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

NCT01464788 | Terminated Phase 2 Results DMC

• 1 other identifier: HSC-MS-11-0464
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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.

Conditions

Ischemic Stroke

Keywords

stroke; Argatroban; thrombin-inhibition; thrombolysis; anticoagulation

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (3)

Low dose Argatroban + rt-PA (alteplase)

EXPERIMENTAL

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; Drug: rt-PA (alteplase)

High dose Argatroban + rt-PA (alteplase)

EXPERIMENTAL

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: High Dose Argatroban; Drug: rt-PA (alteplase)

rt-PA (alteplase)

ACTIVE COMPARATOR

rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour

Drug: rt-PA (alteplase)

Interventions

Low Dose Argatroban DRUG

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

Also known as: Argatroban

Low dose Argatroban + rt-PA (alteplase)

High Dose Argatroban DRUG

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

Also known as: Argatroban

High dose Argatroban + rt-PA (alteplase)

rt-PA (alteplase) DRUG

rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour

High dose Argatroban + rt-PA (alteplase); Low dose Argatroban + rt-PA (alteplase); rt-PA (alteplase)

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Related Publications (3)

• 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.

  PMID: 16908730 BACKGROUND

• 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.

  PMID: 22223235 BACKGROUND

• 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.

  PMID: 28507269 DERIVED

Related Links

• University of Texas Houston Stroke Team Website

MeSH Terms

Conditions

Ischemic Stroke; Stroke

Interventions

argatroban; Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Limitations and Caveats

Study limitations include the open-label design that was necessary due to prohibitive costs of placebo manufacture and sham aPTT tests. Given that vessel imaging was not mandatory, a meaningful analysis of early recanalization rates was not possible.

Results Point of Contact

• Title: Dr. Andrew Barreto
• Organization: McGovern Medical School UTHealth - Houston

andrew.d.barreto@uth.tmc.edu

713-500-7002

Study Officials

• Andrew Barreto, MD

  The University of Texas Health Science Center, Houston

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Neurology

Study Record Dates

• First Submitted: November 1, 2011
• First Posted: November 4, 2011
• Study Start: October 1, 2011
• Primary Completion: June 11, 2015
• Study Completion: June 11, 2015
• Last Updated: May 11, 2017
• Results First Posted: May 11, 2017

Record last verified: 2017-03

Locations

US (1)