Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke (ARTSS-2)

ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke

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.

Study Overview

• Status: Terminated
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Low Dose Argatroban; Drug: rt-PA (alteplase); Drug: High Dose Argatroban

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose Argatroban + rt-PA (alteplase); 100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Drug: Low Dose Argatroban; 100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour; Other Names: Argatroban; Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Experimental: High dose Argatroban + rt-PA (alteplase); 100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour; Drug: High Dose Argatroban; 100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour; Other Names: Argatroban
Active Comparator: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour	Drug: rt-PA (alteplase); rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With 0 or 1 on Modified Rankin Scale	Excellent functional outcome as measured by the number of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment.	90 days
Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration	Symptomatic intracranial hemorrhage (sICH) is defined as any evidence of bleeding on CT scan that in the opinion of the treating physician and/or an independent safety monitor is associated with a clinically significant neurological worsening. A four or more point increase in the NIHSS score from baseline (or last score obtained prior to blood found on CT scan) to subsequent CT scan at the time of potential worsening can be used as a guide by the clinical investigator or safety monitor for what represents a significant worsening in neurologic status but sICH can include any worsening deemed significant by the clinical investigator or independent safety monitor.	48-hours

Collaborators and Investigators

• Sponsor: Andrew D. Barreto, MD
• Collaborators: The University of Texas Health Science Center, Houston

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• University of Texas Houston Stroke Team Website

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): June 11, 2015
• Study Completion (Actual): June 11, 2015

Study Registration Dates

• First Submitted: November 1, 2011
• First Submitted That Met QC Criteria: November 1, 2011
• First Posted (Estimate): November 4, 2011

Study Record Updates

• Last Update Posted (Actual): May 11, 2017
• Last Update Submitted That Met QC Criteria: March 31, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: thrombolysis; stroke; anticoagulation; Argatroban; thrombin-inhibition
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Tissue Plasminogen Activator; Argatroban
• Other Study ID Numbers: HSC-MS-11-0464