ACTION2: Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02730455
• Collaborator: (none)
• Enrollment: 277
• Locations: 53
• Arms: 3
• Actual Duration (Months): 16.1
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the clinical effects of natalizumab versus placebo in acute ischemic stroke on clinical measures of functional independence and activities of daily living. The secondary objective of the study is to explore dose and exposure response and the clinical treatment effects of natalizumab versus placebo in acute ischemic stroke on the following: measures of independence, activities of daily living, neurologic function, quality of life, cognition, and safety and tolerability

Condition or Disease	Intervention/Treatment	Phase
Acute Ischemic Stroke	Drug: natalizumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 277 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Dose-Ranging Study to Evaluate the Safety and Efficacy of Intravenous Natalizumab (BG00002) in Acute Ischemic Stroke
• Actual Study Start Date: Jul 18, 2016
• Actual Primary Completion Date: Nov 20, 2017
• Actual Study Completion Date: Nov 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: natalizumab high dose Single IV (intravenous) dose natalizumab at baseline at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN.	Drug: natalizumab; Administered as specified in the treatment arm; Other Names: BG00002
Experimental: natalizumab low dose Single IV (intravenous) dose natalizumab at baseline at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN.	Drug: natalizumab; Administered as specified in the treatment arm; Other Names: BG00002
Experimental: Placebo Single dose of Placebo IV at baseline at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN.	Drug: Placebo; Matched placebo

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Composite Global Measure of Functional Disability Excellent Outcome at Day 90 [Day 90]

   The composite global measure of functional disability excellent outcome was based on a score of 0 or 1 on the modified Rankin Scale (mRS) and a score of >=95 on the Barthel Index (BI). mRS measures independence, rather than neurological function, with specific tasks pre- and post-stroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.

Secondary Outcome Measures

1. Percentage of Participants With Excellent Outcome in mRS Score at Day 90 [Day 90]

   Excellent mRS is defined as mRS score of 0 or 1. mRS measures independence, rather than neurological function, with specific tasks pre- and poststroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death.

2. Percentage of Participants With Excellent Outcome in BI Score at Day 90 [Day 90]

   Excellent BI outcome is defined as a score of >=95. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.

3. Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at Day 90 [Day 90]

   The SIS-16 is a 16-item physical dimension instrument that was developed as a brief, stand-alone tool for measuring the physical aspects of stroke recovery. The 16 physical aspects are rated on a 1 to 5 scale as follows: not difficult at all (5), a little difficult (4), somewhat difficult (3), very difficult (2), and could not do at all (1). Total score range is 16 to 80, with higher scores indicating higher levels of health-related quality of life and function.

4. Montreal Cognitive Assessment (MoCA) Score at Day 90 [Day 90]

   The MoCA is a global cognitive screening test with favorable psychometric properties It screens 8 domains: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 0 to 30 points; a score of 26 or above is considered normal, <10 (severe cognitive impairment), 10-17 (moderate cognitive impairment) and >=18 (mild cognitive impairment).

5. Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at Day 90 [Baseline, Day 90]

   The NIHSS is a reliable tool for rapidly evaluating the effects of acute cerebral infarction. A trained observer rates the participant's ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss, and extinction and inattention (formerly neglect). There are 15 items. Total score ranges from 0 as normal to a maximum possible total severity score of 42 for all items. Higher the score, more the severity. A negative change from Baseline indicates improvement.

6. Number of Participants Experiencing Adverse Events (AE) [Baseline up to Day 90]

   An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

7. Number of Participants Experiencing Serious Adverse Events (SAE) [Baseline up to Day 90]

   A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization, results in a significant disability/incapacity or congenital anomaly.

8. Percentage of Participants With Dose Response at Day 90 [Day 90]

   Percentage of participants with dose response was evaluated in proportion of excellent outcome on mRS and BI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Clinical diagnosis of supratentorial acute ischemic stroke defined by LKN ≤24 hours prior to study treatment initiation.

• Score of 5 to 23 points, inclusive, on the NIHSS at Screening for subjects initiating treatment ≤9 hours from LKN. Note: NIHSS eligibility must be confirmed within 60 minutes prior to randomization.

• Score of 5 to 15 points, inclusive, on the NIHSS at Screening for subjects initiating treatment >9 to ≤24 hours from LKN. Note: NIHSS eligibility must be confirmed within 60 minutes prior to randomization.

• Prior to index stroke, patient was able to perform basic activities of daily living without assistance: dressing, eating, walking, bathing, and using the toilet.

• For those subjects who underwent a cranial MRI, there is at least 1 acute infarct with a diameter of ≥2 cm on baseline brain diffusion-weighted imaging.

Key Exclusion Criteria:

• Lacunar or isolated brainstem or cerebellar stroke based on clinical assessment and available acute imaging studies performed under the standard of care.

• Presence of acute intracranial hemorrhage on acute brain CT or MRI. However, petechial hemorrhages of ≤1 cm are not exclusionary.

• Severe stroke defined by imaging criteria based on either one of the following:

• Alberta Stroke Program Early CT (ASPECT) score of 0 to 4 based on head CT or

• Acute infarct volume on MRI diffusion weighed imaging greater than or equal to 70 mL

• Seizure at the onset of stroke.

• Known history of prior treatment with natalizumab.

• Known history of active viral hepatitis B or C.

• Signs and symptoms of active or acute infection.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90024
2	Research Site	Sacramento	California	United States	95816
3	Research Site	San Diego	California	United States	92103
4	Research Site	Washington	District of Columbia	United States	20007
5	Research Site	Gainesville	Florida	United States	32611
6	Research Site	Fort Wayne	Indiana	United States	46845
7	Research Site	Boston	Massachusetts	United States	02114
8	Research Site	Saint Louis	Missouri	United States	63110
9	Research Site	New York	New York	United States	10032
10	Research Site	Durham	North Carolina	United States	19104
11	Research Site	Columbus	Ohio	United States	43210
12	Research Site	Portland	Oregon	United States	97201
13	Research Site	Portland	Oregon	United States	97225
14	Research Site	Portland	Oregon	United States	97239
15	Research Site	Abington	Pennsylvania	United States	19001
16	Research Site	Philadelphia	Pennsylvania	United States	19104
17	Research Site	Charleston	South Carolina	United States	29425
18	Research Site	Knoxville	Tennessee	United States	37920-6999
19	Research Site	Altenburg		Germany	04600
20	Research Site	Bad Neustadt/Saale		Germany	97616
21	Research Site	Bamberg		Germany	96049
22	Research Site	Bergisch Gladbach		Germany	51465
23	Research Site	Dresden		Germany	01067
24	Research Site	Dresden		Germany	01307
25	Research Site	Duesseldorf		Germany	40225
26	Research Site	Erlangen		Germany	91054
27	Research Site	Frankfurt		Germany	60528
28	Research Site	Hamburg		Germany	20246
29	Research Site	Heidelberg		Germany	69120
30	Research Site	Leipzig		Germany	04103
31	Research Site	Ludwigshafen		Germany	67063
32	Research Site	Mannheim		Germany	68167
33	Research Site	Minden		Germany	32429
34	Research Site	Muenster		Germany	48149
35	Research Site	Trier		Germany	54292
36	Research Site	Tuebingen		Germany	72076
37	Research Site	Ulm		Germany	89081
38	Research Site	Albacete		Spain	02008
39	Research Site	Badalona		Spain	08916
40	Research Site	Barcelona		Spain	08003
41	Research Site	Barcelona		Spain	08035
42	Research Site	Girona		Spain	17007
43	Research Site	Lugo		Spain	27003
44	Research Site	Madrid		Spain	28007
45	Research Site	Madrid		Spain	28034
46	Research Site	Malaga		Spain	29010
47	Research Site	Sevilla		Spain	41013
48	Research Site	Sevilla		Spain	41017
49	Research Site	Valladolid		Spain	47005
50	Research Site	London	Greater London	United Kingdom	SW17 0QT
51	Research Site	London	Greater London	United Kingdom	W6 8RF
52	Research Site	Harrow	Middlesex	United Kingdom	HA1 3UJ
53	Research Site	Stoke on Trent	Staffordshire	United Kingdom	ST4 6QG

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

• Study Protocol - May 19, 2017
• Statistical Analysis Plan - Dec 5, 2017

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02730455
• Other Study ID Numbers: 101SK202; 2015-004783-11
• First Posted: Apr 6, 2016
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Biogen: Stroke
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia; Natalizumab

Study Results

Participant Flow

Recruitment Details	Participants were recruited from 19 sites in Germany, 4 sites in the United Kingdom (UK), 12 sites in Spain, and 18 sites in the United States (US).
Pre-assignment Detail	A total of 277 participants with acute ischemic stroke were randomized into the study (94 participants in the placebo group, 91 participants in the natalizumab 300 milligram (mg) group, and 92 participants in the natalizumab 600 mg group).

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Period Title: Overall Study
STARTED	94	91	92
Safety Population	91	90	89
Participants Dosed	91	88	91
Who Received Total Volume of Study Drug	90	88	89
COMPLETED	81	77	81
NOT COMPLETED	13	14	11

Baseline Characteristics

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV	Total
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Total of all reporting groups
Overall Participants	94	91	92	277
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.1 (9.54)	66.1 (10.47)	65.6 (11.09)	66.2 (10.36)
Sex: Female, Male (Count of Participants)
Female	29 30.9%	36 39.6%	37 40.2%	102 36.8%
Male	65 69.1%	55 60.4%	55 59.8%	175 63.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.1%	2 2.2%	3 3.3%	7 2.5%
Not Hispanic or Latino	28 29.8%	24 26.4%	24 26.1%	76 27.4%
Unknown or Not Reported	64 68.1%	65 71.4%	65 70.7%	194 70%
Race/Ethnicity, Customized (count of participants) [Number]
Black or African American	2 2.1%	1 1.1%	1 1.1%	4 1.4%
White	27 28.7%	25 27.5%	25 27.2%	77 27.8%
Not Reported Due to Confidentiality Regulations	64 68.1%	65 71.4%	65 70.7%	194 70%
Missing	1 1.1%	0 0%	1 1.1%	2 0.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Composite Global Measure of Functional Disability Excellent Outcome at Day 90
Description	The composite global measure of functional disability excellent outcome was based on a score of 0 or 1 on the modified Rankin Scale (mRS) and a score of >=95 on the Barthel Index (BI). mRS measures independence, rather than neurological function, with specific tasks pre- and post-stroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (MITT) population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is the number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	90	88	89
Number [percentage of participants]	54.1 57.6%	41.5 45.6%	39.9 43.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	Composite Measure: The global odds ratio was based on a linear logistic regression model with baseline National Institute of Health Stroke Scale (NIHSS) category (score 5-15, 16-23), age (<60, 60-69, 70-80), tissue plasminogen activator (tPA) use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, United States of America [USA]) as covariates and unstructured working correlation structure
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	Composite Measure: The global odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Excellent Outcome in mRS Score at Day 90
Description	Excellent mRS is defined as mRS score of 0 or 1. mRS measures independence, rather than neurological function, with specific tasks pre- and poststroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	86	83	82
Number [percentage of participants]	41 43.6%	29 31.9%	26 28.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.222
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Excellent Outcome in BI Score at Day 90
Description	Excellent BI outcome is defined as a score of >=95. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	86	81	81
Number [percentage of participants]	67 71.3%	54 59.3%	54 58.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at Day 90
Description	The SIS-16 is a 16-item physical dimension instrument that was developed as a brief, stand-alone tool for measuring the physical aspects of stroke recovery. The 16 physical aspects are rated on a 1 to 5 scale as follows: not difficult at all (5), a little difficult (4), somewhat difficult (3), very difficult (2), and could not do at all (1). Total score range is 16 to 80, with higher scores indicating higher levels of health-related quality of life and function.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	84	80	77
Mean (Standard Deviation) [score on a scale]	76.21 (30.783)	66.96 (35.493)	68.10 (31.461)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-7.7
	Confidence Interval	(2-Sided) 95%; -16.97 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.202
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-6.1
	Confidence Interval	(2-Sided) 95%; -15.43 to 3.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Montreal Cognitive Assessment (MoCA) Score at Day 90
Description	The MoCA is a global cognitive screening test with favorable psychometric properties It screens 8 domains: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 0 to 30 points; a score of 26 or above is considered normal, <10 (severe cognitive impairment), 10-17 (moderate cognitive impairment) and >=18 (mild cognitive impairment).
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	69	74	69
Mean (Standard Deviation) [score on a scale]	21.23 (8.412)	20.73 (8.141)	20.90 (8.223)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.780
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -2.64 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.622
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.89 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at Day 90
Description	The NIHSS is a reliable tool for rapidly evaluating the effects of acute cerebral infarction. A trained observer rates the participant's ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss, and extinction and inattention (formerly neglect). There are 15 items. Total score ranges from 0 as normal to a maximum possible total severity score of 42 for all items. Higher the score, more the severity. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	77	76	71
Mean (Standard Deviation) [score on a scale]	-6.14 (6.920)	-5.17 (7.937)	-6.28 (6.510)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.315
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -1.10 to 3.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 600 mg IV
	Comments	Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.542
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.96 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants Experiencing Adverse Events (AE)
Description	An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	Baseline up to Day 90

Outcome Measure Data

Analysis Population Description

The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	91	90	89
Number [participants]	84 89.4%	81 89%	82 89.1%

8. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events (SAE)
Description	A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization, results in a significant disability/incapacity or congenital anomaly.
Time Frame	Baseline up to Day 90

Outcome Measure Data

Analysis Population Description

The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	91	90	89
Number [participants]	19 20.2%	23 25.3%	29 31.5%

9. Secondary Outcome

Title	Percentage of Participants With Dose Response at Day 90
Description	Percentage of participants with dose response was evaluated in proportion of excellent outcome on mRS and BI.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Arm/Group Title	Placebo	Natalizumab 300 mg IV	Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Measure Participants	90	88	89
mRS (0, 1)	41 43.6%	29 31.9%	26 28.3%
BI (>=95)	67 71.3%	54 59.3%	54 58.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV, Natalizumab 600 mg IV
	Comments	mRS: The Cochran-Armitage trend test of a monotonically increasing dose response in proportion of excellent outcome. Dose levels are log transformed.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Cochran-Armitage trend test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Natalizumab 300 mg IV, Natalizumab 600 mg IV
	Comments	BI: The Cochran-Armitage trend test of a monotonically increasing dose response in proportion of excellent outcome. Dose levels are log transformed.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	Cochran-Armitage trend test
	Comments

Adverse Events

Time Frame	Baseline up to Day 90
Adverse Event Reporting Description	The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Arm/Group Title	Placebo		Natalizumab 300 mg IV		Natalizumab 600 mg IV
Arm/Group Description	Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).		Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).		Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
All Cause Mortality
	Placebo		Natalizumab 300 mg IV		Natalizumab 600 mg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/91 (5.5%)		6/90 (6.7%)		4/89 (4.5%)
Serious Adverse Events
	Placebo		Natalizumab 300 mg IV		Natalizumab 600 mg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/91 (20.9%)		23/90 (25.6%)		29/89 (32.6%)
Cardiac disorders
Acute myocardial infarction	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Atrial fibrillation	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Cardiac arrest	1/91 (1.1%)		1/90 (1.1%)		2/89 (2.2%)
Cardiac failure congestive	1/91 (1.1%)		0/90 (0%)		1/89 (1.1%)
Cardiogenic shock	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Coronary artery disease	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Coronary artery stenosis	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Sinus node dysfunction	1/91 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Supraventricular tachycardia	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Eye disorders
Retinal detachment	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Gastrointestinal disorders
Constipation	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Ileus paralytic	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Large intestine perforation	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Oesophageal ulcer haemorrhage	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Retroperitoneal haematoma	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
General disorders
Death	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Gait disturbance	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Multiple organ dysfunction syndrome	1/91 (1.1%)		1/90 (1.1%)		0/89 (0%)
Hepatobiliary disorders
Ischaemic hepatitis	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Infections and infestations
Endocarditis	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Endocarditis bacterial	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Enterococcal sepsis	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Febrile infection	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Gastroenteritis	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Gastroenteritis viral	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Haemophilus infection	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Peritonitis	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Pneumonia	2/91 (2.2%)		0/90 (0%)		1/89 (1.1%)
Pneumonia acinetobacter	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Respiratory tract infection	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Sepsis	2/91 (2.2%)		1/90 (1.1%)		0/89 (0%)
Septic encephalopathy	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Septic shock	1/91 (1.1%)		0/90 (0%)		1/89 (1.1%)
Splenic abscess	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Urinary tract infection	1/91 (1.1%)		0/90 (0%)		1/89 (1.1%)
Urosepsis	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Wound infection staphylococcal	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Injury, poisoning and procedural complications
Aortic restenosis	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Brain herniation	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Fall	1/91 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Ilium fracture	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Periprocedural myocardial infarction	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Post procedural complication	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Wound dehiscence	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Investigations
Escherichia test positive	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Metabolism and nutrition disorders
Gout	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Hyperglycaemic hyperosmolar nonketotic syndrome	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma stage IV	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Nervous system disorders
Carotid artery stenosis	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Cerebral artery occlusion	0/91 (0%)		0/90 (0%)		2/89 (2.2%)
Cerebral haemorrhage	0/91 (0%)		3/90 (3.3%)		1/89 (1.1%)
Cerebral infarction	1/91 (1.1%)		0/90 (0%)		2/89 (2.2%)
Cerebral reperfusion injury	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Cerebrovascular accident	2/91 (2.2%)		0/90 (0%)		3/89 (3.4%)
Cytotoxic oedema	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Embolic cerebral infarction	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Generalised tonic-clonic seizure	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Haemorrhagic transformation stroke	1/91 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Headache	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Hydrocephalus	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Ischaemic stroke	0/91 (0%)		3/90 (3.3%)		2/89 (2.2%)
Lacunar infarction	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Neurological decompensation	1/91 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Partial seizures	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Seizure	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Stroke in evolution	1/91 (1.1%)		2/90 (2.2%)		1/89 (1.1%)
Renal and urinary disorders
Haematuria	0/91 (0%)		0/90 (0%)		2/89 (2.2%)
Ureteric rupture	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Urinary retention	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/91 (1.1%)		0/90 (0%)		2/89 (2.2%)
Asthma	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Haemothorax	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Pneumonia aspiration	1/91 (1.1%)		2/90 (2.2%)		1/89 (1.1%)
Pneumothorax	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Pulmonary embolism	0/91 (0%)		3/90 (3.3%)		3/89 (3.4%)
Respiratory failure	1/91 (1.1%)		1/90 (1.1%)		2/89 (2.2%)
Skin and subcutaneous tissue disorders
Idiopathic angioedema	0/91 (0%)		1/90 (1.1%)		0/89 (0%)
Vascular disorders
Aortic embolus	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Deep vein thrombosis	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Orthostatic hypotension	1/91 (1.1%)		0/90 (0%)		0/89 (0%)
Peripheral artery occlusion	0/91 (0%)		0/90 (0%)		1/89 (1.1%)
Other (Not Including Serious) Adverse Events
	Placebo		Natalizumab 300 mg IV		Natalizumab 600 mg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/91 (73.6%)		69/90 (76.7%)		65/89 (73%)
Blood and lymphatic system disorders
Anaemia	3/91 (3.3%)		3/90 (3.3%)		5/89 (5.6%)
Cardiac disorders
Atrial fibrillation	8/91 (8.8%)		6/90 (6.7%)		7/89 (7.9%)
Gastrointestinal disorders
Abdominal pain	1/91 (1.1%)		5/90 (5.6%)		1/89 (1.1%)
Constipation	18/91 (19.8%)		19/90 (21.1%)		23/89 (25.8%)
Diarrhoea	4/91 (4.4%)		5/90 (5.6%)		3/89 (3.4%)
Dysphagia	1/91 (1.1%)		6/90 (6.7%)		2/89 (2.2%)
Nausea	4/91 (4.4%)		7/90 (7.8%)		6/89 (6.7%)
Vomiting	3/91 (3.3%)		7/90 (7.8%)		1/89 (1.1%)
General disorders
Fatigue	5/91 (5.5%)		1/90 (1.1%)		1/89 (1.1%)
Pain	3/91 (3.3%)		7/90 (7.8%)		2/89 (2.2%)
Pyrexia	11/91 (12.1%)		19/90 (21.1%)		14/89 (15.7%)
Infections and infestations
Pneumonia	3/91 (3.3%)		2/90 (2.2%)		8/89 (9%)
Urinary tract infection	11/91 (12.1%)		14/90 (15.6%)		15/89 (16.9%)
Injury, poisoning and procedural complications
Fall	5/91 (5.5%)		7/90 (7.8%)		5/89 (5.6%)
Metabolism and nutrition disorders
Hypokalaemia	6/91 (6.6%)		12/90 (13.3%)		6/89 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/91 (0%)		1/90 (1.1%)		5/89 (5.6%)
Pain in extremity	2/91 (2.2%)		5/90 (5.6%)		2/89 (2.2%)
Nervous system disorders
Haemorrhagic transformation stroke	4/91 (4.4%)		4/90 (4.4%)		5/89 (5.6%)
Headache	15/91 (16.5%)		16/90 (17.8%)		20/89 (22.5%)
Psychiatric disorders
Agitation	8/91 (8.8%)		5/90 (5.6%)		0/89 (0%)
Anxiety	4/91 (4.4%)		2/90 (2.2%)		7/89 (7.9%)
Depression	16/91 (17.6%)		13/90 (14.4%)		10/89 (11.2%)
Insomnia	4/91 (4.4%)		11/90 (12.2%)		10/89 (11.2%)
Renal and urinary disorders
Haematuria	5/91 (5.5%)		3/90 (3.3%)		3/89 (3.4%)
Urinary retention	6/91 (6.6%)		4/90 (4.4%)		3/89 (3.4%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	5/91 (5.5%)		5/90 (5.6%)		1/89 (1.1%)
Vascular disorders
Hypertension	6/91 (6.6%)		7/90 (7.8%)		8/89 (9%)
Hypotension	5/91 (5.5%)		4/90 (4.4%)		7/89 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.