Study of the Combination Therapy of Rt-PA and Eptifibatide to Treat Acute Ischemic Stroke (CLEAR-FDR)

Study Overview
=================
Brief Summary
-----------------
The primary goal of this trial is to determine if individuals with acute ischemic stroke treated with a full dose of IV recombinant tissue plasminogen activator (rt-PA) plus IV eptifibatide started within 3 hours of symptom onset are more likely to have a better outcome than individuals treated with standard IV rt-PA alone.

Detailed Description
-----------------
The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Full Dose Regimen (CLEAR-FDR Stroke Trial) is a Phase II trial and part of the Specialized Program on Translational Research in Acute Stroke (SPOTRIAS). The overall goals of SPOTRIAS are to enhance delivery of acute stroke patient care and train acute stroke translational researchers. Stroke most often occurs when blood flow to the brain stops because it is blocked by a blood clot. When a blood clot blocks the blood supply to the brain, parts of the brain may not get enough blood and oxygen to survive. As a result, permanent brain damage can occur, which can affect a person's ability to walk, talk, and function independently. In order to reduce the risk of permanent damage, it is important to restore blood flow to the brain as quickly as possible. rt-PA, used alone, is already approved by the Food and Drug Administration (FDA) as treatment for patients with a stroke caused by blockage of an artery in the brain and when given within 3 hours of the onset of stroke symptoms. Eptifibatide is also already FDA-approved as a treatment for blood clots causing heart attack. The investigational aspect of this study is the use of eptifibatide for a stroke victim in combination with rt-PA. The CLEAR Stroke Trial demonstrated that the combination of low dose rt-PA plus eptifibatide can be safely given to acute ischemic stroke patients within 3 hours of symptom onset. The CLEAR-ER Stroke Trial demonstrated that the combination of medium dose rt-PA plus eptifibatide can be safely given to acute ischemic stroke patients within 3 hours of symptom onset. The CLEAR-FDR Stroke Trial is designed to provide data concerning the risks when combining eptifibatide with full dose intravenous rt-PA in 30 acute ischemic stroke patients within 3 hours of symptom onset.

Official Title
-----------------
Phase 2 The Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Full Dose Regimen(CLEAR-FDR)

Conditions
-----------------
Stroke, Brain Infarction

Intervention / Treatment
-----------------
* Drug: Eptifibatide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a serious measurable neurological deficit on the NIH Stroke Scale due to focal brain ischemia. An NIH Stroke Scale score >5 at the time the rt-PA is begun. Age: 18 through 85 years (i.e. candidates must have had their 18th birthday, but not had their 86th birthday). Intravenous rt-PA therapy must be initiated within 3 hours of onset of stroke symptoms. Exclusion Criteria: History of stroke in the past 3 months. Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is normal. Hypertension at time of treatment; systolic BP > 185 or diastolic > 110 mmHg or aggressive measures to lower blood pressure to below these limits are needed. Presumed septic embolus. Presumed pericarditis including pericarditis after acute myocardial infarction. Recent (within 30 days) surgery or biopsy of parenchymal organ. Recent (within 30 days) trauma, with internal injuries or ulcerative wounds. Recent (within 90 days) severe head trauma or head trauma with loss of consciousness. Any active or recent (within 30 days) serious systemic hemorrhage. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or oral anticoagulant therapy with International Normalized Ratio (INR) > 1.7. Baseline lab values: positive urine pregnancy test, glucose < 50 or > 400 mg/dl, platelets <100,000 /mm3, Hct <25 %, or creatinine > 4 mg/dl. Ongoing renal dialysis, regardless of creatinine. Subjects who received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) as deep vein thrombosis (DVT) prophylaxis or in full dose within the previous 24 hours. Subjects who received heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, or lepirudin) within 48 hours from screening must have had a normal partial prothrombin time (PTT). Subjects who received Factor Xa inhibitors (such as fondaparinux) or direct thrombin inhibitors (such as dabigatran) within the last 4 days. Arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days. Seizure at onset of stroke. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations. Other serious, advanced, or terminal illness or any other condition that the investigator feels would pose a significant hazard to the patient if rt-PA or eptifibatide therapy were initiated. Patients whose peripheral venous access is so poor that they are unable to have two standard peripheral intravenous lines started. Current participation in another research drug treatment protocol. Patient cannot start another experimental agent until after 90 days. Informed consent is not or cannot be obtained. Any known history of amyloid angiopathy. High density lesion consistent with hemorrhage of any degree. Significant mass effect with midline shift. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment.

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

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eptifibatide<br>All subjects will receive the standard dose of IV rt-PA. All subjects will promptly receive an IV bolus of 135mcg/kg eptifibatide followed by an IV infusion of 0.75 mcg/kg/min eptifibatide for 2 hours. | Drug: Eptifibatide<br>* IV Eptifibatide is an approved drug by the Food and Drug Administration as a treatment for blood clots causing heart attack and chest pain.Eptifibatide inhibits platelet aggregation by blocking activated platelets from binding fibrinogen.<br>* Other names: Integrilin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients Who Experience Symptomatic Intracerebral Hemorrhage (sICH). | Any ICH related to a decline in neurologic status or the development of new neurologic symptoms which in the judgment of the clinical investigator was related to the ICH. Judgment of significant neurological decline was made by the local clinical investigator | within 36 hours after stroke onset | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients Who Experience Any Intracerebral Hemorrhage (ICH). | Any ICH symptomatic (as defined above) or asymptomatic (that visualized on CT or MRI only) | within 36 hours after stroke onset | 
| The Number of Patients Who Develop Parenchymal Hemorrhage Types 1( PH-1) and 2 (PH-2). | Any parenchymal hemorrhage types PH-1 or PH-2 as visualized on CT | within 36 hours after stroke onset | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acute ischemic stroke, stroke, rt-PA, thrombolytic, t-PA, recombinant tissue plasminogen activator, Activase, eptifibatide, Integrilin, fibrinolytic agents, clot dissolving, blood clot