Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial

Study Overview
=================
Brief Summary
-----------------
A transient ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. An ischemic stroke is a cerebral infarction. In POINT, eligibility is limited to brain TIAs and to minor ischemic strokes (with an NIH Stroke Scale [NIHSS] score less than or equal to 3). TIAs are common [25], and are often harbingers of disabling strokes. Approximately 250,000-350,000 TIAs are diagnosed each year in the US. Given median survival of more than 8 years [32], there are approximately 2.4 million TIA survivors. In a national survey, one in fifteen of those over 65 years old reported a history of TIA [33], which is equivalent to a prevalence of 2.3 million in older Americans. Based on the prevalence of undiagnosed transient neurological events, the true incidence of TIA may be twice as high as the rates of diagnosis [33]. Based on our review of the National Inpatient Sample for 1997-2003, there were an average of 200,000 hospital admissions for TIA each year, with annual charges climbing quickly in the period to $2.6 billion in 2003. Composite endpoint of new ischemic vascular events: ischemic stroke, myocardial infarction or ischemic vascular death at 90 days.

Detailed Description
-----------------
Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) Trial, is a prospective, randomized, double-blind, multicenter trial with the primary null hypothesis that, in patients with TIA or minor ischemic stroke treated with aspirin 50-325 mg/day, there is no difference in the event-free survival at 90 days in those treated with clopidogrel (600 mg loading dose then 75 mg/day) compared to placebo when subjects are randomized within 12 hours of time last known free of new ischemic symptoms. Its primary objective is to determine whether clopidogrel 75 mg/day by mouth after a loading dose of 600 mg of clopidogrel is effective in preventing major ischemic vascular events (ischemic stroke, myocardial infarction, and ischemic vascular death) at 90 days when initiated within 12 hours of TIA or minor ischemic stroke onset in patients receiving aspirin 50-325 mg/day (with a dose of 150-200 mg daily for 5 days followed by 75-100 mg daily strongly recommended). Patients over 18 years of age with high-risk TIA (defined as an ABCD2 score greater than or equal to 4) or minor ischemic stroke (with NIHSS less than or equal to 3) who can be treated within 12 hours of time last known free of new ischemic symptoms will be enrolled. Subjects will be randomized 1:1 (clopidogrel: placebo), controlling for clinical center. A study participant's eligibility will be determined by site personnel prior to accessing the Randomization Module in the WebDCU™, a web-enabled clinical trials management system that was developed by the NETT Statistics and Data Management Center (SDMC) at Medical University of South Carolina (MUSC).Qualified users will access the Randomization Interface and complete a protocol-specific eligibility checklist. If the Randomization Interface finds the patient to be eligible based on the information provided, a randomization number and a confirmatory e-mail are generated. Each subject is followed for 90 days from randomization; the trial will be completed in 7 years. A total of 5,840 patients will be recruited. Recruitment will occur over 90 months, with a goal rate of 0.40 subjects/site/month for US sites, and a goal rate of 0.47 subjects/site/month for OUS sites. Current participating sites can be found at: http://www.pointtrial.org/node/18.

Official Title
-----------------
Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial

Conditions
-----------------
Ischemic Attack, Transient

Intervention / Treatment
-----------------
* Drug: Clopidogrel
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Neurological deficit (based on history or exam) attributed to focal brain ischemia and EITHER: High risk TIA: Complete resolution of the deficit at the time of randomization AND ABCD2 score of (greater than or equal to) 4 OR Minor ischemic stroke: residual deficit with NIHSS of (less than or equal to) 3 at the time of randomization Ability to randomize within 12 hours of time last known free of new ischemic symptoms. Head CT or MRI ruling out hemorrhage or other pathology, such as vascular malformation, tumor, or abscess, that could explain symptoms or contraindicate therapy. Ability to tolerate aspirin at a does of 50-325 mg/day. Exclusion Criteria Age <18 years TIA symptoms limited to isolated numbness, isolated visual changes, or isolated dizziness/vertigo. In the judgment of the treating physician, a candidate for thrombolysis, endarterectomy or endovascular intervention, unless the subject declines both endarterectomy and endovascular intervention at the time of evaluation for eligibility. Receipt of any intravenous or intra-arterial thrombolysis within 1 week prior to index event. Gastrointestinal bleed or major surgery within 3 months prior to index event. History of nontraumatic intracranial hemorrhage. Clear indication for anticoagulation (e.g., warfarin, heparin) anticipated during the study period (atrial fibrillation, mechanical heart valve, deep venous thrombosis, pulmonary embolism, antiphospholipid antibody syndrome, hypercoagulable state). Qualifying ischemic event induced by angiography or surgery. Severe non-cardiovascular comorbidity with life expectancy <3 months. Contraindication to clopidogrel or aspirin. Known allergy Severe renal (serum creatinine >2 mg/dL or 176.8umol/L) or hepatic insufficiency (prior or concurrent diagnosis, with International Normalized Ratio (INR)>1.5 or any resultant complication, such as variceal bleeding, encephalopathy, or icterus) Hemostatic disorder or systemic bleeding in the past 3 months Current thrombocytopenia (platelet count <100 x10^9/l) or neutropenia (<1 x10^9/l) History of drug-induced hematologic or hepatic abnormalities Anticipated requirement for long-term (>7 day) non-study antiplatelet drugs (eg, dipyridamole, clopidogrel, ticlopidine), or Non-steroidal Anti-inflammatory Drugs (NSAIDs) affecting platelet function (such as prior vascular stent or arthritis). Inability to swallow medications. At risk for pregnancy: premenopausal or post menopausal woman within 12 months of last menses without a negative pregnancy test or not committing to adequate birth control (e.g., oral contraceptive, two methods of barrier birth control, or abstinence). Unavailability for follow-up. Signed and dated informed consent not obtained from patient. Other neurological conditions that would complicate assessment of outcomes during follow-up. Ongoing treatment in another study of an investigational therapy that may potentially interact with study drug, or treatment in such a study within the last 7 days. Previously enrolled in the POINT study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: clopidogrel<br>Patients assigned to clopidogrel in addition to aspirin | Drug: Clopidogrel<br>* Loading dose of 600mg followed by 75 milligrams, oral, one tablet daily for 89 days<br>* Other names: Plavix;|
| Placebo Comparator: placebo<br>Patients assigned to placebo in addition to aspirin | Drug: placebo<br>* Loading dose of 8 tablets followed by one tablet daily for 89 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Ischemic Stroke, Myocardial Infarction, or Death From Ischemic Vascular Causes | Primary efficacy outcome: Number of Participants with Ischemic Stroke, Myocardial Infarction, or Death From Ischemic Vascular Causes | Up to 90 days | 
| Major Hemorrhage | Primary safety outcome: Number of Participants with major hemorrhage | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic Stroke | Secondary efficacy outcome:Number of participants with Ischemic stroke | Up to 90 days | 
| Myocardial Infarction | Secondary efficacy outcome: Number of participants with Myocardial infarction | Up to 90 days | 
| Death From Ischemic Vascular Causes | Secondary efficacy outcome: Number of participants with Death from ischemic vascular causes | Up to 90 days | 
| Ischemic or Hemorrhagic Stroke | Secondary efficacy outcome: Number of participants with Ischemic or hemorrhagic stroke | Up to 90 days | 
| Composite of Ischemic Stroke, Myocardial Infarction, Death From Ischemic Vascular Causes, or Major Hemorrhage | Secondary efficacy outcome: Number of participants with ischemic stroke, myocardial infarction, death from ischemic vascular causes, or major hemorrhage | Up to 90 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transient Ischemic Attack, TIA, minor stroke