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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by The University of Texas Health Science Center, Houston
Sponsor:
Collaborator:
The University of Texas Health Science Center, Houston
Information provided by (Responsible Party):
Andrew Barreto, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier:
NCT01464788
First received: November 1, 2011
Last updated: May 17, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Ischemic Stroke
Drug: Argatroban
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: ARTSS-2: A Pilot, Phase IIb, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center, Houston:

Primary Outcome Measures:
  • Percentage of patients with 0 or 1 on Modified Rankin Scale [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Excellent functional outcome as measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment.


Secondary Outcome Measures:
  • Incidence of hemorrhage [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]

    1) Safety as measured by the incidence of:

    1. Symptomatic intracranial hemorrhage (sICH);
    2. Parenchymal Hemorrhage 2 (PH-2);
    3. Major systemic hemorrhage.

  • Rates of recanalization [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
    Rates and completeness of arterial recanalization assessed at baseline and 2-3 hours by Transcranial Doppler ultrasound (TCD) or CT-Angiogram (CTA).

  • Improvement in neurological deficits [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Neurological deficits improvement from baseline to 2 hours, 24 hours, end of Argatroban infusion, Day 7/discharge and day 90 as measured by NIHSS.

  • Cost effectiveness [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Cost and cost-effectiveness analysis Medical costs associated with each treatment Incremental cost-effectiveness ratio (change in cost divided by quality of life gained)


Estimated Enrollment: 105
Study Start Date: October 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Low dose Argatroban
100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours.
Drug: Argatroban
100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours.
Other Name: Argatroban
Drug: Argatroban
100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours.
Other Name: Argatroban
Active Comparator: High dose Argatroban
100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours.
Drug: Argatroban
100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours.
Other Name: Argatroban
Drug: Argatroban
100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours.
Other Name: Argatroban
No Intervention: IV tPA only
Standard of care

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 IIa 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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.

  2. Age ≥18.
  3. 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 ICA, MCA (M1 or M2), PCA (P1 or P2), distal vertebral or basilar artery.

    - TCD criteria: TIBI 0, 1, 2 or 3 - CT-Angiogram: 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.

  4. 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.
  5. Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
  6. Signed (written) informed consent by the patient or the patient's legal representative and/or guardian.

Exclusion Criteria:

  1. 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.
  2. Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
  3. NIHSS Level of Consciousness score (1a) ≥ 2.
  4. Pre-existing disability with mRS ≥ 2.
  5. CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
  6. Any evidence of clinically significant bleeding, or known coagulopathy.
  7. INR >1.5.
  8. Patients with an elevated aPTT greater than the upper limit of normal
  9. Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran).
  10. Heparin flush required for an IV line. Line flushes with saline only.
  11. Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms.
  12. Significant bleeding episode [e.g. gastrointestinal (GI) or urinary tract] within the 3 weeks before study enrollment.
  13. Major surgery or serious trauma in last 2 weeks.
  14. Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
  15. Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
  16. Uncontrolled hypertension (SBP > 185 mmHg or DBP >110 mmHg) that does not respond to intravenous anti-hypertensive agents.
  17. Surgical intervention (any reason) anticipated within the next 48 hours.
  18. Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse.
  19. Abnormal blood glucose <50 mg/dL (2.7 mmol/L).
  20. History of primary or metastatic brain tumor.
  21. Current platelet count < 100,000/mm3.
  22. Life expectancy < 3 months.
  23. Patients 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, UFH, LMWH, defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, GPIIb/IIIa inhibitor or warfarin.
  24. Currently participating or has participated in any investigational drug or device study within 30 days before the first dose of study medication.
  25. Known hypersensitivity to Argatroban or its agents.
  26. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01464788

Contacts
Contact: Loren Shen, RN, BSN 713.500.7084 Loren.Shen@uth.tmc.edu
Contact: Andrew D Barreto, MD 713-500-7002 andrew.d.barreto@uth.tmc.edu

Locations
United States, Texas
University of Texas Health Science Center at Houston Recruiting
Houston, Texas, United States, 77030
Contact: Loren Shen, RN, BSN    713-500-7084    Loren.Shen@uth.tmc.edu   
Contact: Amber N Jacobs, BS    713.500.7194    Amber.Nicole.M.Jacobs@uth.tmc.edu   
Principal Investigator: Andrew Barreto, MD         
Principal Investigator: James Grotta, MD         
Sponsors and Collaborators
Andrew Barreto
The University of Texas Health Science Center, Houston
Investigators
Principal Investigator: Andrew Barreto, MD The University of Texas Health Science Center, Houston
  More Information

Additional Information:
Publications:
Responsible Party: Andrew Barreto, Assistant Professor of Neurology, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier: NCT01464788     History of Changes
Other Study ID Numbers: HSC-MS-11-0464
Study First Received: November 1, 2011
Last Updated: May 17, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by The University of Texas Health Science Center, Houston:
stroke
Argatroban
thrombin-inhibition
thrombolysis
anticoagulation

Additional relevant MeSH terms:
Stroke
Cerebral Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Brain Infarction
Brain Ischemia
Tissue Plasminogen Activator
Argatroban
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Hematologic Agents
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anticoagulants
Platelet Aggregation Inhibitors

ClinicalTrials.gov processed this record on July 22, 2014