest  1  4/41 (9.76%)  5/80 (6.25%) 
Respiratory disorder  1  0/41 (0.00%)  2/80 (2.50%) 
Respiratory distress  1  8/41 (19.51%)  21/80 (26.25%) 
Respiratory failure  1  16/41 (39.02%)  20/80 (25.00%) 
Respiratory tract congestion  1  1/41 (2.44%)  0/80 (0.00%) 
Skin and subcutaneous tissue disorders     
Dermatitis  1  0/41 (0.00%)  1/80 (1.25%) 
Vascular disorders     
Shock  1  0/41 (0.00%)  1/80 (1.25%) 
Thrombosis  1  0/41 (0.00%)  1/80 (1.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Control Nusinersen
Affected / at Risk (%) Affected / at Risk (%)
Total   35/41 (85.37%)   70/80 (87.50%) 
Cardiac disorders     
Bradycardia  1  3/41 (7.32%)  4/80 (5.00%) 
Tachycardia  1  5/41 (12.20%)  7/80 (8.75%) 
Gastrointestinal disorders     
Constipation  1  9/41 (21.95%)  28/80 (35.00%) 
Diarrhoea  1  7/41 (17.07%)  11/80 (13.75%) 
Dysphagia  1  9/41 (21.95%)  7/80 (8.75%) 
Flatulence  1  1/41 (2.44%)  4/80 (5.00%) 
Gastrooesophageal reflux disease  1  8/41 (19.51%)  10/80 (12.50%) 
Salivary hypersecretion  1  1/41 (2.44%)  6/80 (7.50%) 
Teething  1  3/41 (7.32%)  14/80 (17.50%) 
Vomiting  1  7/41 (17.07%)  11/80 (13.75%) 
General disorders     
Oedema  1  3/41 (7.32%)  0/80 (0.00%) 
Pyrexia  1  24/41 (58.54%)  43/80 (53.75%) 
Infections and infestations     
Bacterial tracheitis  1  4/41 (9.76%)  1/80 (1.25%) 
Bronchiolitis  1  2/41 (4.88%)  4/80 (5.00%) 
Candida infection  1  3/41 (7.32%)  0/80 (0.00%) 
Conjunctivitis  1  3/41 (7.32%)  5/80 (6.25%) 
Ear infection  1  1/41 (2.44%)  5/80 (6.25%) 
Influenza  1  0/41 (0.00%)  5/80 (6.25%) 
Nasopharyngitis  1  4/41 (9.76%)  14/80 (17.50%) 
Oral candidiasis  1  3/41 (7.32%)  7/80 (8.75%) 
Pneumonia  1  3/41 (7.32%)  7/80 (8.75%) 
Respiratory tract infection  1  2/41 (4.88%)  4/80 (5.00%) 
Rhinitis  1  3/41 (7.32%)  2/80 (2.50%) 
Rhinovirus infection  1  4/41 (9.76%)  4/80 (5.00%) 
Stoma site infection  1  3/41 (7.32%)  1/80 (1.25%) 
Upper respiratory tract infection  1  9/41 (21.95%)  22/80 (27.50%) 
Urinary tract infection  1  0/41 (0.00%)  6/80 (7.50%) 
Viral infection  1  3/41 (7.32%)  4/80 (5.00%) 
Viral upper respiratory tract infection  1  1/41 (2.44%)  6/80 (7.50%) 
Injury, poisoning and procedural complications     
Feeding tube complication  1  3/41 (7.32%)  1/80 (1.25%) 
Investigations     
Oxygen saturation decreased  1  9/41 (21.95%)  9/80 (11.25%) 
Weight decreased  1  1/41 (2.44%)  4/80 (5.00%) 
Metabolism and nutrition disorders     
Hypokalaemia  1  3/41 (7.32%)  0/80 (0.00%) 
Musculoskeletal and connective tissue disorders     
Scoliosis  1  2/41 (4.88%)  4/80 (5.00%) 
Respiratory, thoracic and mediastinal disorders     
Atelectasis  1  9/41 (21.95%)  9/80 (11.25%) 
Bronchial secretion retention  1  2/41 (4.88%)  4/80 (5.00%) 
Cough  1  8/41 (19.51%)  9/80 (11.25%) 
Dyspnoea  1  4/41 (9.76%)  3/80 (3.75%) 
Hypoxia  1  2/41 (4.88%)  4/80 (5.00%) 
Nasal congestion  1  5/41 (12.20%)  8/80 (10.00%) 
Pneumonia aspiration  1  3/41 (7.32%)  3/80 (3.75%) 
Respiratory distress  1  6/41 (14.63%)  4/80 (5.00%) 
Respiratory failure  1  6/41 (14.63%)  0/80 (0.00%) 
Rhinorrhoea  1  3/41 (7.32%)  6/80 (7.50%) 
Sleep apnoea syndrome  1  4/41 (9.76%)  0/80 (0.00%) 
Upper respiratory tract congestion  1  1/41 (2.44%)  6/80 (7.50%) 
Skin and subcutaneous tissue disorders     
Decubitus ulcer  1  3/41 (7.32%)  0/80 (0.00%) 
Dermatitis contact  1  3/41 (7.32%)  2/80 (2.50%) 
Dermatitis diaper  1  4/41 (9.76%)  6/80 (7.50%) 
Erythema  1  3/41 (7.32%)  1/80 (1.25%) 
Rash  1  4/41 (9.76%)  9/80 (11.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Results Point of Contact
Name/Title: Biogen Study Medical Director
Organization: Biogen
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02193074     History of Changes
Other Study ID Numbers: ISIS 396443-CS3B
2013-004422-29 ( EudraCT Number )
First Submitted: July 14, 2014
First Posted: July 17, 2014
Results First Submitted: May 16, 2017
Results First Posted: July 28, 2017
Last Update Posted: July 28, 2017