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

Primary Purpose

Ischemic Stroke, Stroke, Brain Infarction

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Eptifibatide
rt-PA
Sponsored by
University of Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring acute ischemic stroke, stroke, rt-PA, thrombolytic, t-PA, recombinant tissue plasminogen activator, Activase, eptifibatide, Integrilin, fibrinolytic agents, clot dissolving, blood clot

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UCLA Ronald Reagan Medical Center
  • University of California San Diego
  • UCLA Medical Center Santa Monica
  • Washington Hospital Center
  • St. Elizabeth Healthcare Edgewood
  • St. Elizabeth Healthcare Florence
  • St. Elizabeth Healthcare Ft. Thomas
  • Suburban Hospital
  • University of Michigan Medical Center
  • Robert Wood Johnson University Hospital
  • Mission Hospital, Inc.
  • The Christ Hospital
  • University Hospital
  • Good Samaritan Hospital
  • The Jewish Hospital
  • Mercy Hospital, Western Hills
  • Mercy Hospital Mt Airy
  • Bethesda North Hospital
  • Hospital of the University of Pennsylvania
  • West Virginia University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

rt-PA only

rt-PA and Eptifibatide

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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
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).

Secondary Outcome Measures

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.
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.

Full Information

First Posted
May 6, 2009
Last Updated
March 26, 2014
Sponsor
University of Cincinnati
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT00894803
Brief Title
Study of the Combination Therapy of Rt-PA and Eptifibatide to Treat Acute Ischemic Stroke
Acronym
CLEAR-ER
Official Title
The "Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Enhanced Regimen" (CLEAR-ER Stroke Trial)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
July 2009 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cincinnati
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke, Stroke, Brain Infarction
Keywords
acute ischemic stroke, stroke, rt-PA, thrombolytic, t-PA, recombinant tissue plasminogen activator, Activase, eptifibatide, Integrilin, fibrinolytic agents, clot dissolving, blood clot

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
126 (Actual)

8. Arms, Groups, and Interventions

Arm Title
rt-PA only
Arm Type
Active Comparator
Arm Description
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.
Arm Title
rt-PA and Eptifibatide
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Eptifibatide
Other Intervention Name(s)
Integrilin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
rt-PA
Other Intervention Name(s)
Activase
Intervention Description
Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.
Primary Outcome Measure Information:
Title
Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours of Treatment Onset
Description
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
Time Frame
Within 36 hours of initiation of therapy
Title
Modified Rankin Scale (mRS) Score <1 or Return to mRS Baseline
Description
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).
Time Frame
90 days from treatment onset
Secondary Outcome Measure Information:
Title
Barthel Index ≥ 95
Description
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.
Time Frame
90 days from treatment onset
Title
Glasgow Outcome Scale (GOS) of 1
Description
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.
Time Frame
90 days from treatment onset
Other Pre-specified Outcome Measures:
Title
Serious Systemic Bleeding
Description
Incidence of serious systemic bleeding defined as requiring transfusion of 2 or more units of packed red blood cells.
Time Frame
Within 7 days of treatment onset
Title
Symptomatic Intracranial Hemorrhage (sICH) Within 7 Days of Treatment Onset
Description
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
Time Frame
Within 7 days of treatment onset
Title
Asymptomatic Intracranial Hemorrhage (asICH) Within 7 Days of Treatment Onset
Description
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
Time Frame
Within 7 days of treatment onset
Title
Death Within 7 Days of Treatment Onset
Description
Death due to any cause within 7 days of treatment onset
Time Frame
Within 7 days of treatment onset
Title
Death Due to Stroke Within 7 Days of Treatment Onset
Description
Death due to stroke within 7 days of treatment onset. Classified by blinded clinical investigators
Time Frame
Within 7 days of treatment onset
Title
NIH Stroke Scale Score (NIHSS) ≤ 5
Description
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.
Time Frame
Within 2 hours of treatment onset
Title
NIH Stroke Scale Score (NIHSS) ≤ 2
Description
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.
Time Frame
Within 24 hours of treatment onset
Title
NIH Stroke Scale Score (NIHSS) ≤2 at 90 Days
Description
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.
Time Frame
90 days from treatment onset

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arthur M Pancioli, MD
Organizational Affiliation
University of Cincinnati College of Medicine Department of Emergency Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Opeolu M Adeoye, MD
Organizational Affiliation
University of Cincinnati College of Medicine Department of Emergency Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA Ronald Reagan Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90024
Country
United States
Facility Name
University of California San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
UCLA Medical Center Santa Monica
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Washington Hospital Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
St. Elizabeth Healthcare Edgewood
City
Edgewood
State/Province
Kentucky
ZIP/Postal Code
41017
Country
United States
Facility Name
St. Elizabeth Healthcare Florence
City
Florence
State/Province
Kentucky
ZIP/Postal Code
41042
Country
United States
Facility Name
St. Elizabeth Healthcare Ft. Thomas
City
Ft. Thomas
State/Province
Kentucky
ZIP/Postal Code
41075
Country
United States
Facility Name
Suburban Hospital
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20814
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Robert Wood Johnson University Hospital
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
Mission Hospital, Inc.
City
Asheville
State/Province
North Carolina
ZIP/Postal Code
28801
Country
United States
Facility Name
The Christ Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
University Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Good Samaritan Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45220-2489
Country
United States
Facility Name
The Jewish Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45236
Country
United States
Facility Name
Mercy Hospital, Western Hills
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45238
Country
United States
Facility Name
Mercy Hospital Mt Airy
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45239
Country
United States
Facility Name
Bethesda North Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45242
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
West Virginia University Hospital
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23887845
Citation
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.
Results Reference
background
PubMed Identifier
23887841
Citation
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.
Results Reference
result

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Study of the Combination Therapy of Rt-PA and Eptifibatide to Treat Acute Ischemic Stroke

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