Clinical trial NCT01464788: Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke
Official title: ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Ischemic Stroke
Keywords: stroke
Argatroban
thrombin-inhibition
thrombolysis
anticoagulation
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
Collaborators: name: The University of Texas Health Science Center, Houston
First posted: 2011-11-04
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.

Detailed description: Recombinant tissue plasminogen activator (rt-PA), the only proven treatment for acute ischemic stroke, fails to reperfuse brain in most patients with large thrombi. In our Phase 2a low-dose safety study (n=65), the two drugs appeared safe when delivered concomitantly and recanalization rates were greater than historical controls. This study will provide evidence-based hypotheses and data needed to design a larger definitive trial.

The purpose of this trial is to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.

Eligibility criteria: Inclusion Criteria:

* Disabling Ischemic stroke symptoms with onset \< 3 hours treated with IV rt-PA by local standards\*.

  \* or ≤ 4.5 hours according to local standard of care.
* NIHSS ≥ 10\* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery.
* TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 \* NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
* For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
* Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
* Signed (written) informed consent by the patient or the patient's legal representative and/or guardian.

Exclusion Criteria:

* Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization.
* Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
* National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2.
* Pre-existing disability with mRS ≥ 2.
* CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
* Any evidence of clinically significant bleeding, or known coagulopathy.
* INR \>1.5.
* Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal
* Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran).
* Heparin flush required for an IV line. Line flushes with saline only.
* Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms.
* Significant bleeding episode \[e.g. gastrointestinal (GI) or urinary tract\] within the 3 weeks before study enrollment.
* Major surgery or serious trauma in last 2 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 (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
* Uncontrolled hypertension \[Systolic blood pressure (SBP) \> 185 mmHg or diastolic blood pressure (DBP) \>110 mmHg\] that does not respond to intravenous anti-hypertensive agents.
* Surgical intervention (any reason) anticipated within the next 48 hours.
* Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse.
* Abnormal blood glucose \<50 mg/dL (2.7 mmol/L).
* History of primary or metastatic brain tumor.
* Current platelet count \< 100,000/mm3.
* Life expectancy \< 3 months.
* Patient who, in the judgment of the investigator, needs 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) inhibitor or warfarin.
* Participated in any investigational study within 30 days before the first dose of study medication.
* Known hypersensitivity to Argatroban or its agents.
* Additional exclusion criteria if patient presents between 3-4.5 hours:

  1. Age \>80
  2. Currently taking oral anticoagulants (regardless of INR)
  3. A history of stroke and diabetes.
  4. NIHSS \> 25.

Primary outcomes:
measure: Number of Participants With 0 or 1 on Modified Rankin Scale
timeFrame: 90 days
measure: Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration
timeFrame: 48-hours
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
Study officials:
affiliation: The University of Texas Health Science Center, Houston
name: Andrew 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.
citation: Barreto AD, Ford GA, Shen L, Pedroza C, Tyson J, Cai C, Rahbar MH, Grotta JC; ARTSS-2 Investigators. Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke. 2017 Jun;48(6):1608-1616. doi: 10.1161/STROKEAHA.117.016720. Epub 2017 May 15.