Safety and Feasibility of Argatroban, Tissue Plasminogen Activator and Intra-arterial Therapy in Stroke
Safety and Feasibility of Argatroban, Tissue Plasminogen Activator and Intra-arterial Therapy in Stroke
Background:

 Our prior work with combination argatroban + recombinant tissue plasminogen activator (rt-PA)
 (ARTSS-1: Phase IIa low-dose safety study; n=65 and ARTSS-2: Phase IIb randomized low and
 high-dose study; n=90), demonstrated safety of the two drugs when delivered concomitantly and
 recanalization rates were greater than with historical controls. Further, interim analysis of
 neurological outcomes at 75 patients of the randomized Phase IIb trial, demonstrated a signal
 of efficacy when compared to control (rt-PA alone) patients. However, rt-PA fails to
 reperfuse brain in most patients with large thrombi, prompting several recent randomized
 clinical trials which have demonstrated that intra-arterial therapy (IA) following rt-PA
 substantially improves outcome in patients with distal carotid or proximal middle cerebral
 artery occlusions. As a result, rt-PA + IA has become the new standard-of-care for many
 patients with large arterial occlusions such as those treated in ARTSS-1 and 2. Therefore,
 this study is necessary to explore the feasibility and safety of adding Argatroban in acute
 ischemic stroke patients who also receive rt-PA followed by IA.

 Primary Objective:

 To demonstrate the feasibility and safety of treating stroke patients with Argatroban who
 undergo usual thrombolysis care (intravenous rt-PA followed by IA).

 Secondary Objectives:

 1. Assess rates of ultra-early recanalization at commencement of IA;

 2. Assess the completeness and pattern of reperfusion as obtained by IA; 3) Assess clinical
 outcome
Design:

 Prospective, single-arm, open-label, feasibility and safety Phase IIa study.

 Study Population:

 10 total ischemic stroke patients all treated with rt-PA (0-3 hour or 0-4.5 hour according to
 each site's local standard) and IA; age of 18 years or older; proximal (intracranial) artery
 occlusion as imaged by CT-angiogram (CTA).

 Treatment:

 All patients will receive standard-of-care intravenous rt-PA (0.9 mg/kg; maximum 90 mg) and
 IA. Before the end of the 1 hour rt-PA infusion, a 3.0 mcg/kg/min continuous infusion of
 Argatroban, preceded by a 100 mcg/kg bolus will be administered over 3-5 minutes. Infusion
 will be titrated to achieve an aPTT of 2.25 times baseline (not to exceed 10 mcg/kg/min) for
 a maximum of 12 hours.

 Assessments:

 1. Baseline: History and physical exam, vital signs, CBC, liver function tests, PT/INR,
 PTT, non-contrast head CT, CT-Angiogram, NIHSS, mRS, concomitant medications.

 Laboratory results must be reported before study drug administration.

 2. 0-24 hours: Vital signs, aPTT (scheduled 2, 6, 12 hours), NIHSS (24-hours), conventional
 angiography as part of usual care intra-arterial therapy. Repeat parenchymal brain
 imaging (non-contrast head CT or MRI) at 24 hours from rt-PA bolus. Laboratory testing
 work (same as baseline).

 3. Day 7/Discharge (whichever occurs first): Vital signs, mRS, NIHSS

 4. Day 90: mRS (obtained by certified rater).
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. Symptoms must be
 distinguished from another ischemic event such as syncope, seizure, migraine,
 subarachnoid hemorrhage and hypoglycemia. If the patient reports awakening with
 the event, the time of onset should be considered as the last time the patient
 (or a witness to the patient's condition) considered herself/himself normal.

 -  Patients should meet local, institutional criteria to undergo emergent Endovascular
 Therapy (Intra-Arterial) to include:

 1. IAT must be able to begin before 6-hours of stroke onset or last seen well.

 2. CT-Angiogram confirmation of intra-arterial occlusion in any of the following
 locations: terminal ICA, MCA (M1 or M2 territories), PCA, distal vertebral or
 basilar artery.

 3. ASPECTS score on non-contrast head CT must be >/= 6.

 4. IAT must be able to begin within 90 minutes of qualifying CT scan.

 -  Age >/= 18.

 -  Females of childbearing potential must have a negative pregnancy test 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:

 -  Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a
 non-vascular cause of neurologic deficit.

 -  NIHSS Level of Consciousness score (1a) >/= 2.

 -  Pre-existing disability with mRS > 2.

 -  Any evidence of clinically significant bleeding, or known coagulopathy.

 -  INR >1.5.

 -  Patients with an elevated aPTT greater than the upper limit of normal (test can be
 repeated if investigator suspects a falsely elevated value such as when the collection
 tube is not completely filled).

 -  Patients currently, or within the previous 24 hours, on an oral direct thrombin
 inhibitor (i.e., dabigatran), a factor 10a inhibitor (i.e., rivaroxaban, apixaban), or
 any other long-acting anticoagulant.

 -  Heparin flush required for an IV line. Line flushes with saline only.

 -  Any history of intra-cranial hemorrhage, known ateriovenous-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 (SBP > 185 mmHg or 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.

 -  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. [*Caveat:
 However, if in the judgment of the investigator a patient needs to be anticoagulated,
 but this can be deferred for 48 hours, then they could be included.]

 -  Currently participating or has participated in any investigational drug or device
 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.