Clinical trial NCT00268762: Argatroban Stroke Treatment - A Pilot Safety Study
Official title: A Pilot Study To Determine The Safety Of Argatroban Injection In Combination With Tissue Plasmingen Activator (TPA) In Patients With Acute Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ischemic Stroke
Keywords: stroke
thrombin inhibition
thrombolysis
bleeding
outcome
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
First posted: 2005-12-22
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Is the combination of low doses of argatroban in combination with rt-PA safe, and does it increase recanalization in patients with acute ischemic stroke.

Detailed description: All patients with acute ischemic stroke who qualify for IV rt-PA under accepted guidelines, and who have an occluded middle cerebral artery documented on TCD, receive standard dose IV rt-PA and a bolus and 48 hour infusion of argatroban aimed at prolonging the aPTT 1.75 X baseline. Follow up CT scanning and TCD every 30 minutes for 2 hours and then daily will determine the incidence of hemorrhage, recanalization and reocclusion, and serial neurological exam will determine the clinical outcome. For patients without temporal windows, a baseline CT-Angiogram (CTA) demonstrating arterial occlusion can also be enrolled. In those patients, a follow-up CTA (24-36 hours) will be performed.

Eligibility criteria: Inclusion Criteria:

* Ischemic stroke symptoms with onset ≤ 3 hours\*.

  * \*or\<4.5 hours according to local standard of care. Symptoms must be distinguished from another ischemic event such as syncope, seizure, migraine, and hypoglycemia. If the patient reports awakening with the event, the time of onset should be considered as last time the patient (or a witness to the patient's condition) considered herself/himself normal.
* 18-85 years of age.
* A clot causing complete or partial occlusion (TIBI 0, 1, 2, or 3) via TCD in any one of the following areas: distal iternal carotid artery (ICA), Meddle cerebral artery (MCA - M1 or M2), posterior cerebral arteral (ICA - P1 or P2), distal vertebral or basilar occlusions. TCD must be abnormal prior to the start of Argatroban. For patients without temporal windows (or in centers without emergent access to TCD), an abnormal CTA is required for enrollment (TIMI 0 or 1).
* Females of childbearing potential must have a negative serum pregnancy test prior administration of argatroban.
* Signed informed consent by the patient or the patient's legal representative.
* Meet criteria for rt-PA therapy.

Exclusion Criteria:

* Evidence of intracranial hemorrhage on baseline CT scan or non-vascular cause of neurologic deficit.
* National institute health stroke scale (NIHSS) Level of Consciousness score ≥2.
* Baseline (immediately pre-Argatroban) NIHSS ≤ 5 or patient with rapidly resolving deficit or rapidly improving symptoms consistent with TPA.
* Baseline NIHSS ≥15 for right hemisphere strokes and ≥20 for left hemisphere strokes.
* Pre-existing disability with modified rankin scale (mRS) ≥ 2.
* CT scan findings of hypoattenuation of the x-ray signal (hypodensity)involving ≥ 1/2 of the MCA territory.
* Any evidence of clinically significant bleeding, or known coagulopathy.
* Patients currently on warfarin, with an elevated INR ≥ 1.5.
* Patients currently or within previous 48 hrs. on heparin with an elevated aPTT greater than the upper limit of normal.
* Heparin flush required for an IV line. Line flushes with saline only.
* History of ICH or significant bleeding episode within the 3 months before study enrollment.
* Major surgery or serious trauma within the last 6 weeks.
* Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
* Previous stroke, myocardial infarction, post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months of baseline.
* Uncontrolled hypertension.
* Alcohol and/or substance abuse that would increase the risk of hemorrhage in the opinion of the investigator.
* Surgical intervention anticipated within the next 7 days.
* Hepatic dysfunction, defined by liver function tests greater than 3 times upper limit of normal at baseline, specifically serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT).
* Abnormal blood glucose
* History of primary or metastatic brain tumor.
* Severe mental deficit prior to onset of stroke such as organic brain disorder, schizophrenia, etc.
* Concurrent severe neurologic disorder, such as seizure at onset of stroke or uncontrolled seizure disorder that complicates diagnosis of acute ischemic stroke.
* Current platelet count\< 100,000/mm3.
* Life expectancy \<3 months in the opinion of the investigator.
* Need to be on concomitant (i.e, during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, glycoprotein llb/llla (GPIIb/IIIa) or warfarin.(Caveat: If these anticoagulants can be deferred for 48 hours, then they can be included).
* Participated in investigational study within 30 days before the first dose of study medication.
* Hypersensitivity to Argatroban or its agents

Primary outcomes:
measure: Symptomatic and Radiographic Intracerebral Hemorrhage
timeFrame: Within 7 days of enrollment
Secondary outcomes:
measure: Arterial Complete Recanalization at 2 Hours Post tPA Bolus
timeFrame: 2 hours complete recanalization post tPA bolus
measure: Arterial Complete Recanalization at 24 Hours Post tPA Bolus
timeFrame: 24 hours from tPA bolus
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama-Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Dallas
country: United States
facility: University of Texas-Southwestern Dallas
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Hospital-Medical Center
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Southwest Hospital
state: Texas
Study officials:
affiliation: The University of Texas Health Science Center, Houston
name: Andrew D. Barreto, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moye LA, Alexandrov AV, Grotta JC. Argatroban tPA stroke study: study design and results in the first treated cohort. Arch Neurol. 2006 Aug;63(8):1057-62. doi: 10.1001/archneur.63.8.1057.
citation: Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke. 2012 Mar;43(3):770-5. doi: 10.1161/STROKEAHA.111.625574. Epub 2012 Jan 5.