Efficacy and Safety Evaluation of 3K3A-APC in Ischemic Stroke

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of intravenous doses of 3K3A-APC, a recombinant variant of human activated protein C (APC), in the treatment of acute ischemic stroke following treatment with thrombolysis, mechanical thrombectomy or both.

Detailed Description
-----------------
This multicenter, randomized, placebo-controlled, double-blind, Phase 3 study is being performed in coordination with StrokeNet to evaluate efficacy and safety of 3K3A-APC following administration of thrombolysis, mechanical thrombectomy, or both in subjects with moderate to severe acute ischemic stroke. The study will be conducted in two phases. During a lead-in dose-finding phase, a maximum of 360 subjects will be randomized to 3K3A-APC or placebo using a Bayesian adaptive approach. Randomized subjects will receive 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days) or until discharge from the hospital (whichever occurs first). The lead-in phase will transition to one selected 3K3A APC dose-and recruitment will continue-when a single dose proves superior to all other doses and safe. The definitive phase will continue with the selected dose of 3K3A-APC from the lead-in phase. Randomization will be stratified on 4 variables. Lead-in patients who received the dose selected for the definitive phase will be included in the final data analysis.

Official Title
-----------------
A Phase 3 Study to Evaluate the Efficacy and Safety of 3K3A-APC in Combination With Tissue Plasminogen Activator, Mechanical Thrombectomy, or Both in Subjects With Moderate to Severe Acute Ischemic Stroke

Conditions
-----------------
Ischemic Stroke

Intervention / Treatment
-----------------
* Biological: 3K3A-APC
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Acute ischemic stroke Able to receive thrombolysis, mechanical thrombectomy or both National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5 Signed informed consent Agreement to use effective birth control throughout the study Exclusion Criteria: Neurologic deficit is non-disabling History of stroke or penetrating head injury within 90 days prior to enrollment History of previous or current diagnosis of intracranial hemorrhage Moyamoya disease, cerebral arteriovenous malformation, or known unsecured aneurysm requiring intervention during the acute study period Presence of tandem lesions suggesting a likely need for proximal artery stenting during the thrombectomy procedure that would mandate post-operative dual antiplatelet therapy Presence of other neurological or non-neurological co-morbidities, independently of the current stroke, that may lead to further deterioration in the subject's neurological status during the study period Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT) Severe hypertension or hypotension Blood glucose concentration < 50 mg/dL Prior exposure to any exogenous form of a recombinant variant of human APC

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 10mg of 3K3A-APC<br>3K3A-APC, q12h for up to 5 doses | Biological: 3K3A-APC<br>* 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Active Comparator: 15mg of 3K3A-APC<br>3K3A-APC, q12h for up to 5 doses | Biological: 3K3A-APC<br>* 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Active Comparator: 30mg of 3K3A-APC<br>3K3A-APC, q12h for up to 5 doses | Biological: 3K3A-APC<br>* 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Placebo Comparator: Placebo<br>Matching placebo, q12h for up to 5 doses | Other: Placebo<br>* Matching placebo, 0.9% sodium chloride in water, given at 100 mL IV infusion<br>* Other names: Matching Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of 3K3A-APC on 90-day disability | Day 90 mRS scores will be compared between groups using ordinal (shift) analysis | Day 90 mRS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety of 3K3A-APC | The percentage of subjects who experienced any treatment-related AE will be compared using a Fisher's exact test. | Baseline to Day 90 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ischemic Stroke, Stroke, APC, 3K3A, 3K3A-APC, Activated protein C, RHAPSODY