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

• 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)

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.

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.

• 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: Low dose Argatroban
  100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours.
  Interventions:

  • Drug: Argatroban
  • Drug: Argatroban
• Active Comparator: High dose Argatroban
  100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours.
  Interventions:

  • Drug: Argatroban
  • Drug: Argatroban
• No Intervention: IV tPA only
  Standard of care

• 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.
• 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. Epub 2012 Jan 5.

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.