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

Ischemic Stroke Clinical Trial

— ARTSS-2  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01464788
• Other study ID #: HSC-MS-11-0464
• Status: Terminated
• Phase: Phase 2
• First received: November 1, 2011
• Last updated: May 11, 2015
• Start date: October 2011
• Est. completion date: December 2015

Study information

• Verified date: May 2015
• Source: The University of Texas Health Science Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 90
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 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.

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. National institute health stroke scale (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 activated partial thromboplastin time (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 [Systolic blood pressure (SBP) > 185 mmHg or diastolic blood pressure (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. 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.

24. Participated in any investigational 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ischemic Stroke
• Stroke

Intervention

Drug:
• Argatroban
100 micrograms/kilogram bolus, followed by 1 micrograms/kilogram/minute IV infusion for 48 hours.
• Argatroban
100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours.

Locations

Country	Name	City	State
United States	University of Texas Health Science Center at Houston	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Andrew D. Barreto, MD	The University of Texas Health Science Center, Houston

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moyé 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients with 0 or 1 on Modified Rankin Scale	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.	90 days	No
Secondary	Incidence of hemorrhage	1) Safety as measured by the incidence of: Symptomatic intracranial hemorrhage (sICH); Parenchymal Hemorrhage 2 (PH-2); Major systemic hemorrhage.	90 days	Yes
Secondary	Rates of recanalization	Rates and completeness of arterial recanalization assessed at baseline and 2-3 hours by Transcranial Doppler ultrasound (TCD) or CT-Angiogram (CTA).	2 hours	No
Secondary	Improvement in neurological deficits	Neurological deficits improvement from baseline to 2 hours, 24 hours, end of Argatroban infusion, Day 7/discharge and day 90 as measured by National Institute of Health Stroke Scale (NIHSS).	90 days	No
Secondary	Cost effectiveness	Cost and cost-effectiveness analysis Medical costs associated with each treatment Incremental cost-effectiveness ratio (change in cost divided by quality of life gained)	90 days	No

External Links

•   University of Texas Houston Stroke Team Website