Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke

Study Overview
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Brief Summary
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The primary objective of the study is to determine whether one 300 mg dose of intravenous (IV) natalizumab reduces change in infarct volume from Baseline to Day 5 on magnetic resonance imaging (MRI) in participants with acute ischemic stroke when given at ≤6 hours or at >6 to ≤9 hours from when they were last known normal (LKN). The secondary objectives of this study in this study population are as follows: to assess the efficacy of natalizumab on change in infarct volume from Baseline to Day 30; to assess efficacy of natalizumab on change in infarct volume from 24 hours to Day 5 and Day 30; to assess the efficacy of natalizumab on clinical measures of stroke outcome; to assess the safety of natalizumab in participants with acute ischemic stroke.

Official Title
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A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group Study to Evaluate the Safety and Efficacy of Intravenous Natalizumab (BG00002) on Reducing Infarct Volume in Acute Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: natalizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of acute ischemic stroke. Score of ≥6 points on the National Institute of Health Stroke Scale (NIHSS) at Screening. At least 1 acute infarct with largest diameter of more than 2 cm on Baseline brain diffusion-weighted imaging (DWI). Participants who have received reperfusion therapy may be eligible to participate but must meet all eligibility criteria and perform the Baseline study magnetic resonance imaging (MRI) after reperfusion therapy has been completed. Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for at least 3 months after their dose of study treatment. Key Exclusion Criteria: Presence of any intracranial hemorrhage (ICH) on head computed tomography (CT) or non-petechial ICH on screening MRI. Stroke isolated to the brainstem. Presence of coma Expected to die OR unable to be evaluated within 5 days. Hypotension requiring the use of intravenous (IV) vasopressor support or systolic blood pressure <90 mmHg at the time of randomization. Known prior treatment with natalizumab. Immunocompromised subjects, as determined by the Investigator. History of progressive multifocal leukoencephalopathy (PML). Contraindications to MRI, e.g., implanted pacemaker or other contraindicated implanted metal devices, history of or risk for side effects from gadolinium, or claustrophobia that cannot be medically managed. NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: natalizumab<br>300 mg single intravenous (IV) injection | Drug: natalizumab<br>* Administered as described in the treatment arm<br>* Other names: BG00002;|
| Placebo Comparator: Placebo<br>A single IV dose of placebo | Drug: Placebo<br>* Matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Infarct Volume From Baseline (Diffusion-Weighted Imaging [DWI]) to Day 5 (Fluid-Attenuated Inversion Recovery [FLAIR]) | 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. | Baseline, Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Infarct Volume From Baseline (DWI) to 24 Hours (FLAIR) | 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. | Baseline, 24 hrs | 
| Change in Infarct Volume From Baseline (DWI) to Day 30 (FLAIR) | 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. | Baseline, Day 30 | 
| Change in Infarct Volume From 24 Hours (FLAIR) to Day 5 (FLAIR) | 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. | 24 hours, Day 5 | 
| Change in Infarct Volume From 24 Hours (FLAIR) to Day 30 (FLAIR) | 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. | 24 hours, Day 30 | 
| Change in Infarct Volume From Day 5 (FLAIR) to Day 30 (FLAIR) | 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. | Day 5, Day 30 | 
| Change in National Institute of Health Stroke Scale (NIHSS) Score From Baseline to 24 Hours, Day 5, Day 30, and Day 90 | 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. | Baseline, 24 hours, Day 5, Day 30, Day 90 | 
| Modified Rankin Scale (mRS) Distribution at Day 5, Day 30, and Day 90 | 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. | Day 5, Day 30, and Day 90 | 
| Barthel Index at Day 5, Day 30, and Day 90 | 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. | Day 5, Day 30, and Day 90 | 
| Number of Participants Who Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Up to Day 90 ± 5 days |