Ischemic Stroke
Conditions
Keywords
stroke, Argatroban, thrombin-inhibition, thrombolysis, anticoagulation
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.
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 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.
Interventions
DRUGLow Dose Argatroban
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
DRUGHigh Dose Argatroban
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
DRUGrt-PA (alteplase)
rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour
Sponsors
The University of Texas Health Science Center, Houston
Andrew D. Barreto, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * 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.
Exclusion criteria
* 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. * Uncontrolled hypertension \[Systolic blood pressure (SBP) \> 185 mmHg or diastolic blood pressure (DBP) \>110 mmHg\] 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. * 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. * Participated in any investigational study within 30 days before the first dose of study medication. * Known hypersensitivity to Argatroban or its agents. * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 0 or 1 on Modified Rankin Scale | 90 days | 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. |
| Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration | 48-hours | 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. |
Countries
United States
Participant flow
Recruitment details
Patients who have had an ischemic stroke and admitted to the Accident and Emergency Department or Acute Stroke Unit by their treating physician receive IV Recombinant tissue plasminogen activator as per standard treatment, provided they are able to be treated within 4.5 hours of the onset of their stroke symptoms.
Pre-assignment details
Patients who met the inclusion criteria received a head CT scan prior to initiation of rt-PA and the Argatroban infusion. If available, patients also underwent intracranial vessel imaging performed before or immediately after IV-tPA bolus (but before Argatroban bolus). Patients could not be randomized until after the CTA demonstrated an occlusion.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Argatroban + Rt-PA 100 micrograms/kilogram bolus, followed by 1 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 | 30 |
| High Dose Argatroban + Rt-PA 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 | 31 |
| Rt-PA (Alteplase) rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | 29 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Patient had hemorrhage after tPA started | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Low Dose Argatroban + Rt-PA | High Dose Argatroban + Rt-PA | Rt-PA (Alteplase) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 18 Participants | 16 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 13 Participants | 13 Participants | 37 Participants |
| Age, Continuous | 70.9 years STANDARD_DEVIATION 15.1 | 67.1 years STANDARD_DEVIATION 13.4 | 68.9 years STANDARD_DEVIATION 15.4 | 68.9 years STANDARD_DEVIATION 14.6 |
| Region of Enrollment United Kingdom | 8 participants | 9 participants | 8 participants | 25 participants |
| Region of Enrollment United States | 22 participants | 22 participants | 21 participants | 65 participants |
| Sex: Female, Male Female | 13 Participants | 15 Participants | 12 Participants | 40 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 17 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 30 | 3 / 31 | 5 / 29 |
| other Total, other adverse events | 27 / 30 | 25 / 31 | 20 / 29 |
| serious Total, serious adverse events | 15 / 30 | 15 / 31 | 14 / 29 |
Outcome results
Primary
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.
Time frame: 90 days
Population: One patient in the high dose group did not receive Argatroban and another in the high dose group was lost to follow up; however, an intention-to-treat analysis was used and all 31 enrolled patients were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Argatroban + Rt-PA | Number of Participants With 0 or 1 on Modified Rankin Scale | 9 participants |
| High Dose Argatroban + Rt-PA | Number of Participants With 0 or 1 on Modified Rankin Scale | 10 participants |
| Rt-PA (Alteplase) | Number of Participants With 0 or 1 on Modified Rankin Scale | 6 participants |
Primary
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.
Time frame: 48-hours
Population: One patient in the high dose group did not receive Argatroban and another in the high dose group was lost to follow up; however, an intention-to-treat analysis was used and all 31 enrolled patients were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Argatroban + Rt-PA | Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration | 4 participants |
| High Dose Argatroban + Rt-PA | Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration | 2 participants |
| Rt-PA (Alteplase) | Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration | 3 participants |