Combination Anti-Platelet and Anti-Coagulation Treatment After Lysis of Ischemic Stroke Trial (CATALIST)

NCT00061373 | Completed Phase 2 Results DMC

• 2 other identifiers: 03017103-N-0171
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

Ischemic stroke is caused by a blood clot that blocks the flow of blood to the brain and damages brain cells. The clot, or thrombus, is made up of platelets and fibrin. The medicine alteplase, also known as tPA , is the standard drug used to treat patients with acute ischemic stroke. tPA attacks the fibrin portion of the blood clot. While intravenous (iv) tPA alone is effective in treating the fibrin part of the clot approximately 30% of the time, adding other commercially available drugs such eptifibatide to treat other clot components may improve the effectiveness of iv tPA therapy. This is a clinical trial to determine an acceptable dose of eptifibatide in combination with aspirin, the low molecular weight heparin tinzaparin, and standard iv tPA therapy for the treatment of acute ischemic stroke. Use of clinical and imaging based selection criteria are hypothesized to contribute to treatment safety by selecting patients at lower risk of intracerebral hemorrhage. Also,selection and evaluation of patients by magnetic resonance imaging (MRI) criteria will result in a different risk to benefit ratio than selecting patients without MRI criteria and will lead to a different acceptable dose.

Conditions

Ischemic Stroke

Keywords

Alteplase; Recombinant tissue plasminogen activator; Reperfusion therapy; Magnetic Resonance Imaging; Clinical Trial; Tinzaparin; Eptifibatide; Ischemic Stroke

Outcome Measures

Primary Outcomes (5)

• Symptomatic Intracerebral Hemorrhage (ICH)

  This is a primary safety outcome or toxicity measure for all subjects. Symptomatic ICH is defined as the presence of two conditions: evidence of hemorrhage on the 72-hour head CT and an increase in the NIHSS score of 4 or more points from the prior examination. Hemorrhage classifications are according to European Cooperative Acute Stroke Study (ECASS). The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extra ocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patient's ability to answer questions and perform activities. Ratings for each of the 15 items are scored. Patients who have a score of 0 are considered to have "normal" examination. Patients with a score of 40 have the most severe stroke symptoms.

  From the start of study drugs and prior to the 72-hour safety head CT

• Major Systemic Hemorrhage

  Major systemic hemorrhage is defined bleeding associated with an adjusted decrease in hemoglobin of greater than 5 grams per diluent (g/dL), or and adjusted decrease in hematocrit greater than or equal to 15 percentage points or bleeding causing persistent or significant disability or incapacity such as hemorrhage in the eye.

  From the start of study drugs and prior to 72-hour head CT

• Other Serious Adverse Event Related to Study Drug Administration, Including Death.

  This is a primary safety outcome for all subjects.

  From start of study drugs and prior to 72-hour head CT

• MRI Selected Arm: Complete Brain Reperfusion

  This is the primary response outcome measure for patients in the MRI arm. A positive response is measured by evidence of complete reperfusion (or restoration of blood flow)on the perfusion weighted images (PWI) and mean transit time (MTT) maps of MRIs at 2 hours and sustained at 24 hours.

  up to 24 hours from the start of study drugs

• Non-MRI Selected Arm: Substantial Clinical Recovery (Non-MRI Arm)

  This is the primary response outcome measure for subjects in the non-MRI arm. A positive response is measured by a 7 point or more improvement in the NIHSS or for those with less than 7 points at baseline,complete resolution of stroke symptoms. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extra ocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patient's ability to answer questions and perform activities. Ratings for each of the 15 items are scored. Patients who have a score of 0 are considered to have "normal" examination. Patients with a score of 40 have the most severe stroke symptoms.

  up to 24 hours from the start of study drugs

Secondary Outcomes (1)

• Bleeding Events

  2 hr, 24 hr, 72 hr, 5 days, 30 days from start of study drugs

Study Arms (2)

MRI Selected Patients

EXPERIMENTAL

Patients are eligible for the MRI arm if all clinical and all MRI inclusion and exclusion criteria are met. A single dose of aspirin 81 mg orally (or rectal dose equivalent), a single weight-based dose of subcutaneous tinzaparin sodium. Possible dose escalated iv eptifibatide.

Drug: Aspirin; Drug: tinzaparin sodium; Drug: eptifibatide

non-MRI Selected Patients

EXPERIMENTAL

Patients are eligible for the non-MRI arm if all clinical inclusion-exclusion criteria are met, if MRI is contraindicated or if MRI compromises iv tPA delivery within 3-hours of symptom onset. A single dose of aspirin 81 mg orally (or rectal dose equivalent) and a single weight-based dose of subcutaneous tinzaparin sodium. Possible dose escalated iv eptifibatide. \--------------------------------------------------------------------------------

Drug: Aspirin; Drug: tinzaparin sodium; Drug: eptifibatide

Interventions

Aspirin DRUG

A single 81 mg aspirin tablet orally (or rectal suppository equivalent dose) given as soon as possible after start of standard iv tPA and consent.

MRI Selected Patients; non-MRI Selected Patients

tinzaparin sodium DRUG

A single weight-based dose of 80 anti-Xa International Units/kilogram (IU/kg)administered by subcutaneous (SQ) injection.

Also known as: Innohep (registered trademark)

MRI Selected Patients; non-MRI Selected Patients

eptifibatide DRUG

Eptifibatide administered iv according to dose escalation group. The five dosing groups for eptifibatide are 0, 45 µg/kg bolus, 90 µg/kg bolus, 90 µg/kg bolus plus 0.25 µg/kg/min infusion for 24 hours, and 90 µg/kg bolus plus 0.5 µg/kg/min infusion for 24 hours.

Also known as: Integrilin (registered trademark)

MRI Selected Patients; non-MRI Selected Patients

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of acute ischemic stroke with planned start of intravenous tPA. Acute ischemic stroke is defined as a measurable neurological deficit of sudden onset, presumed secondary to focal cerebral ischemia. Stroke onset will be defined as the time the patient was last known to be without the new clinical deficit. If the stroke started during sleep, stroke onset will be recorded as the time the patient was last known to be at baseline.
• Disabling neurological deficit attributable to acute ischemic stroke.
• NIHSS less than or equal to 21 for left hemisphere strokes, NIHSS less than or equal to 16 for others.
• Age 18-85 years, inclusive.
• Body weight greater than 50 kg.
• For MRI Arm only:
• Screening MRI diagnostic of focal cerebral ischemia corresponding to the clinical deficits. The MRI evaluation must involve echo planar diffusion weighted imaging, magnetic resonance angiography(MRA),and MRI perfusion. A normal appearing MRA with an appropriate perfusion deficit is eligible. An apparent stenosis or occlusion on MRA with normal appearing perfusion distally will not be eligible. Poor quality or uninterpretable MRA will not make patient ineligible. Patients who have a normal appearing diffusion weighted image (DWI) are eligible.
• Evidence on perfusion weighted image (PWI) MRI or a perfusion defect corresponding to the acute stroke syndrome. The PWI will be assessed by relative mean transit time (MTT) images obtained prior to the start of tPA therapy.

You may not qualify if:

• Current participation in another study with an investigational drug or device within, prior participation in the present study, or planned participation in another therapeutic trial, prior to the final (day 30) assessment in this trial.
• Symptoms suggestive of subarachnoid hemorrhage, even if CT or MRI scan is negative for hemorrhage.
• Evidence of acute myocardial infarction defined as having at least two of the following three features: 1) Chest pain suggestive of cardiac ischemia; 2) EKG findings of ST elevation of more greater than 0.2 millivolts (mV) in 2 contiguous leads, new onset left bundle branch block, ST segment depression, or T-wave inversion; 3) Elevated troponin I.
• Acute Pericarditis.
• Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.
• Patients who would refuse blood transfusions if medically indicated.
• Neurological deficit that has led to stupor or coma (NIHSS level of consciousness \[item I a\] score greater than or equal to 2).
• High clinical suspicion of septic embolus.
• Minor stroke with non-disabling deficit or rapidly improving neurological symptoms.
• Baseline NIHSS greater than 21 for left hemisphere stroke or greater than 16 for others.
• Evidence of acute or chronic ICH by head CT or MRI.
• CT or MRI evidence of non-vascular cause for the neurological symptoms.
• Signs of mass effect causing shift of midline structures on CT or MRI.
• Persistent hypertension with systolic BP greater than 185 mmHg or diastolic BP greater than 110 mmHg (mean of 3 consecutive arm cuff readings over 20-30 minutes), not controlled by antihypertensive therapy or requiring nitroprusside for control.
• Anticipated need for major surgery within 72 hours after start of study drugs, such as a carotid endarterectomy or hip fracture repair.

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (3)

Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Suburban Hospital

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401.

  PMID: 7477192 BACKGROUND

• Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000 Mar 1;283(9):1145-50. doi: 10.1001/jama.283.9.1145.

  PMID: 10703776 BACKGROUND

• Califf RM. Combination therapy for acute myocardial infarction: fibrinolytic therapy and glycoprotein IIb/IIIa inhibition. Am Heart J. 2000 Feb;139(2 Pt 2):S33-7. doi: 10.1067/mhj.2000.104090.

  PMID: 10650314 BACKGROUND

MeSH Terms

Conditions

Ischemic Stroke

Interventions

Aspirin; Tinzaparin; Eptifibatide

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates; Peptides, Cyclic; Peptides; Amino Acids, Peptides, and Proteins

Limitations and Caveats

All patients enrolled were dosed with aspirin and tinzaparin. None of the patients received iv eptifibatide. The study was closed prior to dosing with eptifibatide due to slow recruitment over the 5-year trial period.

Results Point of Contact

• Title: Steven Warach, MD, PhD; Principal Investigator
• Organization: NIH/NINDS and University of Texas Southwestern, Clinical Research Institute of Austin

swarach@seton.org

512-324-8383

Study Officials

• Steven Warach, MD, PhD

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2003
• First Posted: May 26, 2003
• Study Start: May 1, 2003
• Primary Completion: December 1, 2009
• Study Completion: July 1, 2011
• Last Updated: February 4, 2013
• Results First Posted: February 4, 2013

Record last verified: 2012-12

Locations

US (3)