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

The "Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Enhanced Regimen" (CLEAR-ER Stroke Trial)

The primary goal of this trial is to determine if individuals with acute ischemic stroke treated with a medium dose of IV 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.

Study Overview

• Status: Completed
• Conditions: Stroke; Ischemic Stroke; Brain Infarction
• Intervention / Treatment: Drug: rt-PA; Drug: Eptifibatide

Detailed Description

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA (recombinant tissue plasminogen activator) in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER 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 (NCT00250991) 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 is designed to provide data concerning the risks and benefits of combining eptifibatide with medium dose intravenous rt-PA in 126 acute ischemic stroke patients within 3 hours of symptom onset. Patients will be randomized to a combined intravenous medium-dose rt-PA and eptifibatide regimen, or standard dose rt-PA in a 5 to 1 ratio. This will result in a total of 105 patients treated with a combined regimen, and 21 patients treated with standard dose IV rt-PA alone.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90024
      • UCLA Ronald Reagan Medical Center
    • San Diego, California, United States, 92103
      • University of California San Diego
    • Santa Monica, California, United States, 90404
      • UCLA Medical Center Santa Monica
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • St. Elizabeth Healthcare Edgewood
    • Florence, Kentucky, United States, 41042
      • St. Elizabeth Healthcare Florence
    • Ft. Thomas, Kentucky, United States, 41075
      • St. Elizabeth Healthcare Ft. Thomas
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Suburban Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Robert Wood Johnson University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital, Inc.
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital
    • Cincinnati, Ohio, United States, 45242
      • Bethesda North Hospital
    • Cincinnati, Ohio, United States, 45236
      • The Jewish Hospital
    • Cincinnati, Ohio, United States, 45219
      • University Hospital
    • Cincinnati, Ohio, United States, 45220-2489
      • Good Samaritan Hospital
    • Cincinnati, Ohio, United States, 45238
      • Mercy Hospital, Western Hills
    • Cincinnati, Ohio, United States, 45239
      • Mercy Hospital Mt Airy
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Iinternational Normalized Ratio (INR) > 1.7.
• Baseline lab values: positive urine pregnancy test, glucose < 50 or > 400 mg/dl, platelets <100,000 /mm3, Hct (hematocrit) <25 %, or creatinine > 4 mg/dl.
• Ongoing renal dialysis, regardless of creatinine.
• If heparin has been administered within 48 hours, the patient must have a normal partial thromboplastin time (PTT).
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: rt-PA only; Subject will receive the standard dose (0.9mg/kg) of IV rt-PA given over 60 minutes. One out of 6 subjects will be in this group.	Drug: rt-PA; Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.; Other Names: Activase
Experimental: rt-PA and Eptifibatide; Subject will receive the standard dose (0.9mg/kg) of IV rt-PA. This IV dose will be discontinued at 40 minutes. The subject will immediately receive an IV bolus of 135mcg/kg eptifibatide followed by an IV infusion of 0.75 mcg/kg/min eptifibatide for 2 hours. Five out of six subjects will be in this group.	Drug: rt-PA; Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.; Other Names: Activase; Drug: Eptifibatide; 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.; Other Names: Integrilin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours of Treatment Onset	Primary safety outcome measure - 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 of initiation of therapy
Modified Rankin Scale (mRS) Score <1 or Return to mRS Baseline	Primary efficacy outcome measure - Modified Rankin Scale of 0 or 1 or return to the pre-stroke value at baseline or better. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days were given a value of '6', and assigned the "bad" outcome. Also those lost to follow-up were assigned the "bad" outcome. The Modified Rankin Score (mRS) is a 6 point ordinal scale, measuring functional status. 0 (no symptoms at all), 5 (severe disability; bedridden, incontinent, and requiring constant nursing care).	90 days from treatment onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Barthel Index ≥ 95	Barthel index score of ≥ 95. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Barthel index is a score comprised of 10 individual items. Each item may be scored 0, 5, 10 or 15; not all items use the full range of 4 possible values. The individual items are summed to produce a total score between 0 and 100; where 0 is inferior performance and 100 is optimal. A score of ≥ 95 is usually considered excellent.	90 days from treatment onset
Glasgow Outcome Scale (GOS) of 1	Glasgow outcome scale score of 1 versus greater than 1. The scale was performed by a study site investigator not directly involved with acute treatment of the patient. Study subjects dead at 90 days and those lost to follow-up were assigned the "bad" outcome. The Glasgow Outcome Scale is scored; 1=good recovery, 2=moderately disabled, 3=severely disabled, 4=vegetative survival, 5=dead.	90 days from treatment onset

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Systemic Bleeding	Incidence of serious systemic bleeding defined as requiring transfusion of 2 or more units of packed red blood cells.	Within 7 days of treatment onset
Symptomatic Intracranial Hemorrhage (sICH) Within 7 Days of Treatment Onset	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 7 days of treatment onset
Asymptomatic Intracranial Hemorrhage (asICH) Within 7 Days of Treatment Onset	Any ICH observed on CT by the study site neuroradiologist and the independent study neuroradiologist; the central reader. The ICH would not be 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,where judgment of significant neurological decline was made by the local clinical investigator. A third independent reader will make the final determination if there is disagreement between the treating investigator and the central reader	Within 7 days of treatment onset
Death Within 7 Days of Treatment Onset	Death due to any cause within 7 days of treatment onset	Within 7 days of treatment onset
Death Due to Stroke Within 7 Days of Treatment Onset	Death due to stroke within 7 days of treatment onset. Classified by blinded clinical investigators	Within 7 days of treatment onset
NIH Stroke Scale Score (NIHSS) ≤ 5	Study subjects with an NIH stroke scale score of ≤ 5 at 2 hours from treatment onset, those sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=1). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.	Within 2 hours of treatment onset
NIH Stroke Scale Score (NIHSS) ≤ 2	Study subjects with an NIH stroke scale score of ≤ 2 at 24 hours from treatment onset, those dead (n=1) or sedated and unable to be evaluated by the NIHSS were assigned the "bad" outcome (n=5). The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.	Within 24 hours of treatment onset
NIH Stroke Scale Score (NIHSS) ≤2 at 90 Days	Study subjects with an NIH stroke scale score ≤ 2 points at 90 days from treatment onset compared to baseline value, those dead or unable to be evaluated by the NIHSS were assigned the "bad" outcome. The NIH stroke scale score is scale based on 15 items individually scored between 0-2, 0-3 or 0-4 depending upon the item. The individual items are summed to produce a score between 0 and 42, where 0 indicates no deficit and 42 indicates death.	90 days from treatment onset

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Arthur M Pancioli, MD, University of Cincinnati College of Medicine Department of Emergency Medicine; Principal Investigator: Opeolu M Adeoye, MD, University of Cincinnati College of Medicine Department of Emergency Medicine

Publications and helpful links

General Publications

• Barreto AD, Pedroza C, Grotta JC. Adjunctive medical therapies for acute stroke thrombolysis: is there a CLEAR-ER choice? Stroke. 2013 Sep;44(9):2377-9. doi: 10.1161/STROKEAHA.113.001830. Epub 2013 Jul 25. No abstract available.
• Pancioli AM, Adeoye O, Schmit PA, Khoury J, Levine SR, Tomsick TA, Sucharew H, Brooks CE, Crocco TJ, Gutmann L, Hemmen TM, Kasner SE, Kleindorfer D, Knight WA, Martini S, McKinney JS, Meurer WJ, Meyer BC, Schneider A, Scott PA, Starkman S, Warach S, Broderick JP; CLEAR-ER Investigators. Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke. 2013 Sep;44(9):2381-7. doi: 10.1161/STROKEAHA.113.001059. Epub 2013 Jul 25.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: May 6, 2009
• First Submitted That Met QC Criteria: May 6, 2009
• First Posted (Estimate): May 7, 2009

Study Record Updates

• Last Update Posted (Estimate): April 17, 2014
• Last Update Submitted That Met QC Criteria: March 26, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: stroke; eptifibatide; acute ischemic stroke; blood clot; t-PA; recombinant tissue plasminogen activator; rt-PA, thrombolytic; Activase; Integrilin; fibrinolytic agents; clot dissolving
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Brain Infarction; Platelet Aggregation Inhibitors; Eptifibatide
• Other Study ID Numbers: P50NS04483-06; 00894803 (Registry Identifier: NCT)