Ignite Creation Date:
2024-05-05 @ 5:14 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00417898
Status:
WITHDRAWN
Last Update Posted:
2016-09-02
First Post:
2007-01-02
Brief Title:
Study of Aspirin and TPA in Acute Ischemic Stroke
Sponsor:
Hadassah Medical Organization
Organization:
Hadassah Medical Organization
Study Overview
Official Title:
Phase 1 Study to Assess the Safety of 500mg of Aspirin Added to IV TPA at Standard Doses to Prevent Re-occlusion of Cerebral Vessels After Successful Reperfusion
Status:
WITHDRAWN
Status Verified Date:
2007-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study will determine the safety of 500mg of aspirin added to IV TPA at standard doses to prevent re-occlusion of cerebral vessels after successful reperfusion In ischemic stroke brain arteries are occluded either by an embolus originating in the heart or large vessels leading to the brain or by a process of acute thrombosis of the cerebral arteries over a ruptured atherosclerotic plaque Rupture of the plaque exposes thrombogenic elements within the plaque and leads to accumulation and activation of platelets and induction of the clotting cascade eventually leading to acute thrombosis and occlusion of the artery TPA is currently approved by the Food and Drug Administration to treat heart and brain problems caused by blockage of arteries It activates plasminogen and leads to disintegration of the thrombusembolus It is effective only if begun within 3 to 45 hours of onset of the stroke because of potential deleterious side effects including life threatening symptomatic intracranial hemorrhage sICH when the drug is administered outside of this time window
Reperfusion of the ischemic brain ie timely opening of the occluded artery with TPA is associated with improved outcome However in about 33 of patients that have successfully reperfused after TPA the artery re-occludes within the first few hours resulting in worsening neurological symptoms and worse functional outcome This re-occlusion is speculated to result from re-thrombosis over an existing ruptured atherosclerotic plaque This is explained by the relatively short half life of TPA leaving the exposed ruptured plaque intact which leads to re-activation of platelets and clotting factors and re-thrombosis Thus we hypothesize that the addition of an antiplatelet agent to TPA would result in lower rates of re-occlusion after AIS The FDA approved TPA for patients with AIS but discouraged the concomitant use of anti-platelet or anti-thrombotic drugs for the first 24hours after administration of TPA because of concerns that such therapy may result in increased rates of intracerebral hemorrhage Aspirin is a well known platelet anti-aggregant that works by inhibition of cycloxygenase 1 and reduction in thromboxane A levels It has a rapid onset of action and additional potential beneficial anti-inflammatory effects in patients with AIS The international stroke study showed that acute treatment of stroke patients with 500mg of aspirin is safe and feasible and results in better outcome Furthermore the drug was safe in these circumstances with an ICH rate of only
Therefore the purpose of this clinical trial is to examine the safety and efficacy of the combination of aspirin with rt-TPA in patients with AIS
Reperfusion of the ischemic brain ie timely opening of the occluded artery with TPA is associated with improved outcome However in about 33 of patients that have successfully reperfused after TPA the artery re-occludes within the first few hours resulting in worsening neurological symptoms and worse functional outcome This re-occlusion is speculated to result from re-thrombosis over an existing ruptured atherosclerotic plaque This is explained by the relatively short half life of TPA leaving the exposed ruptured plaque intact which leads to re-activation of platelets and clotting factors and re-thrombosis Thus we hypothesize that the addition of an antiplatelet agent to TPA would result in lower rates of re-occlusion after AIS The FDA approved TPA for patients with AIS but discouraged the concomitant use of anti-platelet or anti-thrombotic drugs for the first 24hours after administration of TPA because of concerns that such therapy may result in increased rates of intracerebral hemorrhage Aspirin is a well known platelet anti-aggregant that works by inhibition of cycloxygenase 1 and reduction in thromboxane A levels It has a rapid onset of action and additional potential beneficial anti-inflammatory effects in patients with AIS The international stroke study showed that acute treatment of stroke patients with 500mg of aspirin is safe and feasible and results in better outcome Furthermore the drug was safe in these circumstances with an ICH rate of only
Therefore the purpose of this clinical trial is to examine the safety and efficacy of the combination of aspirin with rt-TPA in patients with AIS
Detailed Description:
Background and Objectives
Management of acute ischemic stroke consists of thrombolytic drugs aiming at opening occluded vessels Tissue plasminogen activator TPA is the only drug approved by the FDA 1 2 The use of TPA is significantly limited by a relatively narrow therapeutic window of up to 3-45 hours following stroke onset 3 4 Use of TPA outside of this time window is associated with an unacceptably high risk of hemorrhage including symptomatic intracranial hemorrhage sICH 5 6 While TPA is efficacious in reducing stroke associated disability its effects are limited by the phenomenon of early re-occlusion after successful reperfusion of the occluded artery
Previous reports have shown that among patients receiving IV TPA within 3 hours of stroke onset 61 re-perfuse at 1 hour with about 67 of these having partial recanalization and 33 complete recanalization of the occluded artery 7 reperfusion rates at 2 hours tend to be much lower ranging around 30-40 implying early re-occlusion 8 Indeed it was found that 25 of the patients that have successfully reperfused will re-occlude the artery within 2 hours 7 Re-occlusion of an already reperfused artery was more common in elderly patients with severe ipsilateral carotid stenosis and higher NIHSS scores and was associated with poor outcome 7 We speculate that re-occlusion is much more common in atherothrombotic strokes compared with embolic stroke In embolic stroke TPA disintegrates the occluding embolus frequently and there is no remaining exposed endothelium or plaque that would trigger thrombosis 9 In contrast in atherothrombotic stroke TPA disintegrates the occluding thrombus leading to re-perfusion less frequently 9 and the exposed thrombogenic elements within the ruptured plaque remain in place triggering repeated platelet activation and re-thrombosis
Because primary reperfusion is less frequent in patients with atherothrombotic large vessel stroke and re-occlusion is more common in these patients and both these processes involve platelet aggregation and activation at the site of thrombosis we argue that addition of anti-platelet agent would be able to increase reperfusion rates and decrease re-occlusion rates in these patients
Aspirin is the most commonly used antiplatelet agent in stroke patients It has a relatively long half life and a relatively rapid onset of therapeutic effect10 11 Furthermore an additional aspirin bolus may reverse a state of aspirin resistance in patients suffering a stroke while on aspirin12 13 Aspirin is safe when given to patients with acute stroke as soon as the diagnosis is made 14 15
Because the FDA approval of TPA use for stroke patients had a pre-requisite of not using concurrent anti-thrombotic drugs in the 24 hours after TPA administration the safety of aspirin needs to be studied in a randomized trial However it should be noted that pre-TPA aspirin use was not associated with an increased ICH risk in patients given the drug 16 and therefore pre-morbid aspirin use is not considered a contraindication for TPA administration in acute stroke
The study will be a randomized double blind study exploring the safety of adding 500 mg of aspirin given PO to standard doses of IV TPA
STUDY ENDPOINTS
PRIMARY ENDPOINT
1 Safety mortality symptomatic ICH asymptomatic ICH SECONDARY ENDPOINTS
1 Proportion of patients achieving excellent functional outcome as determined by a modified Rankin score mRS 2 and Barthel index BI 85 obtained at 3 months after stroke onset
2 Good neurological outcome as assessed by NIH stroke scale score at discharge 5 or showing improvement of at least 8 points from the initial stroke score
3 Good neurological outcome as assessed by NIH stroke scale score at 3 months 5 or showing improvement of at least 8 points from the initial stroke score
Inclusion and Exclusion Criteria
INCLUSION CRITERIA
Patients must meet all of the inclusion criteria
1 Diagnosis of acute ischemic stroke with onset less than 45 hours prior to the planned start of intravenous alteplase Acute ischemic stroke is defined as a measurable neurological deficit of sudden onset presumed secondary to focal cerebral ischemia Stroke onset will be defined as the time the patient was last known to be without the new clinical deficit Patients whose deficits have worsened in the last 45 hours are not eligible if their first symptoms started more than 45 hours before If the stroke started during sleep stroke onset will be recorded as the time the patient was last known to be at baseline
2 Disabling neurological deficit attributable to acute ischemic stroke in the middle cerebral artery territory
3 NIHSS less than or equal to 18 for left hemisphere strokes NIHSS less than or equal to 16 for others
4 Evidence of MCA occlusion stem or branch prior to drug administration by TCD CTA or MRA
5 Age 18-85 years inclusive
6 Able to sign informed consent
EXCLUSION CRITERIA
Patients will be excluded from study participation for any of the following reasons
1 Current participation in another study with an investigational drug or device within prior participation in the present study or planned participation in another therapeutic trial prior to the final day 30 assessment in this trial
2 Absence of acoustic window to insonate the MCA on the involved side
3 Time interval since stroke onset of less than 3 hours is impossible to determine with high degree of confidence
4 Symptoms suggestive of subarachnoid hemorrhage even if CT or MRI scan is negative for hemorrhage
5 Evidence of acute myocardial infarction defined as having at least two of the following three features 1 Chest pain suggestive of cardiac ischemia 2 EKG findings of ST elevation of more greater than 02 mV in 2 contiguous leads new onset left bundle branch block ST segment depression or T-wave inversion 3 Elevated troponin I
6 Acute Pericarditis
7 Women known to be pregnant lactating or having a positive or indeterminate pregnancy test
8 Neurological deficit that has led to stupor or coma NIHSS level of consciousness item I a score greater than or equal to 2
9 High clinical suspicion of septic embolus
10 Minor stroke with non-disabling deficit or rapidly improving neurological symptoms
11 Baseline NIHSS greater than 18 for left hemisphere stroke or greater than 16 for others
12 Evidence of acute or chronic ICH by head CT or MRI
13 CT or MRI evidence of non-vascular cause for the neurological symptoms
14 Signs of mass effect causing shift of midline structures on CT or MRI
15 Persistent hypertension with systolic BP greater than 185 mmHg or diastolic BP greater than 110 mmHg mean of 3 consecutive arm cuff readings over 20-30 minutes not controlled by antihypertensive therapy or requiring nitroprusside for control
16 Anticipated need for major surgery within 72 hours after start of study drugs eg carotid endarterectomy hip fracture repair
17 Any intracranial surgery intraspinal surgery or serious head trauma any head injury that required hospitalization within the past 3 months
18 Stroke within the past 3 months
19 History of ICH at any time in the past
20 Major trauma at the time of stroke eg hip fracture
21 Blood glucose greater than 200 mgdl
22 Presence or history of intracranial neoplasm except small meninigiomas or arteriovenous malformation
23 Intracranial aneurysm unless surgically or endovascularly treated more than 3 months before
24 Seizure at the onset of stroke
25 Active internal bleeding
26 Major hemorrhage requiring transfusion surgery or hospitalization in the past 21 days
27 Major surgery serious trauma lumbar puncture arterial puncture at a non-compressible site or biopsy of a parenchymal organ in last 14 days Major surgical procedures include but are not limited to the following major thoracic or abdominopelvic surgery neurosurgery major limb surgery carotid endarterectomy or other vascular surgery and organ transplantation For non-listed procedures the operating surgeon should be consulted to assess the risk
28 Presumed or documented history of vasculitis
29 Known systemic bleeding or platelet disorder eg von Willebrands disease hemophilia ITP TTP others
30 Platelet counts less than 100000 cellsmicro L
31 Congenital or acquired coagulopathy eg secondary to anticoagulants causing either of the following
1 Activated partial thromboplastin time aPTT prolongation greater than 2 seconds above the upper limit of normal for local laboratory except if due to isolated factor XII deficiency
2 INR greater than or equal to 14 Patients receiving warfarin prior to entry are eligible provided INR is less than 14 and warfarin can be safely discontinued for at least 48 hours
32 Life expectancy less than 3 months
33 Other serious illness eg severe hepatic cardiac or renal failure acute myocardial infarction or complex disease that may confound treatment assessment
34 Severe renal failure Serum creatinine greater than 40 mgdL or dependency on renal dialysis
35 AST or ALT greater than 3 times the upper limit of normal for the local laboratory
36 Treatment of the qualifying stroke with any thrombolytic anti-thrombotic or GPIIbIIIa inhibitor outside of this protocol
37 Any administration of a thrombolytic drug in the prior 7 days
38 Treatment of the qualifying stroke with intravenous heparin unless aPTT prolongation is no greater than 2 seconds above the upper limit of normal for local laboratory prior to study drug initiation
39 Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid
40 Known hypersensitivity to TPA
41 Anticoagulation evidenced by abnormal INR aPTT or platelet count caused by herbal therapy
METHOD
Eligible patients n20group will be recruited after obtaining informed consent Patients will be randomized to receive rt-TPA 09mgkg 10 of the total dose as an IV bolus and the reminder IV over 60 minutes placebo or rt-TPA 09mgkg aspirin PO at a dose of 500mg at the time of TPA administration Randomization will be accomplished using an IVRS automated system Randomization will be into time tiers of 0-15 hours from symptom onset 15-3 hours from symptom onset and 3-45 hours from symptom onset for each dose tier Overall 60 patients 30 TPA active drug and 30 TPA only are to be recruited Study medications will be supplied by the hospital and will have a total volume color and odor that will be identical to placebo At the end of recruitment the randomization codes will be opened and the data safety monitoring board DSMB will determine the safety of continuing the study in the next dose tier Samples will be collected for safety data renal hepatic and coagulation studies and sent to local laboratories in each center Investigators will be notified immediately on any lab results by fax and email ECGs will be read at a central facility and investigators will be notified on any abnormal result immediately via fax and email All AE and SAE will be reported immediately
EVALUATIONS
Safety
Hemodynamics Patients will be monitored non-invasively for blood pressure heart rate oxygen saturation q2rhs in the first 24 hours post stroke and then every 6 hours for the next 24 hours and then every 12 hours for the reminder of the hospitalization
Coagulation tests PT PTT and PLT blood counts will be evaluated daily in the first 3 days of hospitalization
Blood tests Blood chemistry liver function tests and cardiac enzymes will be evaluated daily for the first 3 days and then at discharge
Cardiac rhythm ECG will be evaluated daily on a 12 lead recording on the first 3 days of hospitalization and then at discharge
CT Brain CT will be obtained prior to drug administration and in included patients repeated scans will be obtained at 96-120 hours to evaluate final infarct size In cases of suspected hematoma brain CT would be obtained immediately and the number of patients sustaining an ICH following drug administration will be recorded
All other adverse events AE and serious adverse events SAE will be recorded and promptly evaluated by the data safety monitoring board that will decide whether or not these events are drug related and which will have the authority to prematurely terminate the study in case an unexpected SAE emerges and appears to be drug related AE and SAE will be defined conventionally such that AE is any adverse event and SAE as an AE necessitating prolongation of hospitalization or any adverse event that is potentially life threatening
NEUROLOGICAL Included patients will be examined before and after randomization with the National Institute of Health stroke scale NIHSS on days 1235 and discharge and on outpatient visits at months 1 and 3-post stroke
FUNCTIONAL OUTCOME Patients will be evaluated with the Barthel index BI and modified Rankin score MRS administered on discharge day and during outpatient visits at month 1 and 3-post stroke
References
1 Tissue plasminogen activator for acute ischemic stroke The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group N Engl J Med 19953331581-1587
2 Hacke W Kaste M Fieschi C et al Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke The European Cooperative Acute Stroke Study ECASS JAMA 19952741017-1025
3 Albers GW Bates VE Clark WM et al Intravenous tissue-type plasminogen activator for treatment of acute stroke the Standard Treatment with Alteplase to Reverse Stroke STARS study JAMA 20002831145-1150
4 Hacke W Donnan G Fieschi C et al Association of outcome with early stroke treatment pooled analysis of ATLANTIS ECASS and NINDS rt-PA stroke trials Lancet 2004363768-774
5 Graham GD Tissue plasminogen activator for acute ischemic stroke in clinical practice a meta-analysis of safety data Stroke 2003342847-2850
6 Burgin WS Staub L Chan W et al Acute stroke care in non-urban emergency departments Neurology 2001572006-2012
7 Rubiera M Alvarez-Sabin J Ribo M et al Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke Stroke 2005361452-1456
8 Molina CA Ribo M Rubiera M et al Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator Stroke 200637425-429
9 Molina CA Montaner J Arenillas JF et al Differential pattern of tissue plasminogen activator-induced proximal middle cerebral artery recanalization among stroke subtypes Stroke 200435486-490
10 Barnett HJ Aspirin in stroke prevention An overview Stroke 199021IV40-43
11 Schror K Antiplatelet drugs A comparative review Drugs 1995507-28
12 Wang TH Bhatt DL Topol EJ Aspirin and clopidogrel resistance an emerging clinical entity Eur Heart J 200627647-654
13 Sztriha LK Sas K Vecsei L Aspirin resistance in stroke 2004 J Neurol Sci 2005229-230163-169
14 The International Stroke Trial IST a randomised trial of aspirin subcutaneous heparin both or neither among 19435 patients with acute ischaemic stroke International Stroke Trial Collaborative Group Lancet 19973491569-1581
15 CAST randomised placebo-controlled trial of early aspirin use in 20000 patients with acute ischaemic stroke CAST Chinese Acute Stroke Trial Collaborative Group Lancet 19973491641-1649
16 Levy DE Brott TG Haley EC Jr et al Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke Stroke 199425291-297
Management of acute ischemic stroke consists of thrombolytic drugs aiming at opening occluded vessels Tissue plasminogen activator TPA is the only drug approved by the FDA 1 2 The use of TPA is significantly limited by a relatively narrow therapeutic window of up to 3-45 hours following stroke onset 3 4 Use of TPA outside of this time window is associated with an unacceptably high risk of hemorrhage including symptomatic intracranial hemorrhage sICH 5 6 While TPA is efficacious in reducing stroke associated disability its effects are limited by the phenomenon of early re-occlusion after successful reperfusion of the occluded artery
Previous reports have shown that among patients receiving IV TPA within 3 hours of stroke onset 61 re-perfuse at 1 hour with about 67 of these having partial recanalization and 33 complete recanalization of the occluded artery 7 reperfusion rates at 2 hours tend to be much lower ranging around 30-40 implying early re-occlusion 8 Indeed it was found that 25 of the patients that have successfully reperfused will re-occlude the artery within 2 hours 7 Re-occlusion of an already reperfused artery was more common in elderly patients with severe ipsilateral carotid stenosis and higher NIHSS scores and was associated with poor outcome 7 We speculate that re-occlusion is much more common in atherothrombotic strokes compared with embolic stroke In embolic stroke TPA disintegrates the occluding embolus frequently and there is no remaining exposed endothelium or plaque that would trigger thrombosis 9 In contrast in atherothrombotic stroke TPA disintegrates the occluding thrombus leading to re-perfusion less frequently 9 and the exposed thrombogenic elements within the ruptured plaque remain in place triggering repeated platelet activation and re-thrombosis
Because primary reperfusion is less frequent in patients with atherothrombotic large vessel stroke and re-occlusion is more common in these patients and both these processes involve platelet aggregation and activation at the site of thrombosis we argue that addition of anti-platelet agent would be able to increase reperfusion rates and decrease re-occlusion rates in these patients
Aspirin is the most commonly used antiplatelet agent in stroke patients It has a relatively long half life and a relatively rapid onset of therapeutic effect10 11 Furthermore an additional aspirin bolus may reverse a state of aspirin resistance in patients suffering a stroke while on aspirin12 13 Aspirin is safe when given to patients with acute stroke as soon as the diagnosis is made 14 15
Because the FDA approval of TPA use for stroke patients had a pre-requisite of not using concurrent anti-thrombotic drugs in the 24 hours after TPA administration the safety of aspirin needs to be studied in a randomized trial However it should be noted that pre-TPA aspirin use was not associated with an increased ICH risk in patients given the drug 16 and therefore pre-morbid aspirin use is not considered a contraindication for TPA administration in acute stroke
The study will be a randomized double blind study exploring the safety of adding 500 mg of aspirin given PO to standard doses of IV TPA
STUDY ENDPOINTS
PRIMARY ENDPOINT
1 Safety mortality symptomatic ICH asymptomatic ICH SECONDARY ENDPOINTS
1 Proportion of patients achieving excellent functional outcome as determined by a modified Rankin score mRS 2 and Barthel index BI 85 obtained at 3 months after stroke onset
2 Good neurological outcome as assessed by NIH stroke scale score at discharge 5 or showing improvement of at least 8 points from the initial stroke score
3 Good neurological outcome as assessed by NIH stroke scale score at 3 months 5 or showing improvement of at least 8 points from the initial stroke score
Inclusion and Exclusion Criteria
INCLUSION CRITERIA
Patients must meet all of the inclusion criteria
1 Diagnosis of acute ischemic stroke with onset less than 45 hours prior to the planned start of intravenous alteplase Acute ischemic stroke is defined as a measurable neurological deficit of sudden onset presumed secondary to focal cerebral ischemia Stroke onset will be defined as the time the patient was last known to be without the new clinical deficit Patients whose deficits have worsened in the last 45 hours are not eligible if their first symptoms started more than 45 hours before If the stroke started during sleep stroke onset will be recorded as the time the patient was last known to be at baseline
2 Disabling neurological deficit attributable to acute ischemic stroke in the middle cerebral artery territory
3 NIHSS less than or equal to 18 for left hemisphere strokes NIHSS less than or equal to 16 for others
4 Evidence of MCA occlusion stem or branch prior to drug administration by TCD CTA or MRA
5 Age 18-85 years inclusive
6 Able to sign informed consent
EXCLUSION CRITERIA
Patients will be excluded from study participation for any of the following reasons
1 Current participation in another study with an investigational drug or device within prior participation in the present study or planned participation in another therapeutic trial prior to the final day 30 assessment in this trial
2 Absence of acoustic window to insonate the MCA on the involved side
3 Time interval since stroke onset of less than 3 hours is impossible to determine with high degree of confidence
4 Symptoms suggestive of subarachnoid hemorrhage even if CT or MRI scan is negative for hemorrhage
5 Evidence of acute myocardial infarction defined as having at least two of the following three features 1 Chest pain suggestive of cardiac ischemia 2 EKG findings of ST elevation of more greater than 02 mV in 2 contiguous leads new onset left bundle branch block ST segment depression or T-wave inversion 3 Elevated troponin I
6 Acute Pericarditis
7 Women known to be pregnant lactating or having a positive or indeterminate pregnancy test
8 Neurological deficit that has led to stupor or coma NIHSS level of consciousness item I a score greater than or equal to 2
9 High clinical suspicion of septic embolus
10 Minor stroke with non-disabling deficit or rapidly improving neurological symptoms
11 Baseline NIHSS greater than 18 for left hemisphere stroke or greater than 16 for others
12 Evidence of acute or chronic ICH by head CT or MRI
13 CT or MRI evidence of non-vascular cause for the neurological symptoms
14 Signs of mass effect causing shift of midline structures on CT or MRI
15 Persistent hypertension with systolic BP greater than 185 mmHg or diastolic BP greater than 110 mmHg mean of 3 consecutive arm cuff readings over 20-30 minutes not controlled by antihypertensive therapy or requiring nitroprusside for control
16 Anticipated need for major surgery within 72 hours after start of study drugs eg carotid endarterectomy hip fracture repair
17 Any intracranial surgery intraspinal surgery or serious head trauma any head injury that required hospitalization within the past 3 months
18 Stroke within the past 3 months
19 History of ICH at any time in the past
20 Major trauma at the time of stroke eg hip fracture
21 Blood glucose greater than 200 mgdl
22 Presence or history of intracranial neoplasm except small meninigiomas or arteriovenous malformation
23 Intracranial aneurysm unless surgically or endovascularly treated more than 3 months before
24 Seizure at the onset of stroke
25 Active internal bleeding
26 Major hemorrhage requiring transfusion surgery or hospitalization in the past 21 days
27 Major surgery serious trauma lumbar puncture arterial puncture at a non-compressible site or biopsy of a parenchymal organ in last 14 days Major surgical procedures include but are not limited to the following major thoracic or abdominopelvic surgery neurosurgery major limb surgery carotid endarterectomy or other vascular surgery and organ transplantation For non-listed procedures the operating surgeon should be consulted to assess the risk
28 Presumed or documented history of vasculitis
29 Known systemic bleeding or platelet disorder eg von Willebrands disease hemophilia ITP TTP others
30 Platelet counts less than 100000 cellsmicro L
31 Congenital or acquired coagulopathy eg secondary to anticoagulants causing either of the following
1 Activated partial thromboplastin time aPTT prolongation greater than 2 seconds above the upper limit of normal for local laboratory except if due to isolated factor XII deficiency
2 INR greater than or equal to 14 Patients receiving warfarin prior to entry are eligible provided INR is less than 14 and warfarin can be safely discontinued for at least 48 hours
32 Life expectancy less than 3 months
33 Other serious illness eg severe hepatic cardiac or renal failure acute myocardial infarction or complex disease that may confound treatment assessment
34 Severe renal failure Serum creatinine greater than 40 mgdL or dependency on renal dialysis
35 AST or ALT greater than 3 times the upper limit of normal for the local laboratory
36 Treatment of the qualifying stroke with any thrombolytic anti-thrombotic or GPIIbIIIa inhibitor outside of this protocol
37 Any administration of a thrombolytic drug in the prior 7 days
38 Treatment of the qualifying stroke with intravenous heparin unless aPTT prolongation is no greater than 2 seconds above the upper limit of normal for local laboratory prior to study drug initiation
39 Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid
40 Known hypersensitivity to TPA
41 Anticoagulation evidenced by abnormal INR aPTT or platelet count caused by herbal therapy
METHOD
Eligible patients n20group will be recruited after obtaining informed consent Patients will be randomized to receive rt-TPA 09mgkg 10 of the total dose as an IV bolus and the reminder IV over 60 minutes placebo or rt-TPA 09mgkg aspirin PO at a dose of 500mg at the time of TPA administration Randomization will be accomplished using an IVRS automated system Randomization will be into time tiers of 0-15 hours from symptom onset 15-3 hours from symptom onset and 3-45 hours from symptom onset for each dose tier Overall 60 patients 30 TPA active drug and 30 TPA only are to be recruited Study medications will be supplied by the hospital and will have a total volume color and odor that will be identical to placebo At the end of recruitment the randomization codes will be opened and the data safety monitoring board DSMB will determine the safety of continuing the study in the next dose tier Samples will be collected for safety data renal hepatic and coagulation studies and sent to local laboratories in each center Investigators will be notified immediately on any lab results by fax and email ECGs will be read at a central facility and investigators will be notified on any abnormal result immediately via fax and email All AE and SAE will be reported immediately
EVALUATIONS
Safety
Hemodynamics Patients will be monitored non-invasively for blood pressure heart rate oxygen saturation q2rhs in the first 24 hours post stroke and then every 6 hours for the next 24 hours and then every 12 hours for the reminder of the hospitalization
Coagulation tests PT PTT and PLT blood counts will be evaluated daily in the first 3 days of hospitalization
Blood tests Blood chemistry liver function tests and cardiac enzymes will be evaluated daily for the first 3 days and then at discharge
Cardiac rhythm ECG will be evaluated daily on a 12 lead recording on the first 3 days of hospitalization and then at discharge
CT Brain CT will be obtained prior to drug administration and in included patients repeated scans will be obtained at 96-120 hours to evaluate final infarct size In cases of suspected hematoma brain CT would be obtained immediately and the number of patients sustaining an ICH following drug administration will be recorded
All other adverse events AE and serious adverse events SAE will be recorded and promptly evaluated by the data safety monitoring board that will decide whether or not these events are drug related and which will have the authority to prematurely terminate the study in case an unexpected SAE emerges and appears to be drug related AE and SAE will be defined conventionally such that AE is any adverse event and SAE as an AE necessitating prolongation of hospitalization or any adverse event that is potentially life threatening
NEUROLOGICAL Included patients will be examined before and after randomization with the National Institute of Health stroke scale NIHSS on days 1235 and discharge and on outpatient visits at months 1 and 3-post stroke
FUNCTIONAL OUTCOME Patients will be evaluated with the Barthel index BI and modified Rankin score MRS administered on discharge day and during outpatient visits at month 1 and 3-post stroke
References
1 Tissue plasminogen activator for acute ischemic stroke The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group N Engl J Med 19953331581-1587
2 Hacke W Kaste M Fieschi C et al Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke The European Cooperative Acute Stroke Study ECASS JAMA 19952741017-1025
3 Albers GW Bates VE Clark WM et al Intravenous tissue-type plasminogen activator for treatment of acute stroke the Standard Treatment with Alteplase to Reverse Stroke STARS study JAMA 20002831145-1150
4 Hacke W Donnan G Fieschi C et al Association of outcome with early stroke treatment pooled analysis of ATLANTIS ECASS and NINDS rt-PA stroke trials Lancet 2004363768-774
5 Graham GD Tissue plasminogen activator for acute ischemic stroke in clinical practice a meta-analysis of safety data Stroke 2003342847-2850
6 Burgin WS Staub L Chan W et al Acute stroke care in non-urban emergency departments Neurology 2001572006-2012
7 Rubiera M Alvarez-Sabin J Ribo M et al Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke Stroke 2005361452-1456
8 Molina CA Ribo M Rubiera M et al Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator Stroke 200637425-429
9 Molina CA Montaner J Arenillas JF et al Differential pattern of tissue plasminogen activator-induced proximal middle cerebral artery recanalization among stroke subtypes Stroke 200435486-490
10 Barnett HJ Aspirin in stroke prevention An overview Stroke 199021IV40-43
11 Schror K Antiplatelet drugs A comparative review Drugs 1995507-28
12 Wang TH Bhatt DL Topol EJ Aspirin and clopidogrel resistance an emerging clinical entity Eur Heart J 200627647-654
13 Sztriha LK Sas K Vecsei L Aspirin resistance in stroke 2004 J Neurol Sci 2005229-230163-169
14 The International Stroke Trial IST a randomised trial of aspirin subcutaneous heparin both or neither among 19435 patients with acute ischaemic stroke International Stroke Trial Collaborative Group Lancet 19973491569-1581
15 CAST randomised placebo-controlled trial of early aspirin use in 20000 patients with acute ischaemic stroke CAST Chinese Acute Stroke Trial Collaborative Group Lancet 19973491641-1649
16 Levy DE Brott TG Haley EC Jr et al Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke Stroke 199425291-297
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None