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

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.

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.