Safety Evaluation of 3K3A-APC in Ischemic Stroke

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of multiple ascending intravenous doses of 3K3A-APC, a Recombinant Variant of Human activated protein C (APC), in in the treatment of acute ischemic stroke following treatment with recombinant tissue plasminogen activator (tPA), mechanical thrombectomy or both.

Detailed Description
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This was a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following treatment with tPA, mechanical thrombectomy or both in subjects with moderate to severe acute ischemic stroke. Approximately 115 subjects were to be randomized, which included the planned 88 subjects in groups of 4 subjects to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional placebo subjects who were enrolled during safety review pauses. This study used a modified version of the continual reassessment method (CRM) in order to establish a maximum tolerated dose (MTD). Eligible subjects received 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days), or until discharge from the hospital, whichever occurred first. Subjects were monitored for safety evaluations through Day 7 (or discharge, if earlier) and were expected to be seen on Day 7, 14, 30, and 90 for safety and outcome evaluations.

Official Title
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A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke

Conditions
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Ischemic Stroke

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute ischemic stroke Able to receive IV tPA, mechanical thrombectomy or both National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5 Signed informed consent Mechanical thrombectomy subjects only: onset time to arterial puncture time < 6 hours Exclusion Criteria: History of stroke or penetrating head injury within 90 days prior to enrollment History of previous or current diagnosis of intracranial hemorrhage that represents a potential for re-hemorrhage if subjected to thrombolytic therapy or mechanical thrombectomy Moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm requiring intervention during the acute study period Presence of other neurological or non-neurological co-morbidities that may lead, independently of the current stroke, to further deterioration in the subject's neurological status during the trial period Presence of premorbid neurological deficits and functional limitations assessed by a retrospective Modified Rankin Scale (mRS) score of ≥ 2 Mechanical thrombectomy subjects only: baseline non-contrast CT scan revealing a large core occlusion as defined by local protocol Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT) Severe hypertension or hypotension Glomerular filtration rate (GFR) <35 mL/min Blood glucose concentration < 50 mg/dL Prior exposure to any exogenous form of APC

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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 |
| --- | --- |
| Active Comparator: 120 µg/kg 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 as 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Active Comparator: 240 µg/kg 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 as 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Active Comparator: 360 µg/kg 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 as 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Active Comparator: 540 µg/kg 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 as 100 mL IV infusion<br>* Other names: 3K3A-Activated Protein C;|
| Placebo Comparator: Placebo<br>Matching placebo, q12h for up to 5 doses | Drug: Placebo<br>* Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion<br>* Other names: Matching Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol | Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT. | 48-hours following last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI | MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test. | Day 30 | 
| PK of 3K3A-APC by Compartmental Analysis (Clearance) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 
| PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 
| PK of 3K3A-APC by Compartmental Analysis (Cmax) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 
| PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf]) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 
| PK of 3K3A-APC by Compartmental Analysis (λz) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 
| PK of 3K3A-APC by Compartmental Analysis (Half-life) | Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, ischemic stroke, APC, 3K3A, 3K3A-APC, activated protein C, RHAPSODY