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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Arthur Pancioli, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00894803
First received: May 6, 2009
Last updated: March 26, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Ischemic Stroke
Stroke
Brain Infarction
Drug: Eptifibatide
Drug: rt-PA
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: The "Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Enhanced Regimen" (CLEAR-ER Stroke Trial)

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours of Treatment Onset [ Time Frame: Within 36 hours of initiation of therapy ] [ Designated as safety issue: Yes ]
    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

  • Modified Rankin Scale (mRS) Score <1 or Return to mRS Baseline [ Time Frame: 90 days from treatment onset ] [ Designated as safety issue: No ]

    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).



Secondary Outcome Measures:
  • Barthel Index ≥ 95 [ Time Frame: 90 days from treatment onset ] [ Designated as safety issue: No ]

    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.


  • Glasgow Outcome Scale (GOS) of 1 [ Time Frame: 90 days from treatment onset ] [ Designated as safety issue: No ]

    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.



Other Outcome Measures:
  • Serious Systemic Bleeding [ Time Frame: Within 7 days of treatment onset ] [ Designated as safety issue: Yes ]
    Incidence of serious systemic bleeding defined as requiring transfusion of 2 or more units of packed red blood cells.

  • Symptomatic Intracranial Hemorrhage (sICH) Within 7 Days of Treatment Onset [ Time Frame: Within 7 days of treatment onset ] [ Designated as safety issue: Yes ]
    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

  • Asymptomatic Intracranial Hemorrhage (asICH) Within 7 Days of Treatment Onset [ Time Frame: Within 7 days of treatment onset ] [ Designated as safety issue: Yes ]
    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

  • Death Within 7 Days of Treatment Onset [ Time Frame: Within 7 days of treatment onset ] [ Designated as safety issue: Yes ]
    Death due to any cause within 7 days of treatment onset

  • Death Due to Stroke Within 7 Days of Treatment Onset [ Time Frame: Within 7 days of treatment onset ] [ Designated as safety issue: Yes ]
    Death due to stroke within 7 days of treatment onset. Classified by blinded clinical investigators

  • NIH Stroke Scale Score (NIHSS) ≤ 5 [ Time Frame: Within 2 hours of treatment onset ] [ Designated as safety issue: No ]

    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.


  • NIH Stroke Scale Score (NIHSS) ≤ 2 [ Time Frame: Within 24 hours of treatment onset ] [ Designated as safety issue: No ]

    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.


  • NIH Stroke Scale Score (NIHSS) ≤2 at 90 Days [ Time Frame: 90 days from treatment onset ] [ Designated as safety issue: No ]

    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.



Enrollment: 126
Study Start Date: July 2009
Study Completion Date: December 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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: 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 Name: Integrilin
Drug: rt-PA
Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.
Other Name: Activase

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00894803

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

Additional Information:
Publications:
Responsible Party: Arthur Pancioli, Dir Academic Med, University of Cincinnati
ClinicalTrials.gov Identifier: NCT00894803     History of Changes
Other Study ID Numbers: P50NS04483-06, 00894803
Study First Received: May 6, 2009
Results First Received: November 27, 2013
Last Updated: March 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Cincinnati:
acute ischemic stroke
stroke
rt-PA, thrombolytic
t-PA
recombinant tissue plasminogen activator
Activase
eptifibatide
Integrilin
fibrinolytic agents
clot dissolving
blood clot

Additional relevant MeSH terms:
Stroke
Cerebral Infarction
Infarction
Ischemia
Brain Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Brain Ischemia
Pathologic Processes
Necrosis
Tissue Plasminogen Activator
Eptifibatide
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Hematologic Agents
Platelet Aggregation Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014