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

Stroke Clinical Trial

— CLEAR-ER  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00894803
• Other study ID #: P50NS04483-06
• Secondary ID: 00894803
• Status: Completed
• Phase: Phase 2
• First received: May 6, 2009
• Last updated: March 26, 2014
• Start date: July 2009
• Est. completion date: December 2012

Study information

• Verified date: March 2014
• Source: University of Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 126
• Est. completion date: December 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Infarction
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

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.
• rt-PA
Intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Mission Hospital, Inc.	Asheville	North Carolina
United States	Suburban Hospital	Bethesda	Maryland
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital	Cincinnati	Ohio
United States	Mercy Hospital Mt Airy	Cincinnati	Ohio
United States	Mercy Hospital, Western Hills	Cincinnati	Ohio
United States	The Christ Hospital	Cincinnati	Ohio
United States	The Jewish Hospital	Cincinnati	Ohio
United States	University Hospital	Cincinnati	Ohio
United States	St. Elizabeth Healthcare Edgewood	Edgewood	Kentucky
United States	St. Elizabeth Healthcare Florence	Florence	Kentucky
United States	St. Elizabeth Healthcare Ft. Thomas	Ft. Thomas	Kentucky
United States	UCLA Ronald Reagan Medical Center	Los Angeles	California
United States	West Virginia University Hospital	Morgantown	West Virginia
United States	Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of California San Diego	San Diego	California
United States	UCLA Medical Center Santa Monica	Santa Monica	California
United States	Washington Hospital Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
University of Cincinnati	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View 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, Brode — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Yes
Other	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	Yes
Other	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	Yes
Other	Death Within 7 Days of Treatment Onset	Death due to any cause within 7 days of treatment onset	Within 7 days of treatment onset	Yes
Other	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	Yes
Other	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	No
Other	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	No
Other	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	No
Primary	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	Yes
Primary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   CLEAR-ER Stroke Trial web site