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

• Sponsor: Arthur Pancioli (Other)
• Overall Status: Completed
• CT.gov ID: NCT01977456
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 27
• Locations: 8
• Arm: 1
• Duration (Months): 19
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke; Brain Infarction	Drug: Eptifibatide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 The Combined Approach to Lysis Utilizing Eptifibatide and Rt-PA in Acute Ischemic Stroke-Full Dose Regimen(CLEAR-FDR)
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eptifibatide 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; 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

Outcome Measures

Primary Outcome Measures

1. The Number of Patients Who Experience Symptomatic Intracerebral Hemorrhage (sICH). [within 36 hours after stroke 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

Secondary Outcome Measures

1. The Number of Patients Who Experience Any Intracerebral Hemorrhage (ICH). [within 36 hours after stroke onset]

   Any ICH symptomatic (as defined above) or asymptomatic (that visualized on CT or MRI only)

2. The Number of Patients Who Develop Parenchymal Hemorrhage Types 1( PH-1) and 2 (PH-2). [within 36 hours after stroke onset]

   Any parenchymal hemorrhage types PH-1 or PH-2 as visualized on CT

Other Outcome Measures

1. The Number of Participants With Good Outcomes According to the Modified Rankin Score. [90 days from the date of stroke onset]

   Modified Rankin score (mRS) dichotomized to good outcome (mRS 0-1 or return to baseline), poor outcome (all others including death). Results reported are good outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Elizabeth Healthcare System Edgewood	Edgewood	Kentucky	United States	41017
2	St. Elizabeth Healthcare Florence	Florence	Kentucky	United States	41042
3	St. Elizabeth Healthcare Ft. Thomas	Ft. Thomas	Kentucky	United States	41075
4	The Christ Hospital	Cincinnati	Ohio	United States	45219
5	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
6	Good Samaritan Hospital	Cincinnati	Ohio	United States	45220
7	Jewish Hospital	Cincinnati	Ohio	United States	45236
8	Bethesda North Hospital	Cincinnati	Ohio	United States	45242

Sponsors and Collaborators

• Arthur Pancioli
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Opeolu Adeoye, MD, University of Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arthur Pancioli, sub investigator, University of Cincinnati
• ClinicalTrials.gov Identifier: NCT01977456
• Other Study ID Numbers: P50NS044283-13; P50NS044283-13
• First Posted: Nov 6, 2013
• Last Update Posted: Jan 21, 2016
• Last Verified: Oct 1, 2015

• Keywords provided by Arthur Pancioli, sub investigator, 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; Ischemic Stroke; Brain Infarction; Infarction; Eptifibatide

Study Results

Participant Flow

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Period Title: Overall Study
STARTED	27
COMPLETED	22
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 22.2%
>=65 years	21 77.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.4 (12.9)
Sex: Female, Male (Count of Participants)
Female	14 51.9%
Male	13 48.1%
Region of Enrollment (participants) [Number]
United States	27 100%
National Institutes of Health Stroke Scale Score (NIHSS) (score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [score]	12

Outcome Measures

1. Primary Outcome

Title	The Number of Patients Who Experience Symptomatic Intracerebral Hemorrhage (sICH).
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 36 hours after stroke onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Measure Participants	27
Number [participants]	1 3.7%

2. Secondary Outcome

Title	The Number of Patients Who Experience Any Intracerebral Hemorrhage (ICH).
Description	Any ICH symptomatic (as defined above) or asymptomatic (that visualized on CT or MRI only)
Time Frame	within 36 hours after stroke onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Measure Participants	27
Number [participants]	2 7.4%

3. Secondary Outcome

Title	The Number of Patients Who Develop Parenchymal Hemorrhage Types 1( PH-1) and 2 (PH-2).
Description	Any parenchymal hemorrhage types PH-1 or PH-2 as visualized on CT
Time Frame	within 36 hours after stroke onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Measure Participants	27
Number [participants]	1 3.7%

4. Other Pre-specified Outcome

Title	The Number of Participants With Good Outcomes According to the Modified Rankin Score.
Description	Modified Rankin score (mRS) dichotomized to good outcome (mRS 0-1 or return to baseline), poor outcome (all others including death). Results reported are good outcome.
Time Frame	90 days from the date of stroke onset

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
Measure Participants	27
Number [participants]	17 63%

Adverse Events

Time Frame	Serious adverse events are monitored through 90 days. Non-serious adverse events are monitored through day 3 or discharge
Arm/Group Title	Eptifibatide
Arm/Group Description	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. 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.
All Cause Mortality
	Eptifibatide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eptifibatide
	Affected / at Risk (%)	# Events
Total	4/27 (14.8%)
Blood and lymphatic system disorders
Anaemias nonhaemolytic and marrow depression	1/27 (3.7%)	1
Cardiac disorders
Cardiac arrhythmias	1/27 (3.7%)	1
Heart failures	1/27 (3.7%)	1
Endocrine disorders
Diabetic complications	1/27 (3.7%)	2
Glucose metabolism disorders (incl diabetes mellitus)	1/27 (3.7%)	1
General disorders
General system disorders NEC	2/27 (7.4%)	2
Metabolism and nutrition disorders
Diabetic complications	1/27 (3.7%)	2
Glucose metabolism disorders (incl diabetes mellitus)	1/27 (3.7%)	1
Nervous system disorders
Neurological disorders NEC	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Eptifibatide
	Affected / at Risk (%)	# Events
Total	17/27 (63%)
Blood and lymphatic system disorders
Coagulopathies and bleeding diatheses (excl thrombocytopenic)	2/27 (7.4%)	2
White blood cell disorders	2/27 (7.4%)	2
Cardiac disorders
Cardiac arrhythmias	4/27 (14.8%)	4
Gastrointestinal disorders
Gastrointestinal motility and defaecation conditions	2/27 (7.4%)	2
Gastrointestinal signs and symptoms	3/27 (11.1%)	3
Infections and infestations
Infections - pathogen unspecified	3/27 (11.1%)	3
Metabolism and nutrition disorders
Electrolyte and fluid balance conditions	2/27 (7.4%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders NEC	2/27 (7.4%)	2
Nervous system disorders
Neurological disorders NEC	2/27 (7.4%)	2
Psychiatric disorders
Anxiety disorders and symptoms	2/27 (7.4%)	2
Renal and urinary disorders
Genitourinary tract disorders NEC	3/27 (11.1%)	3
Urinary tract signs and symptoms	2/27 (7.4%)	2
Skin and subcutaneous tissue disorders
Epidermal and dermal conditions	2/27 (7.4%)	2
Skin vascular abnormalities	2/27 (7.4%)	2
Vascular disorders
Decreased and nonspecific blood pressure disorders and shock	2/27 (7.4%)	2
Vascular haemorrhagic disorders	7/27 (25.9%)	8

Limitations/Caveats

Small sample size and open design. Did not include endovascular therapy patients.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.