Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke

Study Overview
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Brief Summary
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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

Official Title
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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

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: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: natalizumab high dose<br>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<br>* Administered as specified in the treatment arm<br>* Other names: BG00002;|
| Experimental: natalizumab low dose<br>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<br>* Administered as specified in the treatment arm<br>* Other names: BG00002;|
| Experimental: Placebo<br>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<br>* Matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite Global Measure of Functional Disability Excellent Outcome at 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. | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Excellent Outcome in mRS Score at 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. | Day 90 | 
| Percentage of Participants With Excellent Outcome in BI Score at 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. | Day 90 | 
| Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at 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. | Day 90 | 
| Montreal Cognitive Assessment (MoCA) Score at 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). | Day 90 | 
| Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at 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. | Baseline, Day 90 | 
| Number of Participants Experiencing Adverse Events (AE) | 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. | Baseline up to Day 90 | 
| Number of Participants Experiencing Serious Adverse Events (SAE) | 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. | Baseline up to Day 90 | 
| Percentage of Participants With Dose Response at Day 90 | Percentage of participants with dose response was evaluated in proportion of excellent outcome on mRS and BI. | Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke