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Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke (ACTION)

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ClinicalTrials.gov Identifier: NCT01955707
Recruitment Status : Completed
First Posted : October 7, 2013
Results First Posted : July 1, 2016
Last Update Posted : July 1, 2016
Sponsor:
Information provided by (Responsible Party):
Biogen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Acute Ischemic Stroke
Interventions Drug: natalizumab
Drug: Placebo
Enrollment 161
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description A single intravenous (IV) injection of placebo 300 mg single IV injection of natalizumab
Period Title: Overall Study
Started 82 79
Withdrew Prior to Dosing 0 1
Dosed 82 78
Received Total Volume of Study Drug 82 77
Completed 62 57
Not Completed 20 22
Reason Not Completed
Adverse Event             1             2
Lost to Follow-up             2             1
Withdrawal by Subject             0             3
Death             13             14
Not Specified             4             2
Arm/Group Title Placebo Natalizumab Total
Hide Arm/Group Description A single IV injection of placebo 300 mg single IV injection of natalizumab Total of all reporting groups
Overall Number of Baseline Participants 82 79 161
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 82 participants 79 participants 161 participants
71.6  (11.83) 70.3  (13.34) 71.0  (12.57)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 82 participants 79 participants 161 participants
</= 39 years 2 3 5
40 to 59 years 13 11 24
60 to 79 years 41 45 86
>/= 80 years 26 20 46
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 82 participants 79 participants 161 participants
Female
34
  41.5%
38
  48.1%
72
  44.7%
Male
48
  58.5%
41
  51.9%
89
  55.3%
1.Primary Outcome
Title Change in Infarct Volume From Baseline (Diffusion-Weighted Imaging [DWI]) to Day 5 (Fluid-Attenuated Inversion Recovery [FLAIR])
Hide Description Relative growth of infarct volume from Baseline (relative growth = FLAIR at Day 5 divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame Baseline, Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 73 69
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
2.17
(1.60 to 3.17)
2.37
(1.51 to 2.91)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tissue plasminogen activator (tPA) use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean difference (log-scale)
Estimated Value 0.08
Confidence Interval (2-Sided) 90%
-0.09 to 0.26
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.779
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 1.09
Confidence Interval (2-Sided) 90%
0.91 to 1.30
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
2.Secondary Outcome
Title Change in Infarct Volume From Baseline (DWI) to 24 Hours (FLAIR)
Hide Description Relative growth of infarct volume from Baseline (relative growth = FLAIR at 24 hours divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame Baseline, 24 hrs
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 74 69
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
1.73
(1.33 to 2.15)
1.95
(1.36 to 2.20)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean difference (log-scale)
Estimated Value 0.09
Confidence Interval (2-Sided) 90%
-0.09 to 0.27
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.797
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 1.09
Confidence Interval (2-Sided) 90%
0.92 to 1.31
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
3.Secondary Outcome
Title Change in Infarct Volume From Baseline (DWI) to Day 30 (FLAIR)
Hide Description Relative growth of infarct volume from Baseline (relative growth = FLAIR at Day 30 divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame Baseline, Day 30
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 66 55
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
1.27
(0.90 to 1.88)
1.25
(0.78 to 1.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean difference (log-scale)
Estimated Value 0.05
Confidence Interval (2-Sided) 90%
-0.13 to 0.24
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.684
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 1.05
Confidence Interval (2-Sided) 90%
0.88 to 1.27
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
4.Secondary Outcome
Title Change in Infarct Volume From 24 Hours (FLAIR) to Day 5 (FLAIR)
Hide Description Relative growth of infarct volume from 24 hours (relative growth = FLAIR at Day 5 divided by FLAIR at 24 hours). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame 24 hours, Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 70 65
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
1.27
(1.11 to 1.37)
1.25
(1.11 to 1.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to 24 hours using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean difference (log-scale)
Estimated Value -0.00
Confidence Interval (2-Sided) 90%
-0.12 to 0.11
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.487
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 1.00
Confidence Interval (2-Sided) 90%
0.89 to 1.12
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
5.Secondary Outcome
Title Change in Infarct Volume From 24 Hours (FLAIR) to Day 30 (FLAIR)
Hide Description Relative growth in infarct volume from Baseline (relative growth = FLAIR Day 30 divided by FLAIR at 24 hours ). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame 24 hours, Day 30
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 62 53
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
0.75
(0.62 to 1.03)
0.72
(0.56 to 1.09)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to 24 hours using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean difference (log-scale)
Estimated Value -0.02
Confidence Interval (2-Sided) 90%
-0.14 to 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.402
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 0.98
Confidence Interval (2-Sided) 90%
0.87 to 1.11
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
6.Secondary Outcome
Title Change in Infarct Volume From Day 5 (FLAIR) to Day 30 (FLAIR)
Hide Description Relative growth of infarct volume from Day 5 (relative growth = FLAIR at Day 30 divided by FLAIR at Day 5). Geometric mean calculated as the exponential of the mean log relative growth.
Time Frame Day 5, Day 30
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment) with assessments at both time points.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 64 54
Geometric Mean (Inter-Quartile Range)
Unit of Measure: mL
0.60
(0.52 to 0.79)
0.59
(0.42 to 0.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to Day 5 using an autoregressive variance-covariance matrix structure. The model adjusts for for treatment, log baseline DWI volume, treatment time window, and tPA use.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean difference (log-scale)
Estimated Value -0.02
Confidence Interval (2-Sided) 90%
-0.18 to 0.13
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.394
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of relative growth
Estimated Value 0.98
Confidence Interval (2-Sided) 90%
0.84 to 1.14
Estimation Comments Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
7.Secondary Outcome
Title Change in National Institute of Health Stroke Scale (NIHSS) Score From Baseline to 24 Hours, Day 5, Day 30, and Day 90
Hide Description The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Scores for the NIHSS range from 0 to 42, with 0 representing no symptoms and 42 representing death.
Time Frame Baseline, 24 hours, Day 5, Day 30, Day 90
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment); n=participants with assessments at Baseline and given time point.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 82 77
Mean (Standard Deviation)
Unit of Measure: units on a scale
Change at 24 hours; n=82, 77 -1.5  (3.96) -1.5  (5.10)
Change at Day 5; n=79, 72 -3.3  (5.31) -2.1  (6.24)
Change at Day 30; n=73, 62 -5.7  (5.22) -4.9  (5.73)
Change at Day 90; n=62, 56 -7.3  (3.95) -6.8  (5.78)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of NIHSS score and change from Baseline at 24 hours. The repeated measures mixed effects model is modeling absolute change in NIHSS score relative to baseline and using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, baseline NIHSS score and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.427
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean change from baseline
Estimated Value -0.25
Confidence Interval (2-Sided) 90%
-2.48 to 1.98
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of NIHSS score and change from Baseline at Day 5. The repeated measures mixed effects model is modeling absolute change in NIHSS score relative to baseline and using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, baseline NIHSS score and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.896
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean change from baseline
Estimated Value 1.71
Confidence Interval (2-Sided) 90%
-0.52 to 3.94
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of NIHSS score and change from Baseline at Day 30. The repeated measures mixed effects model is modeling absolute change in NIHSS score relative to baseline and using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, baseline NIHSS score and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.989
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean change from baseline
Estimated Value 3.15
Confidence Interval (2-Sided) 90%
0.89 to 5.40
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of NIHSS score and change from Baseline at Day 90. The repeated measures mixed effects model is modeling absolute change in NIHSS score relative to baseline and using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, baseline NIHSS score and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.915
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter adjusted mean change from baseline
Estimated Value 1.93
Confidence Interval (2-Sided) 90%
-0.38 to 4.25
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Modified Rankin Scale (mRS) Distribution at Day 5, Day 30, and Day 90
Hide Description The mRS measures independence, rather than neurologic function, with specific tasks pre- and post-stroke, respectively. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. The distribution of mRS scores was summarized at each timepoint. An excellent outcome on the mRS was defined as a score of 0 or 1, while a good outcome was defined as a score of 0, 1, or 2.
Time Frame Day 5, Day 30, and Day 90
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment), using imputed data; n=number of participants with an assessment at given time point.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 82 77
Measure Type: Number
Unit of Measure: participants
Day 5: Score 0; n=82, 76 0 2
Day 5: Score 1; n=82, 76 3 2
Day 5: Score 2; n=82, 76 10 11
Day 5: Score 3; n=82, 76 13 11
Day 5: Score 4; n=82, 76 25 16
Day 5: Score 5; n=82, 76 29 31
Day 5: Score 6; n=82, 76 2 3
Day 30: Score 0; n=81, 72 0 5
Day 30: Score 1; n=81, 72 7 8
Day 30: Score 2; n=81, 72 14 8
Day 30: Score 3; n=81, 72 17 17
Day 30: Score 4; n=81, 72 22 14
Day 30: Score 5; n=81, 72 13 11
Day 30: Score 6; n=81, 72 8 9
Day 90: Score 0; n=78, 72 4 8
Day 90: Score 1; n=78, 72 12 10
Day 90: Score 2; n=78, 72 12 10
Day 90: Score 3; n=78, 72 15 13
Day 90: Score 4; n=78, 72 14 11
Day 90: Score 5; n=78, 72 8 6
Day 90: Score 6; n=78, 72 13 14
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of distribution of mRS scores at Day 5. Odds ratio from a proportional-odds logistic regression model assuming a common odds ratio across all cut points of the mRS score. Covariates include baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.564
Comments One sided p-value based on Van Elteren's test, adjusting for baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Method Van Elteren's test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.89
Confidence Interval (2-Sided) 90%
0.55 to 1.45
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of distribution of mRS scores at Day 30. Odds ratio from a proportional-odds logistic regression model assuming a common odds ratio across all cut points of the mRS score. Covariates include baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.077
Comments One-sided p-value based on Van Elteren's test, adjusting for baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Method Van Elteren's test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.30
Confidence Interval (2-Sided) 90%
0.80 to 2.10
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of the distribution of mRS scores at Day 90. Odds ratio from a proportional-odds logistic regression model assuming a common odds ratio across all cut points of the mRS score. Covariates include baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.243
Comments One -sided p-value based on Van Elteren's test, adjusting for baseline DWI volume (< median vs >= median), treatment time window, location of stroke abnormality (cortical/subcortical), and tPA use (yes/no).
Method Van Elteren's test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.15
Confidence Interval (2-Sided) 90%
0.71 to 1.86
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Barthel Index at Day 5, Day 30, and Day 90
Hide Description The Barthel Index consists of 10 items that measure a person’s daily functioning, specifically the activities of daily living and mobility, and can be used to determine a baseline level of functioning and to monitor change in activities of daily living over time. The scores for each of the items are summed to create a total score up to a potential of 100, with higher scores representing a greater level of independence.
Time Frame Day 5, Day 30, and Day 90
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intention to treat (all participants who were randomized and received the entire infusion of study treatment); n=participants with assessment at given time point.
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 82 77
Median (Full Range)
Unit of Measure: units on a scale
Day 5; n=78, 73
35.0
(0 to 100)
30.0
(0 to 100)
Day 30; n=73, 60
70.0
(0 to 100)
80.0
(0 to 100)
Day 90; n=61, 55
80.0
(0 to 100)
95.0
(0 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of Barthel Index at Day 5. The repeated measures mixed effects model is modeling Barthel Index using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.455
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value 0.68
Confidence Interval (2-Sided) 90%
-9.19 to 10.56
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of Barthel Index at Day 30. The repeated measures mixed effects model is modeling Barthel Index using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.420
Comments one-sided p-value
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value 1.21
Confidence Interval (2-Sided) 90%
-8.76 to 11.19
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Natalizumab
Comments Analysis of Barthel Index at Day 90/Final Visit. The repeated measures mixed effects model is modeling Barthel Index using an autoregressive variance-covariance matrix. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, tPA use, and location of stroke.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.283
Comments [Not Specified]
Method repeated measures mixed effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value 3.56
Confidence Interval (2-Sided) 90%
-6.64 to 13.75
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Number of Participants Who Experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description AE: any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as severe, moderate, or mild, and related or not related to study treatment.
Time Frame Up to Day 90 ± 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population (all participants who were randomized and received any portion of the infusion of study treatment).
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description:
A single IV injection of placebo
300 mg single IV injection of natalizumab
Overall Number of Participants Analyzed 82 78
Measure Type: Number
Unit of Measure: participants
Participants with an event 81 77
Participants with a moderate or severe event 60 53
Participants with a severe event 27 22
Participants with a related event 7 6
Participants with a serious event 38 36
Participants discontinuing due to an event 0 0
Participants withdrawing from study due to event 2 1
Time Frame From informed consent (SAE) or initiation of study drug (AE) until Final Visit Day 90 ± 5 days or early termination follow-up.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Natalizumab
Hide Arm/Group Description A single IV injection of placebo 300 mg single IV injection of natalizumab
All-Cause Mortality
Placebo Natalizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Natalizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   38/82 (46.34%)   36/78 (46.15%) 
Blood and lymphatic system disorders     
Splenic haemorrhage  1  0/82 (0.00%)  1/78 (1.28%) 
Cardiac disorders     
Acute myocardial infarction  1  1/82 (1.22%)  0/78 (0.00%) 
Atrial fibrillation  1  0/82 (0.00%)  1/78 (1.28%) 
Cardiac arrest  1  0/82 (0.00%)  1/78 (1.28%) 
Cardiac failure  1  2/82 (2.44%)  0/78 (0.00%) 
Cardiac failure chronic  1  1/82 (1.22%)  0/78 (0.00%) 
Intracardiac thrombus  1  0/82 (0.00%)  1/78 (1.28%) 
Myocardial infarction  1  2/82 (2.44%)  0/78 (0.00%) 
Pulseless electrical activity  1  1/82 (1.22%)  0/78 (0.00%) 
Ventricular tachycardia  1  0/82 (0.00%)  1/78 (1.28%) 
Endocrine disorders     
Toxic nodular goitre  1  1/82 (1.22%)  0/78 (0.00%) 
General disorders     
Death  1  0/82 (0.00%)  1/78 (1.28%) 
Device dislocation  1  0/82 (0.00%)  1/78 (1.28%) 
Multi-organ failure  1  0/82 (0.00%)  2/78 (2.56%) 
Hepatobiliary disorders     
Cholecystitis acute  1  1/82 (1.22%)  0/78 (0.00%) 
Infections and infestations     
Diverticulitis  1  1/82 (1.22%)  0/78 (0.00%) 
Endocarditis  1  1/82 (1.22%)  0/78 (0.00%) 
Gastroenteritis  1  0/82 (0.00%)  1/78 (1.28%) 
Influenza  1  0/82 (0.00%)  1/78 (1.28%) 
Pneumonia  1  2/82 (2.44%)  3/78 (3.85%) 
Respiratory tract infection  1  1/82 (1.22%)  1/78 (1.28%) 
Septic shock  1  0/82 (0.00%)  1/78 (1.28%) 
Urinary tract infection  1  2/82 (2.44%)  0/78 (0.00%) 
Urinary tract infection pseudomonal  1  1/82 (1.22%)  0/78 (0.00%) 
Injury, poisoning and procedural complications     
Avulsion fracture  1  0/82 (0.00%)  1/78 (1.28%) 
Brain herniation  1  1/82 (1.22%)  1/78 (1.28%) 
Fall  1  1/82 (1.22%)  0/78 (0.00%) 
Femur fracture  1  2/82 (2.44%)  0/78 (0.00%) 
Hip fracture  1  0/82 (0.00%)  1/78 (1.28%) 
Metabolism and nutrition disorders     
Dehydration  1  1/82 (1.22%)  0/78 (0.00%) 
Hyponatraemia  1  1/82 (1.22%)  0/78 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cholangiocarcinoma  1  0/82 (0.00%)  1/78 (1.28%) 
Glioma  1  1/82 (1.22%)  0/78 (0.00%) 
Nervous system disorders     
Basilar artery thrombosis  1  1/82 (1.22%)  0/78 (0.00%) 
Brain midline shift  1  1/82 (1.22%)  1/78 (1.28%) 
Brain oedema  1  2/82 (2.44%)  1/78 (1.28%) 
Carotid artery stenosis  1  1/82 (1.22%)  3/78 (3.85%) 
Cerebral infarction  1  2/82 (2.44%)  4/78 (5.13%) 
Cerebral ischaemia  1  1/82 (1.22%)  1/78 (1.28%) 
Cerebrovascular accident  1  2/82 (2.44%)  2/78 (2.56%) 
Convulsion  1  0/82 (0.00%)  2/78 (2.56%) 
Dementia  1  0/82 (0.00%)  1/78 (1.28%) 
Dementia alzheimer's type  1  1/82 (1.22%)  0/78 (0.00%) 
Encephalopathy  1  0/82 (0.00%)  1/78 (1.28%) 
Epilepsy  1  0/82 (0.00%)  1/78 (1.28%) 
Generalised non-convulsive epilepsy  1  0/82 (0.00%)  1/78 (1.28%) 
Haemorrhage intracranial  1  0/82 (0.00%)  1/78 (1.28%) 
Haemorrhagic transformation stroke  1  3/82 (3.66%)  4/78 (5.13%) 
Headache  1  1/82 (1.22%)  0/78 (0.00%) 
Intracranial pressure increased  1  0/82 (0.00%)  1/78 (1.28%) 
Ischaemic stroke  1  1/82 (1.22%)  1/78 (1.28%) 
Nervous system disorder  1  0/82 (0.00%)  1/78 (1.28%) 
Neurological decompensation  1  2/82 (2.44%)  1/78 (1.28%) 
Partial seizures  1  1/82 (1.22%)  0/78 (0.00%) 
Stroke in evolution  1  0/82 (0.00%)  2/78 (2.56%) 
Subdural hygroma  1  1/82 (1.22%)  0/78 (0.00%) 
Vocal cord paralysis  1  1/82 (1.22%)  0/78 (0.00%) 
Psychiatric disorders     
Aggression  1  1/82 (1.22%)  0/78 (0.00%) 
Delirium  1  2/82 (2.44%)  0/78 (0.00%) 
Renal and urinary disorders     
Renal failure  1  1/82 (1.22%)  0/78 (0.00%) 
Renal failure chronic  1  1/82 (1.22%)  0/78 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/82 (1.22%)  1/78 (1.28%) 
Pneumonia aspiration  1  1/82 (1.22%)  1/78 (1.28%) 
Respiratory distress  1  1/82 (1.22%)  0/78 (0.00%) 
Respiratory failure  1  0/82 (0.00%)  2/78 (2.56%) 
Surgical and medical procedures     
Endarterectomy  1  1/82 (1.22%)  0/78 (0.00%) 
Vascular disorders     
Peripheral embolism  1  1/82 (1.22%)  0/78 (0.00%) 
Peripheral ischaemia  1  1/82 (1.22%)  0/78 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Natalizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   75/82 (91.46%)   68/78 (87.18%) 
Blood and lymphatic system disorders     
Anaemia  1  4/82 (4.88%)  8/78 (10.26%) 
Cardiac disorders     
Atrial fibrillation  1  10/82 (12.20%)  7/78 (8.97%) 
Bradycardia  1  5/82 (6.10%)  1/78 (1.28%) 
Tachycardia  1  5/82 (6.10%)  3/78 (3.85%) 
Gastrointestinal disorders     
Constipation  1  23/82 (28.05%)  24/78 (30.77%) 
Nausea  1  11/82 (13.41%)  9/78 (11.54%) 
Vomiting  1  15/82 (18.29%)  5/78 (6.41%) 
General disorders     
Pain  1  6/82 (7.32%)  9/78 (11.54%) 
Pyrexia  1  26/82 (31.71%)  32/78 (41.03%) 
Infections and infestations     
Pneumonia  1  6/82 (7.32%)  10/78 (12.82%) 
Respiratory tract infection  1  9/82 (10.98%)  4/78 (5.13%) 
Urinary tract infection  1  13/82 (15.85%)  19/78 (24.36%) 
Injury, poisoning and procedural complications     
Fall  1  4/82 (4.88%)  8/78 (10.26%) 
Investigations     
Alanine aminotransferase increased  1  1/82 (1.22%)  5/78 (6.41%) 
Aspartate aminotransferase increased  1  2/82 (2.44%)  4/78 (5.13%) 
Gamma-glutamyltransferase increased  1  5/82 (6.10%)  4/78 (5.13%) 
Metabolism and nutrition disorders     
Diabetes mellitus  1  2/82 (2.44%)  4/78 (5.13%) 
Hypercholesterolaemia  1  3/82 (3.66%)  6/78 (7.69%) 
Hyperglycaemia  1  3/82 (3.66%)  9/78 (11.54%) 
Hypokalaemia  1  10/82 (12.20%)  10/78 (12.82%) 
Hyponatraemia  1  5/82 (6.10%)  3/78 (3.85%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  6/82 (7.32%)  4/78 (5.13%) 
Pain in extremity  1  4/82 (4.88%)  4/78 (5.13%) 
Nervous system disorders     
Brain oedema  1  3/82 (3.66%)  6/78 (7.69%) 
Cerebral haemorrhage  1  0/82 (0.00%)  4/78 (5.13%) 
Haemorrhagic transformation stroke  1  21/82 (25.61%)  18/78 (23.08%) 
Headache  1  19/82 (23.17%)  13/78 (16.67%) 
Neurological decompensation  1  2/82 (2.44%)  4/78 (5.13%) 
Somnolence  1  3/82 (3.66%)  4/78 (5.13%) 
Psychiatric disorders     
Agitation  1  3/82 (3.66%)  11/78 (14.10%) 
Anxiety  1  1/82 (1.22%)  6/78 (7.69%) 
Depression  1  13/82 (15.85%)  5/78 (6.41%) 
Insomnia  1  13/82 (15.85%)  7/78 (8.97%) 
Post stroke depression  1  2/82 (2.44%)  4/78 (5.13%) 
Sleep disorder  1  7/82 (8.54%)  8/78 (10.26%) 
Renal and urinary disorders     
Urinary retention  1  6/82 (7.32%)  5/78 (6.41%) 
Vascular disorders     
Hypertension  1  10/82 (12.20%)  15/78 (19.23%) 
Hypotension  1  12/82 (14.63%)  2/78 (2.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
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: NCT01955707     History of Changes
Other Study ID Numbers: 101SK201
EUDRA CT NO: 2013‐001514‐15
First Submitted: September 30, 2013
First Posted: October 7, 2013
Results First Submitted: February 4, 2016
Results First Posted: July 1, 2016
Last Update Posted: July 1, 2016