This study will evaluate the safety and effectiveness of two types of blood thinners, abciximab (ReoPro) and reteplase (Retavase) for restoring normal brain blood flow after ischemic stroke (stroke resulting from a blood clot in the brain).
The only therapy approved by the Food and Drug Administration to treat ischemic stroke is the clot buster drug rt-PA. This treatment, however, is effective only if begun within 3 hours of onset of the stroke and most patients do not get to the hospital early enough to benefit from it. There is thus a pressing need to develop effective stroke treatments that can be initiated more than 3 hours after onset.
Patients between 18 and 80 years of age who have experienced a mild or moderate acute stroke between 3 and 24 hours before starting study drugs may be eligible for this study. Candidates will be screened with a physical examination, blood tests and a magnetic resonance imaging (MRI) scan (if an MRI was not done during the stroke evaluation).
All participants will receive ReoPro. Some will also receive Retavase, which may boost the effectiveness of ReoPro. Retavase is administered in a single dose through a needle in the vein over 2 minutes. ReoPro is infused into the vein over 12 hours. Patients will be monitored with physical examinations, blood tests, computed tomography (CT) scans, and three or four MRI scans of the brain to evaluate both the response to treatment and side effects of the drugs. An MRI scan will be done 24 hours, 5 days and 30 days after starting the study medication, and possibly during screening for this study.
CT involves the use of specialized x-rays to obtain images of the brain. The patient lies still in the scanner for a short time while the X-ray images are formed. MRI uses a strong magnetic field and radio waves to demonstrate structural and chemical changes in tissue. MRI is more sensitive than x-ray in evaluating acute stroke. The patient lies on a table in a metal cylinder (the scanner) while the pictures are being taken. During part of the MRI, a medicine called gadolinium contrast is injected in a vein. This medicine brightens the images, creating better pictures of the blood flow.
Objectives: This is a clinical trial to determine an acceptable dose of reteplase in combination with a fixed dose of abciximab for ischemic stroke 3-24 hours from onset.
Study Population: Patients will be selected by criteria to minimize likelihood of toxicity and maximize likelihood of response. These criteria include age 18-80 years old, acute ischemic stroke of moderate severity (NIH Stroke Scale less than or equal to 16 and lesion volume on diffusion MRI less than approximately one third of the volume of the middle cerebral artery territory), positive MRI evidence of hypoperfusion corresponding to the acute stroke symptoms, no MRI evidence of chronic micro-hemorrhages, and no other clinical, radiological or laboratory features associated with risk of hemorrhage with thrombolytic therapy.
Design: The study is open-label, dose escalation, safety and proof of principle study of the combination of intravenous abciximab and reteplase. A fixed dose of abciximab will be used in all patients: 0.25 mg/kg bolus (to a maximum of 30 mg) followed by a 0.125 microgram/kg/minute infusion (to a maximum of 10.0 microgram/minute) for 12 hours. The five dosing groups for the reteplase dose are 0 U, 2.5 U, 5.0 U, 7.5 U, and 10.0 U. A maximum of 72 patients will be treated using an adaptive statistical design, in which data on both the response and toxicity will be used to determine the dose for subsequent patients, thereby minimizing exposure to either ineffective or toxic doses. Non-investigational patient management will be standardized across all patients according to the NIH Stroke Center Clinical Care Pathway.
Outcome Measures: The primary efficacy endpoint for response will be reperfusion by MRI 24 hours after start of therapy. The primary safety endpoint for determination of toxicity will be any one of the following: symptomatic intracranial hemorrhage (ICH), major systemic hemorrhage, or other serious adverse event related to study drug administration, including death, within 48 hours from start of therapy. The maximum acceptable rate of toxicity will be 10% of patients treated at any dose level and the minimum acceptable rate of response will be 50% of patients treated at any dose level. The outcomes will be monitored by a Data and Safety Monitoring Committee, which will have the authority to stop or recommend modifications of the trial for safety concerns. Other clinical outcome variables and imaging variables will be recorded and analyzed in secondary and exploratory analyses. If an acceptable dose is identified, then that will be investigated in a subsequent randomized placebo-controlled trial.
- Abciximab (ReoPro®)Drug
Intervention Desc: Intravenous platelet aggregation inhibitor, monoclonal antibody directed against the platelet glycoprotein GP IIb-IIIa receptor
- Reteplase (Retavase®)Drug
Intervention Desc: Intravenous thrombolytic agent. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA). Longer plasma half-life allows bolus intravenous dosing.
- Abciximab (ReoPro) and Reteplase (Retavase) Drug
Intervention Desc: N/A ARM 1: Kind: Experimental Label: 1 Description: CT ARM 2: Kind: Experimental Label: 2 Description: MRI
- Purpose: Treatment
All patients will receive diagnostic imaging and a neurological examination prior to treatment. All eligible patients will receive a 0.25 mg/kg bolus (maximum 30 mg) of abciximab, followed by a 0.125 ug/kg/minute infusion (maximum 10.0 ug/minute) for 12 hours. Patients will be divided into five dosage groups for reteplase, and will receive either 0 U, 2.5 U, 5.0 U, 7.5 U, or 10.0 U of the drug. Patients will undergo a follow-up MRI at 24 hours, and will be monitored for 48 hours post-treatment.
|Type||Measure||Time Frame||Safety Issue|
|Primary||MRI-measured reperfusion at 24 hours post-treatment; incidence of symptomatic ICH, major systemic hemorrhage, or other serious adverse events, including death, at 48 hours post-treatment.|
|Primary||Occurrence of symptomatic ICH, major systemic hemorrhage, or other serious adverse event, including death, within 48 hrs from start of study drug.||30 days||Yes|
|Secondary||All ICH types (fatal, symptomatic, asymptomatic), all bleeding (major, minor, insignificant), deaths, all serious adverse events (by subtype) at the 48 hours, 5 days, and 30 days tabulated by dose group and overall.|