Conditions: Ischemic Attack, Transient
Keywords: Transient Ischemic Attack TIA minor stroke
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4881
Healthy volunteers: no

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.

Arms:
arm 1: Patients assigned to clopidogrel in addition to aspirin arm 2: Patients assigned to placebo in addition to aspirin

Interventions: intervention 1: Clopidogrel intervention 2: placebo
Intervention descriptions: intervention 1: Loading dose of 600mg followed by 75 milligrams, oral, one tablet daily for 89 days intervention 2: Loading dose of 8 tablets followed by one tablet daily for 89 days

Protocol document:
Prot_001.pdf: 
 
Platelet-Oriented Inhibition in New TIA 
and minor ischemic stroke 
(POINT) Trial 
 
Study Protocol 
Supported by  
The National Institute of Neurological Disorders and Stroke (NINDS) 
Principal Investigator 
S. Claiborne Johnston, MD, PhD 
Professor of Neurology and Epidemiology 
University of California San Francisco 
Co-Principal Investigator 
J. Donald Easton, MD 
Clinical Professor of Neurology 
University of California San Francisco 
Co-Principal Investigator 
Anthony Kim, MD, MAS 
Clinical Professor of Neurology 
University of California San Francisco 
 
Protocol Version 6.0 
 
NCT00991029 
EudraCT 2013-001185-41 
 


POINT Trial Protocol 
 
 
Version 6.0 29 February 2016 
Amended: 11.30.2016 
 
Page 2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Version (6.0) dated (30NOV2016) 
I have read this protocol and agree to adhere to the requirements.   
 
I will provide copies of this protocol and all pertinent information to the study personnel under my 
supervision. I will discuss this material with them and ensure they are fully informed regarding the 
investigational plan and the conduct of the study, applicable laws, regulations, international standards, 
and ethical and safety considerations, including 21 CFR Parts 50, 54 and 56, International Conference 
on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines, and Institutional Review Board (IRB) 
or Ethics Committee (EC) requirements.   
 
 
 
_____________________________________ 
 
 
________________ 
Clinical Site  
 
 
 
 
 
 
 
Date 
 
 
_____________________________________ 
 
 
________________ 
Site Principal Investigator Signature  
 
 
 
 
Date 
 
 
_____________________________________ 
 
 
________________ 
Site Principal Investigator Printed Name  
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 


POINT Trial Protocol 
 
 
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Amended: 11.30.2016 
 
Page 3 
COUNTRY COORDINATOR PROTOCOL SIGNATURE PAGE 
Protocol Version (6.0) dated (30NOV3018) 
I have read this protocol and agree to adhere to the requirements.   
 
I will provide copies of this protocol and all pertinent information to the study personnel under my 
supervision. I will discuss this material with them and ensure they are fully informed regarding the 
investigational plan and the conduct of the study, applicable laws, regulations, international standards, 
and ethical and safety considerations, including 21 CFR Parts 50, 54 and 56, International Conference 
on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines, and Institutional Review Board (IRB) 
or Ethics Committee (EC) requirements.   
 
 
 
_____________________________________ 
 
 
________________ 
Country/Clinical Site  
 
 
 
 
 
Date 
 
 
_____________________________________ 
 
 
________________ 
Country Coordinator Signature   
 
 
 
Date 
 
 
_____________________________________ 
 
 
________________ 
Country Coordinator Printed Name  
 
 
 
Date 
 
 
 
 
 
 
 


POINT Trial Protocol 
 
 
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Amended: 11.30.2016 
 
Page 4 
Table of Contents 
 
 
PROTOCOL SIGNATURE PAGE .................................................................................................................... 2 
Table of Contents ....................................................................................................................................... 4 
POINT PROTOCOL SYNOPSIS ...................................................................................................................... 8 
1 
STUDY FLOWCHARTS ........................................................................................................................ 12 
1.1 
Graphical Study Design ............................................................................................................. 12 
1.2 
Schedule of Activities and Assessments ................................................................................... 13 
2 
BACKGROUND AND SIGNIFICANCE ................................................................................................... 14 
2.1 
TIA Incidence ............................................................................................................................ 15 
2.2 
Short-term Prognosis ............................................................................................................... 15 
2.3 
Underlying Pathophysiology of TIA and Minor Ischemic Stroke .............................................. 17 
2.4 
Potential Therapies .................................................................................................................. 17 
2.4.1 
Aspirin ................................................................................................................................... 18 
2.4.2 
Clopidogrel ........................................................................................................................... 18 
2.4.3 
Combination Clopidogrel-Aspirin ......................................................................................... 19 
2.4.4 
Dipyridamole ........................................................................................................................ 22 
2.5 
Advantages of a TIA Acute Treatment Trial ............................................................................. 22 
2.6 
Preliminary Studies ................................................................................................................... 22 
2.6.1 
Predictors of Stroke Risk after TIA ........................................................................................ 23 
2.6.2 
Importance of Recovery:  Risk of Stroke after Recovery in NINDS tPA, TOAST Trials .......... 24 
2.6.3  
Current Utilization of Antithrombotics after TIA .............................................................. 24 
3 
STUDY OBJECTIVES ............................................................................................................................ 25 
3.1 
Secondary ................................................................................................................................. 25 
4 
STUDY DESIGN AND MANAGEMENT OVERVIEW .............................................................................. 25 
4.1 
Study Design Overview ............................................................................................................. 25 
4.2 
Study Milestones ...................................................................................................................... 26 
4.3 
Organizational Structure and Communication Flow ................................................................ 26 
4.3.1 
Trial Organization ................................................................................................................. 29 
4.4 
Site Training, Certification, and Update ................................................................................... 29 


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4.5 
Contact Schedule and Measurements ..................................................................................... 30 
4.6 
Outcomes ................................................................................................................................. 30 
4.6.1 
Definitions of Clinical Outcomes/Serious Adverse Events ................................................... 30 
5 
PARTICIPANT SELECTION .................................................................................................................. 33 
5.1 
Study Population ...................................................................................................................... 33 
5.2 
Inclusion and Exclusion Criteria ................................................................................................ 34 
6 
TREATMENTS ..................................................................................................................................... 35 
6.1 
Study Drugs .............................................................................................................................. 35 
6.2 
Assignment to a Treatment Group ........................................................................................... 36 
7 
STUDY DRUG HANDLING ................................................................................................................... 36 
7.1 
Supply and Storage ................................................................................................................... 36 
7.2 
Packaging .................................................................................................................................. 37 
7.3 
Responsibilities ......................................................................................................................... 38 
7.4 
Concurrent Treatment.............................................................................................................. 38 
7.4.1 
Prohibited Concomitant Treatments.................................................................................... 38 
7.4.2 
Permitted Concurrent Treatments ....................................................................................... 38 
7.5 
Treatment Discontinuation ...................................................................................................... 39 
7.5.1 
Permanent Treatment Discontinuation ............................................................................... 39 
7.6 
Blinding System and Emergency Unblinding Procedure .......................................................... 40 
8 
SAFETY ............................................................................................................................................... 40 
8.1 
Protection/ Minimization of Risk.............................................................................................. 40 
8.2 
Serious Adverse Events ............................................................................................................ 41 
8.2.1 
Management of SAEs/Clinical Outcomes ............................................................................. 41 
8.3 
Definitions ................................................................................................................................ 41 
8.4 
Classification of Adverse Events ............................................................................................... 42 
8.5 
SAEs/Clinical Outcomes ............................................................................................................ 42 
8.5.1 
SAEs/Clinical Outcomes into the Study Database ................................................................ 42 
8.5.2 
Reporting Recurrent SAEs/Clinical Outcomes ...................................................................... 43 
8.5.3 
Procedure for Expedited Reporting of SAEs/Clinical Outcomes .......................................... 43 
8.5.4 
Site Monitoring and SAE/Clinical Outcome Reporting ......................................................... 44 
8.5.5 
Clinical Outcome Event Reporting ........................................................................................ 44 
8.6 
Protocol Violations ................................................................................................................... 45 


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9 
STUDY PROCEDURES ......................................................................................................................... 46 
9.1 
Screening Evaluation ................................................................................................................ 46 
9.2 
Baseline Evaluation .................................................................................................................. 48 
9.3 
Randomization ......................................................................................................................... 48 
9.3.1 
Treatment Protocols ............................................................................................................. 49 
9.3.2 
Risk Factor Evaluation and Management ............................................................................. 50 
9.4 
Follow-up .................................................................................................................................. 51 
9.4.1 
Follow-up 7 Day Phone Call .................................................................................................. 51 
9.4.2 
90 Day In-Person or Phone Follow- up ................................................................................. 52 
9.4.3 
Event Visit ............................................................................................................................. 53 
9.4.4 
Adherence to Treatment ...................................................................................................... 53 
10 
STATISTICAL CONSIDERATIONS .................................................................................................... 54 
10.1 
Statistical Analysis Plans ........................................................................................................... 54 
10.1.1 
Randomization Scheme .................................................................................................... 54 
10.1.2 
Sample Size Estimates ...................................................................................................... 54 
10.1.3 
Secondary Outcomes........................................................................................................ 55 
10.2 
Statistical Analyses ................................................................................................................... 55 
10.2.1 
Primary Outcomes ............................................................................................................ 55 
10.2.2 
Secondary Outcome Events ............................................................................................. 55 
10.3 
Data and Safety Monitoring Procedure and Plan ..................................................................... 55 
10.3.1 
Interim Analyses and Stopping Rules ............................................................................... 55 
11 
ETHICAL AND REGULATORY STANDARDS ..................................................................................... 56 
11.1 
Ethical Considerations .............................................................................................................. 56 
11.2 
Regulatory Requirements ......................................................................................................... 56 
11.3 
Institutional Review Board (IRB) or Ethics Committee (EC) ..................................................... 56 
11.4 
Informed Consent ..................................................................................................................... 56 
12 
STUDY MONITORING .................................................................................................................... 57 
12.1 
Site Monitoring, Quality Assurance and Remedial Actions ...................................................... 57 
12.1.1 
Site Visits .......................................................................................................................... 57 
12.1.2 
Remedial Action ............................................................................................................... 57 
12.2 
Data Management .................................................................................................................... 58 
12.2.1 
Data Quality Monitoring ................................................................................................... 58 


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13 
PUBLICATION OF RESEARCH FINDINGS ........................................................................................ 58 
14 
ANCILLARY STUDIES ...................................................................................................................... 58 
14.1 
Optional POINT Biomarkers Ancillary Study............................................................................. 59 
15 
REFERENCES ................................................................................................................................. 60 
 
 
 


POINT Trial Protocol 
 
 
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Page 8 
POINT PROTOCOL SYNOPSIS 
Title: 
Platelet-Oriented Inhibition in New TIA and minor ischemic 
stroke (POINT) Trial, a randomized, double-blind, multicenter 
clinical trial 
Primary Objective: 
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 
subjects are randomized within 12 hours of time last known 
free of new ischemic symptoms 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). 
Study Design: 
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. 
Patient Population: 
Patients 18 years of age or older with high-risk TIA (defined as 
an ABCD2 score > 4) or minor ischemic stroke (with NIHSS <3) 
who can be randomized within 12 hours of time last known free 
of new ischemic symptoms will be enrolled.   
Inclusion/Exclusion Criteria: 
Inclusion Criteria 
• 
Neurologic deficit (based on history or exam) attributed to 
focal brain ischemia and EITHER: 
o High risk TIA: Complete resolution of the deficit at 
the time of randomization AND ABCD2 score >4 
Or 
o Minor ischemic stroke:  residual deficit with NIHSS 
<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 dose of 50-325 mg/day. 


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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 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 x109/l) 
or neutropenia/granulocytopenia (<1 x109/l) 
 
History of drug-induced hematologic or hepatic 
abnormalities 
• 
Anticipated requirement for long-term (>7 day) non-study 
antiplatelet drugs (e.g., dipyridamole, clopidogrel, 


POINT Trial Protocol 
 
 
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Page 10 
ticlopidine), or NSAIDs affecting platelet function (such as 
prior vascular stent or arthritis). 
• 
Not willing or able to discontinue prohibited concomitant 
medications. 
• 
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. 
Randomization: 
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 
Neurological Emergencies Treatment Trials (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 email will be generated.   
Primary Endpoint: 
Composite endpoint of new ischemic vascular events: ischemic 
stroke, myocardial infarction or ischemic vascular death at 90 
days. 
Study Duration for Each 
Subject: 
Each subject is followed for 90 days from randomization; the 
trial will be completed in 7 years. 


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Number of Centers: 
Up to a total of 350 investigational sites in partnership with the 
NINDS NETT Network and the POINT Clinical Research 
Collaboration (CRC).   
Sample Size: 
Total sample size for the study is 5,840 subjects.  
Primary Statistical Analysis: 
 
The primary efficacy hypothesis is tested with the log-rank test 
of the equality of survival curves.  The log-rank statistic is tested 
at the two-sided alpha level of 0.05. 
Ancillary Biomarkers Study: 
Participants who consent to the POINT Trial will be asked to 
consent to an optional ancillary study consisting of a one-time 
venous blood sample of approximately 10mL collected at the 
time of enrollment in the trial. 
 
 
 


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1 
STUDY FLOWCHARTS 
 
1.1 
Graphical Study Design 
 
Group 
1
Group 
2
``
clopidogrel 600 mg
aspirin 50-325 mg
(aspirin dosage at discretion of 
study physician*)
clopidogrel 75 mg 
LOADING DOSE 
(LD)
LOADING DOSE 
(LD)
``
DAY 2 TO DAY 90
aspirin 50-325 mg
(aspirin dosage at discretion of 
study physician*)
DAY 2 TO DAY 
90
R
placebo
aspirin 50-325 mg
(aspirin dosage at discretion of 
study physician*)
aspirin 50-325 mg
(aspirin dosage at discretion of 
study physician*)
7 Day Phone 
Follow-Up      
(7 +/- 2 Days)
 30 Day Phone 
Follow-Up        
(30 +/- 2 Days)
 90 Day In-Person 
or Phone Follow-
Up (90 +/- 14 Days)
placebo
*150-200 mg/day for first 5 days followed by 
75-100 mg/day for remainder of participation in 
study strongly recommended
 


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1.2 
Schedule of Activities and Assessments 
Contact Schedule and Measurements 
 Measurements 
Screening 
Baseline/ 
Randomization 
Phone 
F/U Day 7 
+/-2 
Phone 
F/U Day 
30ʘ 
Phone or In-
Person F/U 
Day 90 +/-
14† 
Event 
Visit*** 
 
End of 
Study 
Screen Failure Log 
x 
 
 
 
 
 
 
Eligibility Form 
 
x 
 
 
 
 
 
Consent (including optional study) 
 
x 
 
 
 
 
 
Randomization Form 
 
x 
 
 
 
 
 
Enrollment/ Demographics  
 
x 
 
 
 
 
 
ABCD2 Score  
 
x 
 
 
 
 
 
Modified Rankin Scale (mRS) 
 
 
 
 
x 
x 
 
NIH Stroke Scale  
 
x 
 
 
x 
x 
x 
Medical History  
 
x 
 
 
 
 
 
Prior Medications  
 
x 
 
 
 
 
 
Index TIA/Minor Stroke Symptoms 
x 
Vital Signs  
 
x 
 
 
 
 
 
Blood Sample (optional) 
 
x*² 
 
 
 
 
 
Head CT/MRI Scan  
 
x* 
 
 
x* 
x* 
 
ECG  
 
x* 
 
 
x* 
x* 
 
Carotid  Imaging  
 
x*1 
 
 
x*1 
x* 
 
Stroke-Free Questionnaire: QVSFS  
 
 
x 
(x) 
x 
x 
 
Morisky Questionnaire  
 
 
x 
(x) 
x 
x 
 
Concomitant Medications Form  
 
 
x 
 
x 
x 
 
SAE/Clinical Outcome  Reporting  
 
 
x 
 
x 
x 
 
Study Drug Compliance  
 
 
 
(x) 
 
 
x 
Final Diagnosis 
 
x 
 
 
 
 
 
End of Study Form  
 
 
 
 
 
 
x 
Protocol Violation 
x 
x 
x 
 
x 
x 
x 


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*Part of standard evaluation; cost not covered by study. 
** As needed (visit can occur more than once). 
*** Event Visits for MI can be completed by telephone. 
† Preferably as soon as possible after the completion of 90 days. 
1 Encouraged as part of best practices but not required for study entry or at 90 days.  If performed, 
record results on CRF. 
² Blood sample obtained with subject’s consent for optional ancillary study 
 ʘ No study data collected. 
Note: Certain follow-up assessments, such as the mRS and QVSFS, by telemedicine are acceptable. 
 
2 
BACKGROUND AND SIGNIFICANCE 
A transient ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal 
brain, spinal cord, or retinal ischemia, without acute infarction. Restricted diffusion on an MRI at the 
appropriate site to explain the transient dysfunction indicated acute infarction and qualifies the 
transient event as an ischemic stroke. An ischemic stroke is a cerebral infarction. In POINT, eligibility is 
limited to brain TIAs and to minor ischemic strokes (with a National Institutes of Health Stroke Scale 
[NIHSS] score <3). 
TIAs are common, with an estimated 250,000-350,000 occurring each year in the US, an incidence 
about 30-40% that of stroke.   Rapid recovery of cerebral ischemia is a defining characteristic of TIA 
and distinguishes it from completed stroke.  This recovery defines a distinct pathophysiologic feature 
that generally indicates the presence of previously ischemic tissue still at risk:  a characteristic that may 
be responsible for greater instability. The same is true for patients with minor ischemic strokes. The 
distinction between minor ischemic stroke and TIA is unimportant in terms of prognosis.  Both groups 
are at high short-term risk for new ischemic stroke. The newly proposed definition of TIA already 
complicates the distinction between TIA and stroke, and the trial will ultimately promote a more 
unified view of these syndromes.   In fact, numerous studies have shown that short-term risk of stroke 
is high after TIA and minor ischemic stroke, particularly in the first few days, even in patients treated 
with aspirin, the current standard of care.  Antithrombotic therapy may play a distinct role in this acute 
pathophysiology.  Effective therapies in those with TIA could significantly reduce the overall burden of 
stroke if initiated immediately.  However, no large-scale trial has evaluated an acute intervention in 
these patients. 
Platelet aggregation is an important contributing factor in cerebral ischemia, as in other forms of 
ischemia.  Antiplatelet agents reduce the risk of ischemic stroke in a variety of settings with distinct 
pathophysiologies (e.g., atrial fibrillation, small-vessel stroke, and large-vessel atherothrombosis).  
Aspirin given to patients with a history of stroke or TIA reduces subsequent risk of stroke.  
Furthermore, aspirin initiated as an acute intervention after stroke reduces risk of death and recurrent 
stroke.  Trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination 
reduces risk of stroke but increases risk of major hemorrhage.  However, the risk of thrombosis is 
extremely high in the acute period after TIA and risk of hemorrhage is expected to be lower than after 
a completed stroke, so the combination may be particularly effective and relatively safe in this setting.  
Even more compelling, clopidogrel combined with aspirin reduced the 90-day risk of stroke by 36% 


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compared to aspirin alone in a pilot trial of 392 patients treated acutely after minor stroke or TIA, and 
it was well tolerated.  Clopidogrel also has advantages in being oral, without major side effects other 
than hemorrhage, and it will be inexpensive by trial completion.  Nonetheless, antiplatelet therapy has 
never been tested in a pivotal trial as an acute intervention after TIA, a setting with distinct 
pathophysiology that may favor the use of this class of agents.  
TIA is a unique,  important type of cerebral ischemia characterized by substantial instability, in which 
acute treatment is potentially highly consequential and has never been properly studied. Currently, 
the treatment choice ranges from immediate hospitalization and initiation of intravenous antiplatelet 
agents or heparin to outpatient evaluation and treatment with aspirin.   
2.1 
TIA Incidence 
TIAs are common, 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.       
2.2 
Short-term Prognosis 
TIAs are ominous, carrying a substantial short-term risk of stroke, hospitalization for cardiovascular 
events, and death.  Numerous studies have also shown that the short-term risk of stroke is particularly 
high, with most studies finding risks as high as 27% within 90 days after a TIA.  These studies have 
recently been summarized in three systematic reviews, which have confirmed the extremely high rates 
and have noted that studies with cases identified in the emergency department and with systematic 
follow-up have demonstrated particularly high rates [2, 34, 35]. 
Risk is particularly high in the first few days after TIA, with the majority of studies finding that one-
quarter to one-half of the strokes that occur within 3 months of the onset of the TIA occur within the 
first 2 days [16, 30, 36-40].  Studies in Northern California and Oxfordshire found the risk of stroke in 
the first 24 hours after TIA to be 4%,[16, 41] about twice the risk of myocardial infarction or death in 
patients presenting with acute coronary syndromes (about 2% at 24 hours) [42]. See Table 2.1.This risk 
of stroke was over 50 times that expected in a cohort of similar age [3, 11], and the risk of cardiac 
events was 7 times greater [12].  The vast majority of strokes were fatal or disabling, requiring 
prolonged hospitalization.  Most TIA patients were treated with aspirin (68%), and 92% were treated 
with an antiplatelet agent or anticoagulation.  Stroke risk remained elevated in those treated with 
aspirin (10%) or with anticoagulation (14%).  These findings underscore the need for prompt 
evaluation and treatment of patients with symptoms of ischemia, and show that current therapy is of 
limited benefit. 
 
 
 


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Table 2.1.  Short-term stroke risk after TIA and after stroke 
 
  
  
Publication 
Year 
N 
Delay 
(days) 
Stroke 
Risk 
Projected 90-
Day Stroke 
Risk* 
Rochester, Minnesota  [43] 
Population-based cohort study 
1973 
198 
0 
10%/3 m 
10% 
London, UK  [44] 
Cohort study 
1981 
117 
0 
29%/ 6 m 
27% 
Iowa City, Iowa  [45]
Cohort study
1985
74
1 
6.8%/6 d
13%
Iowa City, Iowa  [46] 
Pilot trial (placebo group) 
1989 
55 
2 
9.1%/6 d 
16% 
Oxfordshire, UK  [41, 47] 
Population-based cohort study 
1990 
209 
0 
12%/1 m 
15% 
Northern California [16] 
Cohort study 
2000 
1707 
0 
10.6%/3 m 
11% 
Oxfordshire, UK [48] 
Population-based cohort study 
2004 
87 
0 
17.3/3 m 
17% 
NASCET [38] 
Randomized trial (med therapy) 
2004 
603 
0 
20.1%/3 m 
20% 
Nueces County, Texas [37] 
Population-based study 
2004 
612 
0 
4.03%/3 m 
4% 
Alberta, Canada [39] 
Population-based cohort study 
2004 
2285 
1 
9.5%/3 m 
10% 
Ontario, Canada [36] 
Cohort study 
2004 
265 
0 
6%/3 m 
6% 
Southwest Germany[49] 
Population-based cohort study 
2004 
1150 
0 
13%/6 m 
11% 
Cincinnati, OH [30] 
Population-based cohort study 
2005 
927 
0 
14.6%/3m 
15% 
Scotland, UK [50] 
Cohort study 
2005 
205 
0 
7%/1m 
11% 
Northern Portugal [51] 
Population-based cohort study 
2006 
141 
0 
12.8%/7d 
17% 
Athens, Greece [52] 
Cohort study 
2006 
226 
0 
9.7%/1 m 
13% 
Barcelona, Spain [53] 
Cohort study 
2007 
345 
0 
4.9%/7 d 
9% 
Northern California [17] 
Cohort study (ED) 
2007 
1069 
0 
10%/3 m 
10% 
Northern California [17] 
Cohort study (clinic) 
2007 
962 
2 
6%/3 m 
10% 
Oxfordshire [17] 
Population-based cohort study 
2007 
545 
0 
9%/ 3 m 
9% 
Oxfordshire [17] 
Cohort study (clinic) 
2007 
315 
0 
7%/ 3m 
7% 
AVERAGE 
  
 
  
 
  
11% 
 
Recent results from the OXVASC cohort study and from the FASTER pilot trial suggest that minor 
ischemic stroke carries a similar high risk of subsequent stroke as TIA.  In fact, event rates were higher 
for patients with minor ischemic stroke enrolled in the FASTER trial. 
Risk of cardiac events is also elevated after TIA. In one large study, 2.6% were hospitalized for major 
cardiovascular events (myocardial infarction, unstable angina, or ventricular arrhythmia) within 90 


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days.[71] Over the course of 5 or more years nearly equal numbers of patients with TIA will have 
myocardial infarction or sudden cardiac death as will have a cerebral infarction.[72] 
2.3 
Underlying Pathophysiology of TIA and Minor Ischemic Stroke 
The extent of early improvement after presentation with acute cerebral ischemia may be associated 
with risk of subsequent stroke because rapid recovery may indicate a distinct, unstable 
pathophysiology in some instances [73-78]. Rapid recovery is an indicator of return of normal function 
in a previously ischemic territory, often due to return in blood flow.  The previously ischemic tissue 
remains at risk.  When in-situ thrombosis at a ruptured atherosclerotic plaque is responsible for the 
initial ischemic event, a rapid recovery may signify resolution of the thrombosis.  However, the plaque 
may remain highly thrombogenic, thereby elevating the risk of a subsequent ischemic event.  
Contrarily, if the ruptured plaque leads to a completed stroke in the distal vascular territory, additional 
thrombosis will generally be asymptomatic; the situation is more stable and risk of new stroke is lower.  
Thus, an elevated risk of deterioration would be anticipated after rapid recovery, suggesting reversal 
of ischemia, compared to after an ischemic event with no rapid recovery.      
The pathophysiology of TIAs and those with rapid but incomplete improvement in ischemia (as 
characterizes the majority of those with minor ischemic stroke arriving acutely) is analogous to that of 
acute coronary syndromes (i.e., unstable angina and non-Q-wave myocardial infarction) in which 
thrombosis and thrombolysis are acutely active and protracted [79]. Similarly, cerebral ischemia that 
acutely recovers may be a marker for ongoing thrombosis-thrombolysis, whereas major ischemia that 
persists may be a result of a largely completed thrombosis that is not amenable to acute antiplatelet 
therapy [66, 77, 78, 80].  Aggressive, early antiplatelet therapy with combinations of agents is highly 
effective in acute coronary syndromes [81-84], and it is hypothesized that the same will be true for the 
major events of TIA studied here. 
2.4 
Potential Therapies 
There are few established, effective therapies for stroke prevention after TIA or minor ischemic stroke.  
Other than aspirin, the only approved therapy for acute cerebral ischemia, intravenous tPA, is explicitly 
contraindicated in patients with TIA and is generally considered inappropriate in those with minor 
ischemic stroke [80].  Physicians, fully aware of the impotence of current therapy, are frustrated by 
their inability to improve outcomes after TIA.  This has contributed to substantial practice variability in 
TIA management [85].  Clearly, an effective secondary prevention strategy after TIA is required.  It is 
hypothesized that very early treatment with clopidogrel in conjunction with aspirin treatment will 
substantially reduce the risk of recurrent ischemia.   
Platelet activation and aggregation are important processes in most ischemic strokes, regardless of 
underlying etiology.  Platelet thrombi contribute to small vessel strokes, large vessel thombosis and 
embolism, and cardiac embolism [86, 87].  Inhibiting platelets reduces risk of ischemic stroke from all 
these major etiologies [88, 89] and also reduces risk of ischemic cardiac complications in those at high 
risk [88].  In all these settings, the benefits of oral antiplatelet agents, including aspirin and clopidogrel, 
have exceeded an increase in risk of major hemorrhage.  Thus, antiplatelet agents appear to have wide 
effectiveness in those at high risk of cerebral and cardiovascular ischemia.  
The benefits of platelet inhibition may be greatest in the acute period.  Platelets are activated 
dramatically and transiently in patients with acute cerebral ischemia, both from TIA and from ischemic 


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stroke [90, 91], coincident with a period of greater risk for recurrence and progressive thrombosis [92, 
93].  Antiplatelet therapy with clopidogrel added to aspirin in patients with acute cerebral ischemia 
blunts platelet activation compared to aspirin alone [94], reduces micro-embolic signals [95], and 
tends to reduce clinical ischemic events during the days after a stroke or TIA. New data from the 
FASTER pilot trial [8] supports the safety and potential efficacy of clopidogrel-aspirin in reducing stroke 
risk in the short-term after TIA or minor stroke (Section 2.3.3). 
Usman et al. report metanalyses of 13 studies comparing mean bleeding frequencies for aspirin (≤325 
mg/day), clopidogrel, anticoagulants (warfarin and other vitamin K antagonists), aspirin plus 
clopidogrel, and aspirin plus extended-release dipyridamole (ER-DP). Total bleeding occurred at mean 
rates of 4.8% with aspirin (≤325 mg/day) alone, 2.9% with clopidogrel alone, 3.6% with aspirin plus ER-
DP, 10.1% with aspirin plus clopidogrel, and 16.8% with anticoagulation. Major bleeding occurred at 
mean rates of 1% with aspirin (≤325 mg/day) alone, 0.85% with clopidogrel, 0.93% with aspirin plus 
ER-DP, 1.7% with aspirin plus clopidogrel, and 2.5% with anticoagulation. In conclusion, the 
combination of aspirin and clopidogrel is associated with significantly greater bleeding than either 
aspirin (≤325 mg/day) or clopidogrel alone. Aspirin plus ER-DP has a greater bleeding rate than 
clopidogrel but a lower rate than aspirin (≤325 mg/day) alone. [186] 
2.4.1 
Aspirin 
Aspirin has been a mainstay for long-term prevention of vascular events after stroke, and reduces the 
incidence of stroke, myocardial infarction, and vascular death by 22% [96].  Aspirin appears to be 
effective in reducing risk of small vessel strokes, large vessel atherothrombosis, and in atrial fibrillation 
[88]. 
In patients presenting acutely with stroke, aspirin also improves outcomes, but the effect is modest 
and is reduced by a small increased risk of intracerebral hemorrhage.  The CAST and IST studies, each 
enrolling about 20,000, found that acute treatment with aspirin after ischemic stroke reduced the risk 
of recurrent ischemic stroke by 30% (an absolute change of 0.7%) with a small increase in intracranial 
hemorrhage (25% relative and 0.2% absolute increase) over 2-4 weeks of treatment [64, 65, 89].  The 
overall benefit of acute treatment with aspirin was present in those with and without atrial fibrillation 
and with and without a lacunar syndrome [89].  Thus, aspirin has become the standard of care in the 
acute treatment of patients with stroke.  The optimum dose of aspirin continues to be vigorously 
argued, but is probably in the range of 50-325 mg/day [97].  Aspirin is also considered standard 
therapy in TIA, with clopidogrel and aspirin-dipyridamole acceptable alternatives, but none has been 
tested as acute therapy in this setting [97-99]. In planning a prior trial in acute TIA, international 
experts agreed that aspirin should be given to all patients but they could not agree on a specific dose 
within the range of 50-325 mg/day recommended in published consensus guidelines.  However, given 
recent American College of Cardiology guidelines and potential safety issues with clopidogrel use, it is 
reasonable to strongly recommend lower doses of aspirin.  An initial dose of 150-200 mg/day for 5 
days (per the CAST trial) followed by 75-100 mg/day will be strongly recommended. 
2.4.2 
Clopidogrel 
Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation by blocking the P2Y12 ADP 
receptor [100, 101], a mechanism independent of the thromboxane-mediated pathway inhibited by 
aspirin.  In the CAPRIE trial, clopidogrel 75 mg/day reduced long-term risk of stroke, myocardial 
infarction, or vascular death by 8.7% relative to aspirin in patients with vascular disease, without 


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increasing risk of hemorrhage or other major side effects [102].  The trial was not designed to evaluate 
clopidogrel as an acute therapy, and no trial has evaluated the efficacy of clopidogrel after TIA. 
Clopidogrel may be useful as an acute intervention after vascular events.  With a loading dose of 600 
mg, clopidogrel produces platelet inhibition faster than 300 mg, with greater inhibition at 3 and 4 
hours after administration and 600 mg is more likely to be effective in those with clopidogrel 
resistance [103, 104].  It has been shown to be safe in multiple trials of acute coronary syndrome 
(ACS), with no increase in bleeding events compared to lower loading doses even when used in 
combination with other potent antithrombotics, and it has become the de facto standard for 
comparison with new antiplatelet agents [105-108]. 
  
In January 2009, the FDA released a report from MedWatch, the FDA Safety Information and Adverse 
Event Reporting Program regarding clopidogrel (Plavix®), notifying healthcare professionals that “the 
makers of Plavix have agreed to work with the FDA to conduct studies to obtain additional information 
that will allow a better understanding and characterization of the effects of genetic factors and all 
other drugs (especially the proton pump inhibitors (PPIs)) on the effectiveness of clopidogrel. FDA is 
aware of published reports that clopidogrel (marketed as Plavix®) is less effective in some patients 
than it is in others. Differences in effectiveness may be due to genetic differences in the way the body 
metabolizes clopidogrel or that using certain other drugs with clopidogrel can interfere with how the 
body metabolizes clopidogrel.” In March 2010, a black box warning was added to the label for 
clopidogrel: “Reduced effectiveness in patients who are poor metabolizers of the drug – that some 
patients do not convert Plavix to its active form as well as other patients. These patients may not get 
the same benefit from Plavix and are known as poor metabolizers.” 
Some writers have advocated genotyping patients prior to initiating clopidogrel therapy to determine 
if they carry a reduced-function gene variant (primarily the CYP2C19*2 polymorphism) because these 
carriers appear to have an excess risk of cardiovascular events and mortality on clopidogrel. Studies do 
not address cerebrovascular disease. This issue remains controversial and caused the American College 
of Cardiology Foundation/American Heart Association on June 28, 2010 to issue a Clopidogrel Clinical 
Alert: Approaches to the FDA “Boxed Warning” stating, “Overall, however, the evidence is insufficient 
to recommend routine genetic or platelet-function testing at the present.” [183] Also, in an important 
study regarding this matter, it was concluded that CYP2C19 loss-of-function variants do not modify the 
efficacy and safety of clopidogrel [184]. 
2.4.3 
Combination Clopidogrel-Aspirin 
Clopidogrel has been studied in combination with aspirin in several trials of vascular disease, including 
two that included patients with stroke or TIA [115,116].  Although results from these trials have not 
supported long-term use of clopidogrel after stroke/TIA, the drug has never been tested as an acute 
therapy in this population and the trials support that it may be more beneficial and particularly safe 
after TIA.  It is also a logical agent to test because it is cheap (soon to go off patent), has well 
established, favorable pharmacodynamics and safety profile, and is delivered conveniently in the 
outpatient setting. 
Aspirin and clopidogrel synergistically antagonize platelet aggregation [102, 109-111], and combined, 
may provide added benefit in stroke prevention.  Aspirin and clopidogrel are used together after 
coronary, carotid, and intracranial stenting, and appear to be well tolerated [112, 113].  Evidence 
supporting clopidogrel also comes from cardiac trials, non-acute stroke/TIA trials, and most 
importantly, from an acute pilot trial of TIA and minor stroke, as reviewed below. 


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Cardiac Trials:  The CURE trial of patients with acute coronary syndromes, also taking aspirin, found 
that clopidogrel 75 mg/day after a loading dose of 300 mg reduced the risk of stroke, myocardial 
infarction, and vascular death by 20% at 3-12 month follow-up, and the effect was apparent in the first 
10 days [81].  Myocardial infarction and vascular death accounted for the vast majority of events in 
this trial.  There was a small increase in risk of major hemorrhage but no difference in life-threatening 
hemorrhage.  In the CREDO study, clopidogrel also reduced the 1-year risk of cardiovascular events by 
27% among those treated with aspirin undergoing percutaneous coronary intervention [114].  An early 
benefit was seen only in those who received a loading dose of clopidogrel 6 hours before the 
procedure, reinforcing the importance of an initial loading dose when ischemic events may occur 
within hours.  There was a 1% absolute increase in risk of major bleeding at 28 days, but most of this 
was associated with procedures such as bypass surgery.  Thus, clopidogrel reduces ischemic events in 
patients treated acutely after coronary ischemia or prior to percutaneous coronary intervention. 
Non-Acute Stroke/TIA Trials:  The MATCH (Management of atherothrombosis with clopidogrel in high-
risk patients with recent TIA or ischemic stroke) trial was a secondary stroke prevention trial that 
enrolled 7599 patients, mostly in Europe [115].  This study compared aspirin plus clopidogrel to 
clopidogrel.  The majority of patients (79%) enrolled suffered a prior stroke, rather than TIA.  The 
overall trial was negative, with a small insignificant 1% absolute benefit in terms of reduced risk of 
ischemic events balanced by a 1% but significant absolute increased risk of major hemorrhage.  In 
subgroup analysis, however, there was a trend toward greater benefit in those treated sooner after 
the qualifying stroke or TIA, with a 17% RRR in those treated within 7 days.  The CHARISMA trial 
randomized patients with vascular disease, who are treated with aspirin 75-162 mg/day, to clopidogrel 
75 mg or placebo [116].  Similar to MATCH, the trial was negative with a small reduction in ischemic 
events balanced with a small significant increase in severe hemorrhages. However, also similar to 
MATCH, there was greater benefit in patients treated sooner after a clinical qualifying event (including 
stroke and TIA).  In unpublished analysis of the 4320 patients enrolled in CHARISMA after TIA or stroke, 
a study involving Drs. Johnston and Easton (reviewed here to maintain continuity), the RRR of stroke 
with clopidogrel was 26% in those randomized within 30 days of the event and 17% in those 
randomized later, again suggesting that patients treated early are more likely to benefit. There was no 
increased risk of hemorrhage in those treated within 30 days or later among those randomized after 
stroke or TIA.  In the PRoFESS trial, patients were initially randomized to clopidogrel combined with 
aspirin in one arm of the trial but this was changed to clopidogrel alone 8 months into the study after 
publication of the MATCH trial results and events on this combination have not been reported [24]. 
Pilot Acute TIA/Stroke Trials:  FASTER was a pilot trial based in Canada and run by collaborators who 
participated in the design of this trial [8].  It evaluated clopidogrel (300 mg load and 75 mg/day 
afterwards) and simvastatin in a factorial design on a background of aspirin in patients presenting 
within 24 hours of a TIA or minor stroke. The main principle motivating the trial was the recognition of 
the high frequency of poor outcomes in patients presenting with acute cerebral ischemia who are not 
candidates for thrombolysis.  The trial enrolled 392 patients from 18 centers over 30 months (0.73 
patients/site/month, with slow recruitment attributed to the requirement to randomize to no statins).  
The risk of stroke (ischemic or hemorrhagic) at 90 days was 11% in those treated with aspirin alone 
and 7% in those treated with clopidogrel and aspirin, a non-significant 36% RRR in this pilot trial 
(p=0.19). There were two intracranial hemorrhages, both in patients treated with clopidogrel-aspirin; 
one occurred in a patient with minor stroke and uncontrolled blood pressure and the other occurred in 
a patient with TIA but details are uncertain.  These hemorrhages were included in the primary 
outcome and did not overwhelm the benefit. The trial serves as an excellent pilot for the proposed 


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trial, reconfirming a high risk of stroke in patients with TIA and minor stroke and suggesting that a 
large effect size is possible.   
Another pilot double-blind, placebo-controlled trial, CARESS, evaluated the impact of clopidogrel-
aspirin vs. aspirin alone on presence of TCD micro-embolic signals in 107 patients with recently 
symptomatic carotid stenosis [95].  At 7 days, 44% on the combination and 73% on aspirin alone had 
persistent micro-embolic signals (p=0.005), suggestive of a reduction in ongoing thrombo-embolism.  
There were more strokes and TIAs in the aspirin-only group (11 vs. 4) but the difference was not 
significant.        
Clopidogrel/Aspirin: Conclusions:  The FASTER pilot trial provides strong support for POINT, but other 
negative trials of clopidogrel-aspirin also support testing it in the acute setting, where relative risk 
reductions have been consistently high in a number of trials from a variety of clinical settings (Figure 
2.1).  Taken together, they suggest that the combination of clopidogrel-aspirin may be particularly 
effective early after acute ischemia, when the risk of recurrent ischemia is particularly high and 
platelet aggregation likely to be highly relevant.  Of course, the risk of hemorrhagic conversion is also 
high in patients with acute infarction.  However, patients with TIA have minimal or no infarction, so 
their risk of hemorrhage may be more similar to those with cardiac disease than to those with 
completed strokes that are disabling enough to meet entry criteria in prior trials [117].  In fact, the risk 
of brain hemorrhage is lower after less debilitating stroke [118, 119].  For example, in the TOAST study, 
risk of serious brain bleeding with danaparoid was 14% in those with an NIH Stroke Scale score >15 
and only 0.5% in those with less severe stroke [118].   
 
 
 
In the FASTER trial, intracranial and serious extracranial hemorrhages were rare, were concentrated in 
the group presenting with stroke rather than TIA, and did not overwhelm a benefit in reduced ischemic 
events.  Though there was an excess of mild and moderate extracranial and asymptomatic hemorrhage 
with clopidogrel in FASTER, these events were all transient while strokes produced permanent injury 
that was disabling in 35% [J. Kennedy, personal communication], which is lower than the disability rate 
published in prior cohort studies (e.g., 85% of strokes in our study were disabling with 21% fatal [16]).  
Thus, hemorrhage risk with the combination of aspirin and clopidogrel should be relatively low after 
TIA and less consequential than the expected avoidance of ischemic events.   


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In a meta-analysis of results from FASTER, CHARISMA, CARESS, and MATCH for patients enrolled within 
24 hours of onset of TIA or stroke, there was a RRR of 34% with clopidogrel-aspirin vs. aspirin alone for 
the composite outcome measure of stroke, TIA, acute coronary syndrome, and all-cause death [8], 
providing further evidence that the impact of clopidogrel-aspirin may be substantial in the acute 
period. 
CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) was a 
randomized, double-blind, placebo-controlled trial conducted at 114 centers in China. 5170 patients 
were randomly assigned within 24 hours after the onset of minor ischemic stroke or high-risk TIA to 
clopidogrel plus aspirin vs. aspirin alone for 21 days, followed by clopidogrel vs. aspirin for the 
subsequent 69 days. 
The primary outcome, ischemic or hemorrhagic stroke (ischemic or hemorrhagic) occurred in 8.2% in 
the clopidogrel-aspirin arm, and 11.7% in the aspirin arm, a  significant hazards reduction, with no 
increase in major hemorrhage.[185] The result supports that more intense antiplatelet therapy is 
beneficial and superior to aspirin alone in this patient population. Whether this is generalizable to non-
Chinese populations is unknown.  
The POINT DSMB reviewed the accrued data in POINT, the CHANCE results and the opinion of a 
Bioethics Committee engaged by the National Institute of Neurological Disorders and Stroke (NINDS) 
to assess the ethics of continuing POINT in light of the CHANCE results. Following that review, the 
DSMB approved a modification to the informed consent to address the CHANCE results, and 
recommended POINT proceed as planned. 
2.4.4 
Dipyridamole 
Two trials have demonstrated the efficacy of dipyridamole in preventing stroke recurrence:  ESPRIT 
[120] and ESPS-II [121].  Both tested dipyridamole combined with aspirin and found it superior to 
aspirin alone.  Neither trial evaluated the acute period after a stroke or TIA (median time to enrollment 
was >1 month), so safety and efficacy during this time period is unknown.   
The PROFESS trial randomized patients with ischemic stroke to clopidogrel or aspirin/extended-release 
dipyridamole [24].  Enrollment occurred up to 90 days after the most recent ischemic event, with 40% 
enrolled within 10 days.  Recurrent stroke occurred in 9.0% of patients treated with dipyridamole-
aspirin and in 8.8% of patients treated with clopidogrel during a mean 2.5-year follow-up.  Major 
hemorrhage and intracranial hemorrhage were more common in the group receiving dipyridamole-
aspirin.  Given these findings, and a greater risk of early headache with dipyridamole, many 
practitioners have limited its use.  Guidelines do not reflect PRoFESS findings at this point [98, 99].   
2.5 
Advantages of a TIA Acute Treatment Trial 
Secondary prevention of stroke after TIA is an excellent model for testing a new antiplatelet drug in 
combination with aspirin, and may be a great model for testing other interventions aimed at 
preventing acute ischemia.   
2.6 
Preliminary Studies 
During the past 12 years, a large number of studies that serve as background for this trial have been 
performed.  Many were designed to address issues raised in proposing this trial.  These include studies 


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assessing the prevalence and community knowledge of TIA [127], establishing the high risk of stroke 
and cardiovascular events after TIA [16, 17, 71], identifying risk factors for stroke and other adverse 
events [16, 17, 71, 128, 129], defining the importance of early neurological recovery in identifying 
instability, evaluating current patterns of antithrombotic prescription and other aspects of care after 
TIA [85, 130-132], identifying predictors of site recruitment in randomized stroke/TIA trials [133], 
confirming ability to recruit to an acute TIA trial, creating metrics to evaluate the potential impact of 
clinical trials so that the planned trial can be evaluated in this light [123].  Numerous reviews and 
editorials have also been written clarifying the urgency of treatment for TIA and the inadequacy of 
current therapies [98, 134-139].  Due to space constraints, published preliminary work is only reviewed 
very selectively and briefly. 
A series of studies have documented that the risk of stroke is very high in the days to months after a 
TIA.  These results have been confirmed in multiple studies from other institutions, as reviewed in 
Table 2.1.  The first of these studies on this topic was the Emergency Department TIA Study, a cohort 
study of 1707 patients diagnosed with TIA by emergency physicians at one of 16 hospitals in the 
Kaiser-Permanente Northern California (KPNC) medical care plan 1997-1998 [16].  Over 90% of 
patients arrived within 12 hours of symptom onset and 92% received an antithrombotic medication at 
emergency-department discharge.  A total of 180 strokes occurred within 90 days of the index TIA, 
with an overall 90-day stroke risk of 10.5% (95% CI 9.1% - 12.0%).  Hospitalization for myocardial 
infarction occurred in 1.4% (n=24) during the first 90 days.  The 90-day risk of vascular death was 2.3% 
(n=40), with most deaths attributable to stroke.  For the composite outcome of stroke, myocardial 
infarction, and vascular death, the 90-day risk was 13.0% (n=221).  One third of events occurred in the 
first 24 hours, 50% occurred within the first 5 days, and 73% within the first month.   
To validate findings from the pilot study of TIA evaluated in the emergency department, a cohort study 
of all 976 patients in KPNC who were given a diagnosis of TIA in urgent care clinics 1997-1998 was 
performed [17].  The median delay between symptom onset and first evaluation was 24 hours and 161 
(17%) were considered unlikely to represent TIA on neurologist review.  Even so, the 90-day stroke risk 
in this cohort was 6.2%, and 1.9% were hospitalized with a cardiovascular event.  Overall, the risk of 
stroke, cardiovascular event, or vascular death was 7.9%.  Among the 560 judged to have true TIA first 
seen within 24 hours of onset, the 90-day risk was 8.4% for stroke and 10.0% for the composite 
outcome, very similar to results from the emergency-department cohort.   
There has been concern that the diagnosis of TIA is variable and unreliable.  It was found that over 90% 
of patients with TIA diagnosed by emergency physicians had the diagnosis confirmed when a 
neurologist reviewed it.  More importantly, the high risks of stroke have been documented in cases 
identified by non-neurologists so the true incidence of stroke in a population with confirmed TIA is 
higher.  Some symptom complexes are associated with particularly low risk of stroke, and this may 
help to identify a population with true TIA and more likely to benefit from aggressive treatment. 
2.6.1 
Predictors of Stroke Risk after TIA 
There are several clinical and imaging factors that are associated with risk of stroke after TIA.  The 
most extensively validated factors are the clinical elements that have come to constitute the ABCD2 
score.  Five simple independent risk factors for stroke within the 90 days after a TIA were identified in 
the original cohort study [16]: age ≥ 60 years, diabetes, duration ≥ 10 minutes, speech impairment, 
and weakness.  These risk factors were confirmed in two independent cohorts from California [17], 
four cohorts from Oxford [17], and in another cohort in Greece [140].  In a meta-analysis combining 
two cohorts from California and Oxford and validating a new model in four remaining cohorts from the 


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two regions, the ABCD2 score was created [17].  It includes all the elements of the original score and 
adds a couple of additional modifications.  The score is created by summing points for each of several 
independent risk factors:  age ≥ 60 years (1), blood pressure ≥ 140/90 mmHg (1), clinical symptoms of 
unilateral weakness (2) or speech impairment without weakness (1), duration 10-59 minutes (1) or ≥ 
60 minutes (2), and diabetes (1).  Stroke risk was strongly associated with total score, with 90-day 
stroke risks ranging from 20% with a score of 6-7 to < 1% with a score of 0-1.   
The ABCD and ABCD2 scores have now been independently validated by other groups, as well [18, 140-
142].  Having such a score available and well validated will allow selection of the subgroup at highest 
risk of stroke, which increases power and focuses the trial on those most likely to benefit, in whom a 
potentially elevated risk of hemorrhage is easily justified.  Selecting those with ABCD2 scores ≥ 4 
increases the expected event rate from 12.1% to 15.3% at 90 days while excluding only 30% of 
otherwise eligible cases, in whom the risk of outcome events is only 4.3%. 
Patients with isolated numbness, visual changes, or dizziness/vertigo, who constituted 16% of those 
diagnosed with TIA, were at low risk of stroke [129].  In the combined emergency department cohorts, 
the 90-day risk of stroke was 2% in the 451 patients with these isolated symptoms.  This group of 
patients was also less likely to have a final diagnosis of TIA after expert review (p<0.005).  A lower risk 
of stroke has been confirmed by other groups in patients with isolated dizziness [143], isolated visual 
symptoms [144], and isolated numbness [Rothwell P, personal communication].  
2.6.2 
Importance of Recovery:  Risk of Stroke after Recovery in NINDS tPA, TOAST Trials 
Data from four randomized trials—the NINDS tPA trial [80], TOAST [66], GAIN [78], and ASTIN [77]—
was obtained to determine whether acute recovery was associated with a high risk of subsequent 
neurological deterioration due to causes other than intracranial hemorrhage.  Results of these four 
analyses were all very similar.  In brief, patients with greater initial recovery after presenting with 
cerebral ischemia were at greater risk of subsequent neurological deterioration attributable to 
ischemia.  For patients with complete recovery at 24 hours, constituting a TIA subgroup, the risk was 
particularly high; for example, in the NINDS tPA study those with complete resolution at 24 hours had 
a 30% risk of subsequent deterioration compared to a 10% risk for those with no or less initial recovery 
(p=0.001).  Risk was intermediate for those with partial initial recovery compared to no recovery.  This 
provides additional confirmation of the hypothesis that TIA (with complete recovery) and lesser 
degrees of acute ischemic recovery represent a distinct pathophysiological characteristic associated 
with greater instability and risk of deterioration attributable to new ischemia.     
2.6.3  
Current Utilization of Antithrombotics after TIA 
Background usage of antithrombotic medications after TIA may impact event rates and could inform 
appropriate selection of comparators.  To estimate background utilization, usage of antithrombotic 
medications after TIA in three populations was evaluated:  KPNC, the Coverdell Registry for California 
(CASPR, Johnston PI), and the Ethos Registry.  In the KPNC ED cohort, the vast majority of patients 
(92%) were treated with an antithrombotic medication, most commonly aspirin (68%).  The 90-day risk 
of the composite outcome was not significantly lower in those taking aspirin compared to others (12% 
vs. 15%, p=0.11).  (Similarly, there was no difference in stroke risk between those taking a cholesterol-
lowering agent (n=152) compared to others (13% vs. 13%, p=0.94), as was also seen in the FASTER pilot 
trial [8]). 


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Among 174 patients with acute TIA in the 11 hospitals of the California Coverdell Registry [130], 153 
(88%) were treated with an antithrombotic agent, of which 37% were treated with aspirin alone, 9% 
treated with clopidogrel alone, and 14% with clopidogrel combined with aspirin.  Among 5090 with TIA 
in the 71 hospitals in the Ethos Registry 2001-2006, which is a nationwide quality improvement stroke 
and TIA registry [131], 4767 (94%) were discharged on an antithrombotic agent, of which 31% were 
treated with aspirin alone, 12% with clopidogrel, and 23% with clopidogrel combined with aspirin 
[132].  Combination clopidogrel-aspirin use decreased after publication of the MATCH trial, but 
remained at 17% in 2005.  Data are not yet available about use of dipyridamole after the PRoFESS trial 
results were reported in May 2008, but use was expected to decrease. 
Sites were polled as to current practices in patients with TIA.  Of 75 sites contacted, 57 provided 
complete responses to the survey.  For patients with acute TIA, sites reported acute use of clopidogrel 
in combination with aspirin (among patients without stents) always (7 sites, 12%), often (3 sites, 5%), 
sometimes (15 sites, 26%), rarely (19 sites, 33%), and never (14 sites, 25%).  Sites estimated that 50% 
of subjects are taking an antiplatelet agent at the time of the TIA but only 7% said they would be 
uncomfortable randomizing such patients into the POINT trial (with the risk of receiving aspirin alone). 
Thus, antithrombotic medications are commonly prescribed after TIA and current estimates of event 
rates are already impacted by this frequent use.  Aspirin is most frequently prescribed but clopidogrel 
combined with aspirin is used frequently.  Described rates of stroke after TIA incorporate baseline 
single-agent and dual-agent usage, and aspirin is an appropriate background therapy based on current 
patterns of usage (as well as on data from trials). 
3 
STUDY OBJECTIVES 
 
 
 
 
 
 
The Primary Specific Aim of this randomized, double-blind, multicenter clinical trial is to determine 
whether clopidogrel 75 mg/day by mouth after a loading dose of 600 mg is effective in improving 
survival free from ischemic vascular events (ischemic stroke, myocardial infarction, and ischemic 
vascular death) at 90 days when subjects are randomized within 12 hours of time last known free of 
new ischemic symptoms in patients receiving aspirin 50-325 mg/day. 
3.1 
Secondary 
Several secondary analyses will be performed, including as treated analysis and evaluations of the 
impact of therapy on risk of the composite of major ischemic vascular events or major hemorrhage 
(primary outcome plus major hemorrhage), and on risk of major systemic or intracranial hemorrhage 
separately.  Additional tertiary/exploratory analyses will include evaluation of the impact of therapy 
on:  1) ischemic stroke, 2) hemorrhagic stroke, 3) all-cause death, and 4) new handicap/disability.  The 
impact of therapy on the composite outcome will also be evaluated in specific subject groups (e.g., 
African Americans, those previously taking aspirin, those with index TIA vs. minor ischemic stroke).  
4 
STUDY DESIGN AND MANAGEMENT OVERVIEW 
4.1 
Study Design Overview 
The primary null hypothesis of this randomized, double-blind multicenter clinical trial is, 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) 


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compared to placebo when subjects are randomized within 12 hours of time last known free of new 
ischemic symptoms.  The primary outcome event is defined as a composite outcome—ischemic stroke, 
myocardial infarction, or ischemic vascular death. 
Patients with high-risk TIA (defined as an ABCD2 score ≥ 4) or minor ischemic stroke (defined as an 
NIHSS ≤ 3), who can be randomized within 12 hours of time last known free from new ischemic 
symptoms will be enrolled.  Subjects will be randomized to receive a clopidogrel 600 mg loading dose 
then 75 mg/day for the duration of the study, or to receive matching placebo.  All subjects will receive 
aspirin 50-325 mg/day with the dose determined by the treating physician; an aspirin dose of 150-200 
mg daily x 5 days, followed by 75-100 mg daily will be strongly recommended. Concomitant use of 
dipyridamole will be prohibited.  Subjects will be followed for 90 days and risks of the composite 
outcome—ischemic stroke, myocardial infarction, and ischemic vascular death—will be compared in 
the treatment groups.  The trial will be completed in 7 years, with 5,840 subjects recruited from 350 
centers in partnership with the NINDS Neurological Emergencies Treatment Trials (NETT) Network and 
the POINT Clinical Research Collaboration (CRC).  Recruitment will occur over 90 months, with a goal 
rate of 0.40 subjects per site per month for U.S. sites, and 0.47 subjects per site per month for sites 
outside the U.S., which is based on prior studies of recruitment, on the recruitment rate in the pilot 
FASTER trial, and on the expectations and past achievements of identified centers.  From the 
perspective of the sites, the trial will be simple.  A total of 530 primary outcome events is anticipated. 
To increase efficiency, the duration of follow-up will be brief so that event rates are high throughout 
the period of study.  A composite outcome measure has been chosen to fully reflect the potential 
benefits of treatment and to reduce the necessary sample size. In a secondary analysis, the composite 
outcome will be combined with major hemorrhage to capture anticipated life-changing risks and 
benefits in a single measure.    
4.2 
Study Milestones 
A 7 year budget and recruitment plan have been created; key study milestones below. 
 
 
 
 
STUDY MILESTONES 
Pre-enrollment Study Initiation   
 9 months 
Recruitment and Follow-up 
             90 months 
Completion of Follow-up 
 
 3 months 
Data Analysis and Publication 
 
 6 months 
Total Duration  
 
            108 months 
4.3 
Organizational Structure and Communication Flow 
The trial management is a partnership of the UCSF Clinical Coordinating Center (UCSF CCC) based in 
the Stroke Sciences Group (SSG), the NINDS NETT Network, which will be responsible for data 
management and oversight of NETT sites, and the POINT CRC, which will manage the non-NETT sites, 
including the sites outside the United States.  Details of the trial leadership, management, and 
communications are provided in the Manual of Procedures. 
The UCSF SSG involves 30 faculty and staff with expertise in study design, epidemiology, biostatistics, 
nursing, and study coordination.  It has coordinated multicenter observational studies and clinical trials 
for the last decade.   


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As a trial of a neurological emergency, POINT is well suited for involvement of the NETT.  Most subjects 
will likely be identified in the emergency department.  The NETT includes 17 “Hub” institutions, each 
with approximately three “Spoke” hospitals that work together to recruit patients into simple trials of 
acute neurological diseases.   
POINT is well suited for CRC physicians due to its simple design and compelling question that should 
attract a wide breadth of neurologists treating acute stroke in the community.  The CRC has over 1,100 
physicians registered from 47 states.  Use of central basic research training and a central Institutional 
Review Board (IRB) facilitates research participation of physicians who practice in a community 
setting.  The CRC has experience activating sites over a short period of time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Point Trial Organization 
Data
Site Management
POINT CRC Site Manager
 
Advisory Committee
 
 
Executive Committee 
 
POINT Trial Principal Investigators
Clay Johnston, MD, PhD: Principal Investigator
Don Easton, MD: co-Principal Investigator
 
NINDS
 
 
Data Safety and 
Monitoring Board
 
Clinical and Logistical Aspects
Mary Farrant, MBA, RN
UCSF CCC Project Director
UCSF Clinical Coordinating Center (CCC)
Clay Johnston, MD, PhD
Director
POINT CRC
Anne Lindblad, PhD
Director
POINT CRC Centers
US and International Sites
 
Data Management
Catherine Dillon
 
Statistics (Blinded)
Yuko Palesch, PhD 
Statistics 
(Unblinded)
 Jordan Elm, PhD
NETT Statistics and Data Management Center (SDMC)
Yuko Palesch, PhD
Director
NINDS NETT
Bill Barsan, MD
Director
Enrollment
Outcomes
QA
Adjudication Packets
NETT-CCC Centers
US Hubs and Spokes
Clinical and 
Logistical
Questions
Enrollment
Outcomes
QA
Adjudication Packets
Data
Site Management
NETT-CCC Site Manager
POINT Trial Organization
 


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4.3.1 
Trial Organization 
The trial will be directed by the Principal Investigator, who will have ultimate responsibility for all 
activities and products of the trial, and will oversee all functions. The Co-Principal Investigator will 
assist with trial oversight and will substitute for the PI as necessary.  The trial will take advantage of 
the proven skills of three major entities:  the UCSF CCC, the NINDS NETT Network, and the POINT CRC.  
The NINDS NETT, through its Statistical and Data Management Center (SDMC), will provide statistical 
support and data management services, including reports to the DSMB and Clinician Event 
Coordinator, and shielding the UCSF CCC, NETT-CCC and POINT CRC from access to unblinded data 
during the performance of the trial.  The Director of the NETT SDMC will be responsible for the 
randomization protocol, final statistical analysis plan and final data analysis.   
The Operations Committee (OC), chaired by the Principal Investigator, will oversee the entire 
performance of the trial.  The OC will meet every week, with members outside San Francisco joining by 
teleconference.  Membership of the OC is provided in the Manual of Procedures.   
Sanofi has agreed to contribute clopidogrel and its placebo at no cost and with no restrictions through 
May 2016. From May 2016 forward, additional supplies of study drug will be provided by Sharp Clinical 
Services, Inc. 
4.4 
Site Training, Certification, and Update 
Both the NETT and the CRC have already provided training to their sites in Good Clinical Practice 
Guidelines and in some outcome assessments (e.g., NIHSS, modified Rankin Scale).  Online modules for 
training new sites are also available. 
Prior to initiation of subject enrollment, Site Investigators and Coordinators will complete online 
training programs and their certifications.  In these training modules, the subject selection criteria and 
follow-up procedures will be reviewed.  Case studies illustrating potential problems in adhering to 
study protocol and blinding will be discussed.   
All investigators must complete the following training modules, and receive certification: 
• 
Study procedures 
• 
Primer on the diagnosis of TIA and its mimics   
• 
Use of the ABCD2 score 
• 
POINT eligibility 
• 
Modified Rankin Scale 
• 
NIHSS   
Successful completion of the training program and confirmation of approval from the local Institutional 
Review Board for human research will be required before a site is certified to enroll subjects.  Web-
based meetings, with the PI and key staff available to address questions, will occur intermittently.  
Certification of competence will be obtainable on the Web. 
A detailed Manual of Procedures will serve as the primary document describing all study related 
procedures.  It will serve as a guide for training of clinical site personnel and will be updated 
periodically throughout the study, as needed. A system will be implemented for the clinical sites to call 


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or e-mail any procedural questions regarding the study.  The UCSF CCC will formulate answers in 
consultation with the Operations Committee, and will periodically distribute to the participating 
centers a set of frequently asked questions (FAQ) and answers.  These questions and answers will also 
be available on the POINT Resources and Training page under FAQs and can be searched by topic.  
Intermittently, the answers to questions will be incorporated into Manual of Procedures revisions.  
The NETT will manage and conduct site visits for its sites and the CRC will manage and conduct site 
visits for the non-NETT sites.  Each site will be visited at least once during the trial, and as needed if 
questions about data quality or problems with recruitment arise, or there is a concern about 
noncompliance requiring specific or systemic corrective actions. 
4.5 
Contact Schedule and Measurements 
Subject encounters will include screening, randomization, telephone follow-up, and a final telephone 
or in-person visit.  In addition, event visits are to occur whenever subject contact suggests that 
possible stroke, TIA or MI may have occurred.  Stroke and TIA events can be evaluated via 
telemedicine when necessary.  Event visits for MI may be conducted over the telephone. Event visits 
are conducted as needed and can be done more than once for the same subject.  Measurements to be 
taken at these encounters are listed in Section 1.2, Schedule of Activities and Assessments.  Details of 
the visits are provided in the Study Procedures section (Section 9). 
Refer to the Manual of Procedures and Data Collection Guidelines for more specific details on 
how/when to submit Case Report Forms for events. 
4.6 
Outcomes 
The primary outcome of the trial is a composite outcome:  ischemic stroke, myocardial infarction, and 
ischemic vascular death.  The primary safety outcome is major hemorrhage.  Additional efficacy and 
safety outcomes also will be assessed.  All components of the primary and safety outcomes will be 
adjudicated. 
4.6.1 
Definitions of Clinical Outcomes/Serious Adverse Events 
Ischemic stroke:  An acute focal infarction of the brain or retina (and does not include anterior 
ischemic optic neuropathy (AION)).   
Criteria:   
1) Rapid onset of a new focal neurological deficit with clinical or imaging evidence of infarction 
and not attributable to a non-ischemic etiology (not associated with brain infection, trauma, 
tumor, seizure, severe metabolic disease, or degenerative neurological disease); or 
2) Rapid worsening of an existing focal neurological deficit that is judged by the Investigator to be 
attributable to a new infarction. Criteria for symptoms attributable to new infarction may 
include symptoms that persist and are judged by the investigator to be attributable to new 
infarction, imaging evidence of infarction, or no evidence of a non-ischemic etiology. 
TIA:  A neurological deficit of sudden onset, resolving completely, attributed to focal brain or retinal 
ischemia without evidence of associated acute focal infarction of the brain.   


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Criteria:  Rapid onset of a focal neurological deficit that is without evidence of acute focal infarction of 
the brain, and is not attributable to a non-ischemic etiology (brain infection, trauma, tumor, seizure, 
severe metabolic disease, or degenerative neurological disease). 
Symptomatic hemorrhagic transformation of an ischemic stroke: Any extravascular blood within an 
area of known acute/subacute infarction which is judged to be nontraumatic, and responsible for 
neurologic symptoms. To be considered symptomatic, the hemorrhagic transformation must be judged 
to be partially responsible for the subject’s clinical neurologic presentation (i.e., the area of infarction 
is not adequate to explain the neurologic deficit, or a secondary neurologic deterioration occurred 
corresponding to the timing of hemorrhagic transformation.)  
Criteria (must meet both of the following): 
1) Imaging evidence (by CT or MR) of extravascular blood within the area of infarction. 
2) Symptoms judged to be related to the hemorrhagic transformation. Scenarios which may be 
judged as symptomatic: (i), If blood is already present on imaging at presentation, symptoms 
are out of proportion to what would be expected for the size and location of the infarct at 
presentation; (ii) Clinical deterioration, defined by an increase of 4 points or more in the score 
on the NIHSS or leading to death, occurring after the initial ischemic event, and identified as 
the result of the hemorrhagic transformation; or (iii) Mass effect secondary to the 
hemorrhagic transformation causing symptoms. 
Asymptomatic hemorrhagic transformation of an ischemic stroke: Any extravascular blood within an 
area of known acute/subacute infarct, judged to be nontraumatic, without any related neurologic 
symptoms. 
Criteria (must meet both of the following) 
1) Imaging evidence (by CT or MR) of extravascular blood within the area of infarct. 
2) No symptoms related to the hemorrhagic transformation. 
Symptomatic intracerebral hemorrhage: Any extravascular blood in the brain parenchyma, judged to 
be nontraumatic, and not in the area of an acute/subacute ischemic infarct, associated with and 
identified as the predominant cause of new neurologic symptoms (including headache) or death. In the 
case of a mixed intracranial hemorrhage (Intracerebral Hemorrhage (ICH), Subarachnoid Hemorrhage 
(SAH), Subdural Hemorrhage (SDH) and/or Intraventricular Hemorrhage (IVH), the event should be 
classified according to the primary site of hemorrhage by the judgment of the clinician. For example, if 
a subject has a large ICH with a small amount of SAH, and the ICH is felt to be the primary site of 
bleeding, this should be classified as ICH. 
Criteria: Evidence of hemorrhage in the brain parenchyma demonstrated by head imaging, surgery, or 
autopsy, which is not in the same territory of an underlying acute or subacute ischemic stroke, and is 
judged to be associated with any new neurologic symptoms (including headache) or leading to death. 
Asymptomatic intracerebral hemorrhage: An acute extravasation of blood into the brain parenchyma, 
judged to be nontraumatic, and not in an area of an acute/subacute ischemic infarct, without 
associated neurologic symptoms or leading to death. In the case of a mixed intracranial hemorrhage 
(ICH, SAH, SDH and/or IVH), the event should be classified according to the primary site of hemorrhage 
by the judgment of the clinician. 
For example, if a subject has a large ICH with a small amount of SAH, and the ICH is felt to be the 
primary site of bleeding, this should be classified as ICH.  


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Criteria: Evidence of hemorrhage in the brain parenchyma demonstrated by head imaging, surgery or 
autopsy, which is not in the same territory of an underlying acute or subacute ischemic stroke, and is 
not judged to be associated with any new neurologic symptoms or leading to death. 
Other symptomatic intracranial hemorrhage: Any extravascular blood within the cranium judged to 
be nontraumatic, and the predominant cause of the clinical deterioration or that led to death. Other 
Intracranial Hemorrhage is defined as an acute extravasation of blood into the subarachnoid space, 
epidural space, subdural space or intraventricular space with associated symptoms (including 
headache). In the case of a mixed intracranial hemorrhage (ICH, SAH, SDH and/or IVH), the event 
should be classified according to the primary site of hemorrhage by the judgment of the clinician. 
For example, if a subject has a large ICH with a small amount of SAH, and the ICH is felt to be the 
primary site of bleeding, this should be classified as ICH. 
Criteria: Evidence of hemorrhage in the subarachnoid space, epidural space, or subdural space 
demonstrated by head imaging, surgery, or autopsy. 
Other asymptomatic intracranial hemorrhage: An acute extravasation of blood into the subarachnoid 
space, epidural space, subdural space or intraventricular space without associated symptoms, and 
judged to be nontraumatic. In the case of a mixed intracranial hemorrhage (ICH, SAH, SDH and/or IVH), 
the event should be classified according to the primary site of hemorrhage by the judgment of the 
clinician.  For example, if a subject has a large ICH with a small amount of SAH, and the ICH is felt to be 
the primary site of bleeding, this should be classified as ICH. 
Criteria: Evidence of hemorrhage in the subarachnoid space, epidural space, or subdural space 
demonstrated by head imaging, surgery, or autopsy. 
Myocardial infarction with coronary revascularization: Evidence of myocardial necrosis in a clinical 
setting consistent with myocardial ischemia, treated with coronary revascularization, such as 
angioplasty/stenting or coronary artery bypass graft (CABG), within 14 days.   
Criteria:  The diagnosis of MI will be based on an algorithm developed from the Universal Definition of 
Myocardial Infarction (Circulation 2007 116:2634-2653) that takes into account 5 categories of clinical 
information from the acute event: rise and/or fall of cardiac biomarkers, ECG abnormalities, clinical 
setting, imaging evidence, and pathology.   
Myocardial infarction without coronary revascularization: Evidence of myocardial necrosis in a clinical 
setting consistent with myocardial ischemia, not treated with coronary revascularization within 14 
days. 
Criteria:  The diagnosis of MI will be based on an algorithm developed from the Universal Definition of 
Myocardial Infarction (Circulation 2007 116:2634-2653) that takes into account 5 categories of clinical 
information from the acute event: rise and/or fall of cardiac biomarkers, ECG abnormalities, clinical 
setting, imaging evidence, and pathology.   
Coronary revascularization without myocardial infarction:  A procedure to improve coronary blood 
flow for documented coronary artery disease, but with no documentation of new post-randomization 
myocardial infarction.   
Criteria:  Documented coronary angioplasty, stenting, or bypass surgery for demonstrated or 
presumed coronary artery disease.  
Major hemorrhage other than intracranial hemorrhage (life-threatening or non-life-threatening):  A 
hemorrhagic event, judged to be nontraumatic, that results in intraocular bleeding causing loss of 


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vision, the need for a transfusion of two or more units of red cells or the equivalent amount of whole 
blood, or the need for hospitalization or prolongation of existing hospitalization [24]. This may include 
bleeding events related to surgical procedures but not those related to accidental trauma. Life-
threatening hemorrhagic events will be defined as those that are fatal or require use of intravenous 
inotropic medication to maintain blood pressure, interventional treatment (including surgical, 
endoscopic or endovascular interventions), or transfusion of four or more units of red cells or the 
equivalent amount of whole blood.  Non-life-threatening hemorrhagic events will be defined as those 
classified as major hemorrhagic events but not as life-threatening.   
Minor hemorrhage other than intracranial hemorrhage:  All hemorrhagic events leading to 
interruption or discontinuation of the study drug but not classifiable as major hemorrhagic events [24].  
This may include bleeding events related to surgical procedures but not those related to accidental 
trauma. 
Ischemic vascular death:  Death due to ischemic stroke, myocardial infarction, sudden cardiac death, 
arrhythmia, pulmonary embolism, bowel or limb infarction, or any death not readily attributable to a 
non-ischemic cause. 
Hemorrhagic Vascular death:  Death due to intracranial or systemic hemorrhage. 
Other Serious Adverse Event: Any adverse event, not belonging to the other outcome event 
categories, that is fatal or life threatening, is permanently or substantially disabling, requires or 
prolongs hospitalization, results in a congenital anomaly, or requires intervention to prevent 
permanent impairment or damage. 
5 
PARTICIPANT SELECTION 
During the course of the trial, approximately 350 sites will enroll approximately 5,840 subjects with TIA 
or minor ischemic stroke.  Before enrolling subjects into the study, all collaborating sites will obtain 
approval from local IRBs or ethics committees, which will have access to all study documentation and 
educational materials. 
5.1 
Study Population 
The study will include both TIA and minor ischemic stroke, with the latter accounting for no more than 
50% of enrollment; if 2920 subjects with minor ischemic stroke are enrolled, only TIAs will be 
permitted in the trial subsequently.  Most enrolled subjects will be elderly (mean age 72 years with 
78% older than 60 years in the Northern California study), with about an equal number of males and 
females (53% were female in the Northern California study).  Neurological impairment at the time of 
enrollment is expected to be minimal since the deficits prompting diagnosis will have largely resolved.  
Vascular risk factors, including diabetes, hypertension, and coronary artery disease, are expected to be 
common [16]. 
Pregnant women will be excluded from the study because the safety of clopidogrel is  not established 
in this population, and this drug may increase risk of harm to the fetus.  Women at risk for pregnancy 
(see Exclusion Criteria) will also be excluded.  No other vulnerable population will be excluded from 
the study.   
 
 


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5.2 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
• 
Neurologic deficit (based on history or  exam) attributed to focal brain ischemia and 
EITHER: 
o High risk TIA: Complete resolution of the deficit at the time of  randomization 
AND ABCD2 score >4 
OR 
o Minor ischemic stroke:  residual deficit with NIHSS <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 dose 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 the 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 non-traumatic 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: 
o Known allergy 


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o Severe renal (serum creatinine >2 mg/dL or 176.8umol/L) or hepatic 
insufficiency (prior or concurrent diagnosis, with INR>1.5, or any resultant 
complication, such as variceal bleeding, encephalopathy, or icterus) 
o Hemostatic disorder or systemic bleeding in the past 3 months 
o Current thrombocytopenia (platelet count <100 x109/l) or 
neutropenia/granulocytopenia (<1 x109/l) 
o History of drug-induced hematologic or hepatic abnormalities 
• 
Anticipated requirement for long-term (>7 days) nonstudy antiplatelet drugs (eg, 
dipyridamole, clopidogrel, ticlopidine), or NSAIDs affecting platelet function (such as 
prior vascular stent or arthritis).  
• 
Not willing or able to discontinue prohibited concomitant medications. 
• 
Inability to swallow medications. 
• 
At risk for pregnancy:  premenopausal or postmenopausal 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. 
6 
TREATMENTS 
 
6.1 
Study Drugs 
This randomized double-blind study is primarily designed to compare a clopidogrel/aspirin 
combination versus an aspirin alone regimen. The two types of study tablets (75 mg active clopidogrel 
and placebo) are indistinguishable, identical in size, shape, color, appearance, and taste. 
Minor side effects are unusual with the medication [102], so it is not anticipated that either subjects or 
clinicians will be able to differentiate the placebo from the active drug. Standard laboratory tests 
cannot detect the effects of clopidogrel. 
Investigators will not have access to the randomization (treatment) code, except in exceptional 
circumstances, such as occurrence of a serious adverse event for which knowledge of the study 
medication would be considered essential for treating the subject. 
Sanofi supplied the blinded study drugs, clopidogrel 75mg and matching placebo, distributed by the 
UCSF Drug Product Service Laboratory (DPSL) for US sites and Pharmacy Services partners for OUS sites 


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in quantities sufficient to last through May 2016. From June 2016 forward, additional supplies of 
blinded study drug (clopidogrel and matched placebo) after that date will be provided by Sharp Clinical 
Services, Inc. in quantities sufficient to last through the end of enrollment. 
Aspirin tablets will be open label with the dose in a range 50-325 mg daily determined by the treating 
physician.  A dose of 150-200 mg daily x 5 days, followed by 75-100 mg daily will be strongly 
recommended. 
The clopidogrel/aspirin group will receive the following treatment: 
• 
Day 1*: 8  tablets of clopidogrel 75 mg  (loading dose of 600 mg) 
• 
From D2 to D90:  one tablet of clopidogrel 75 mg and 50-325 mg of aspirin per day  
The placebo/aspirin group will receive the following treatment: 
• 
Day 1*: 8  tablets of placebo 75 mg  (loading dose of 600 mg) 
• 
From D2 to D90:  one tablet of placebo 75 mg and 50-325 mg of aspirin per day  
*Subjects will receive open label aspirin (50 mg – 325 mg), with dose at the discretion of the   
treating physician. 
6.2 
Assignment to a Treatment Group 
The randomization will take place centrally via the WebDCU™. Subjects will be randomized 1:1 
(clopidogrel: placebo), stratified by clinical center. The computer program developed at the NETT-
SDMC makes the treatment assignment based on the current status of treatment group distribution 
within each clinical center as well as overall balance of treatment assignment.  
7 
STUDY DRUG HANDLING
7.1 
Supply and Storage 
The manufacturer Sanofi supplied the blinded study drugs (clopidogrel 75mg tablets, and placebo to 
match clopidogrel tablets) used in POINT and distributed by the UCSF Drug Product Services 
Laboratory (DPSL) to sites in the United States, and by Pharmacy Services partners to sites outside the 
US in quantities sufficient through May 2016. Additional supplies of study drug after that date will be 
provided by Sharp Clinical Services, Inc. in quantities sufficient to last through the end of enrollment. 
There will be at least four drug shipments for the study: Sanofi will initially ship clopidogrel and 
placebo to the UCSF DPSL in April 2010 with a second shipment in 2012 and a third shipment will be 
sent in the second quarter of 2014. The fourth shipment will be handled by Sharp Clinical Services in 
May 2016. A fifth shipment may be necessary, and will depend on the expiration dates and the rate of 
enrollment into the study. After May 2016, supplies of study drug will be shipped directly from Sharp 
Clinical Services or the Pharmacy Services partner or depot to the research pharmacist/drug recipient 
at the POINT Clinical Site. Final verification of all study drugs will be completed by the research 
pharmacist or designee to ensure that the site maintains correct inventory. 


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Aspirin tablets will be open label with the dose in a range of 50-325 mg daily determined by the 
treating physician. A dose of 150-200  mg daily x5 days, followed by 75-100 mg daily will be strongly 
recommended.  
All investigational drug supplies in the study will be stored in a secure, safe place, under the 
responsibility of the Investigator or other authorized individual, and under the conditions described on 
the labeling. 
Study drug will be stored at a controlled room temperature of 25⁰ C (77⁰ F); excursions permitted to 
15⁰- 30⁰ C (59⁰ - 86⁰ F) Note: This temperature guideline should be followed; it differs from the USP 
guideline for controlled room temperature. 
Storage temperature should be monitored and recorded daily, preferably by a continuous automated 
measuring and recording device. A daily manual temperature log must be maintained if automated 
temperature surveillance is not possible. 
Systems must be in place for identifying and alerting staff when proper temperature storage 
conditions have been compromised (e.g., thermometer with alarm functions). 
If storage conditions have been compromised (e.g., temperature exceeds allowable range) or if there is 
any suspicion that study product(s) have not been stored properly, the following actions must be 
taken: 
• 
Quarantine study products suspected of improper storage 
• 
Maintain products under correct storage conditions until further notice 
• 
Contact the UCSF-CCC and, if necessary, Sanofi (through May 2016) and Sharp Clinical 
Services thereafter 
• 
Document the occurrence, including amount of storage/temperature violation and 
amount of storage violation time 
• 
Determine whether drug will need to be replaced and take steps to dispose of study 
drug and secure replacement drug 
Procedures outlining roles and responsibilities should be in place at the local Pharmacy to ensure that 
storage issues have been addressed and rectified in an efficient manner. Sites will receive a template 
Local Site Pharmacy Standard Operating Procedures (SOP). This template SOP provides a customizable 
written format for documenting such procedures and responsibilities. 
7.2 
Packaging  
Each subject will be assigned 97 tablets of study drug (eight (8) tablets for loading dose, and an 89-day 
supply for one tablet daily) according to the randomization assignment, to be used as directed. 
The labels for shipments one to three, with computer-generated randomization codes that are to be 
used for the study drug bottles, will be produced centrally via the NETT SDMC, since the information 
on the labels is linked to the trial’s randomization scheme. The labels have been designed in 
compliance with CA Code 4076 requirements for prescription container labeling and international 
guidelines. The labels for shipments four and five will be produced by Sharp Clinical Services and 
affixed to the bottles of study drug by Sharp. 


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7.3 
Responsibilities 
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense study drug 
will be responsible for ensuring that the study drug used in the clinical trial is securely maintained and 
in accordance with the applicable regulatory requirements. 
All study drug shall be dispensed in accordance with the Investigator's prescription, and it is the 
Investigator's responsibility to ensure that an accurate record of study drug issued and returned is 
maintained.  Any remaining drug will be destroyed by the site after a subject has completed 
participation.   
Any quality issue noticed with the receipt or use of a study drug (deficient in condition, appearance, 
pertaining documentation, labeling, expiry date, etc.) should be promptly reported. Drug 
Accountability logs will be maintained within the WebDCUTM study database.  
7.4 
Concurrent Treatment 
 
7.4.1 
Prohibited Concomitant Treatments 
Use of the following medications after randomization and during the study period represents a 
protocol violation. However, if there is a clinical need that justifies the added risk of these 
interventions in the setting of study drug use, they should be employed at the discretion of the 
treating physician. 
• 
NSAIDs, Cox1 inhibitors. If absolutely necessary, NSAIDs may be given for as short a time as 
possible but not sooner than 8 days after randomization 
• 
Anticoagulants (both oral and parenteral, see listing on CRF 18) 
• 
Open-label thienopyridines (e.g., ticlopidine, clopidogrel) 
• 
Dipyridamole 
• 
Other antiplatelets 
• 
Thrombolytics (e.g., tPA) 
• 
Vascular intervention (surgery and / or angioplasty of any vessel). 
If intervention is absolutely necessary within the three months after randomization, study drug will be 
stopped 5 days prior to the intervention. Study treatment will then be restarted unless the subject 
needs to take open label clopidogrel or aspirin. In this case, study drug will be restarted only when 
treatment with open label antiplatelet therapy other than aspirin has been stopped. 
7.4.2 
Permitted Concurrent Treatments 
Any drugs other than those listed above are permitted at the discretion of the Investigator. Given 
uncertainty about an interaction between omeprazole and other proton-pump inhibitors (PPIs) and 
clopidogrel, those previously taking a PPI will be evaluated for the appropriateness of other agents, 
such as H2 blockers.  New prescriptions for PPIs will be avoided whenever an H2 blocker or other agent 
is an acceptable option.  Similarly, other drugs that theoretically may affect clopidogrel metabolism 


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will be avoided, with others substituted.  This list includes:  esomeprazole (Nexium), cimetidine (which 
is available by prescription Tagamet and OTC as Tagamet HB), fluconazole (Diflucan), ketoconazole 
(Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, 
Serafem, Symbyax), and fluvoxamine (Luvox).   
7.5 
Treatment Discontinuation 
The study drug should be continued whenever possible. If temporary interruption of study medication 
is required for surgery or other therapy, the subject’s regimen will be resumed when it is considered 
safe by the subject’s neurologist or primary care physician.  Study medications will be restarted after 
carotid endarterectomy.  If a clear indication for anticoagulation is revealed during the 90-day study 
period (atrial fibrillation, for example), study medications will be stopped and anticoagulation will be 
initiated. 
If the study drug is stopped, it should be determined if the discontinuation can be made temporarily; 
permanent study drug discontinuation should be a last resort. Pregnancy will lead to definitive 
treatment discontinuation in all cases.  In any case, all randomized subjects should remain in the study 
and followed per the protocol to 90 days from randomization, or to death, whichever comes first, even 
if the subject discontinues the POINT study drug regimen, unless the subject withdraws consent to 
participate in the trial.  
7.5.1 
Permanent Treatment Discontinuation 
A subject should discontinue the study drug for any of the following reasons: 
• 
Intercurrent condition that requires discontinuation of the study (e.g. lab 
abnormalities, surgical procedure, serious bleeding) 
• 
Positive serum pregnancy test or desire to become pregnant 
• 
Clear indication for anticoagulation (e.g., atrial fibrillation) 
• 
Contraception cessation 
Subjects will be followed according to the study procedures as specified in this protocol up to the 
scheduled date of study completion.  All subjects who have discontinued the study drug will be 
followed per the protocol up to 150 days from randomization, or to death, whichever comes first, 
unless the subject withdraws consent to participate in the trial.   
For subjects considered lost to follow-up, CRFs must be completed up to the last visit performed. For 
subjects who do not complete any assessments for the 90 Day visit, the Investigator should make 
every effort to contact the subject and to identify the reason why he/she failed to attend the visit and 
to determine his/her health status at 90 days by telephone contact with the subject or the subject's 
alternative contacts. Complete guidelines can be found in the CRF Data Collection Guidelines. 
Subjects who have withdrawn consent from the study cannot be included again in the study. Their 
subject number and treatment must not be reused.  The investigator will indicate treatment 
discontinuation and/or the subject’s withdrawal in WebDCU™. Randomized subjects will not be 
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7.6 
Blinding System and Emergency Unblinding Procedure 
Medication bottles will be coded with unique randomization numbers.  The dataset linking the 
randomization number to the actual treatment (clopidogrel or placebo) will be generated and 
maintained at the NETT-SDMC.  The electronic file that contains partially unblinded treatment 
assignment (e.g., A=clopidogrel, B=placebo) will only be accessible to unblinded personnel when 
preparing unblinded (closed) reports for the DSMB.  
Unblinding is likely to be rare in the study. There are no data suggesting that taking clopidogrel is a 
contraindication to thrombolytic therapy.  A major hemorrhagic event may result in the 
discontinuation of study medications, but knowledge of treatment assignment is unlikely to change 
therapy for these subjects [154], and therefore, unblinding is likely to be unnecessary.  However, in 
case of an emergency need for unblinding of a particular subject, the clinical site PI or his/her designee 
can call the POINT emergency call number (1-866-94POINT or 415-663-4444), activate the pager 
system, and enter a call-back number. Within 20 minutes, the UCSF CCC On-call Physician will return 
the call. If it is determined that unblinding is necessary, the UCSF CCC On-call Physician will log onto 
the WebDCU™ study database and initiate the unblinding request with the subject’s ID number or 
randomization number. Once this is completed, the site PI or designee can log onto WebDCU and 
review the Randomization Form for the subject, which will have the treatment assignment displayed. 
The treatment assignment is revealed for 30 minutes only. After 30 minutes, the treatment assignment 
is concealed. 
After the unblinding, the Randomization CRF will have a message stating that the subject’s treatment 
assignment has been unblinded due to site request.  
Prior to the unblinding, the randomization form will have a message that states: “Subject has NOT 
been unblinded”.  This process will generate an automatic email notification of the unblinding to the 
POINT Executive Committee.  
8 
SAFETY 
 
8.1 
Protection/Minimization of Risk 
The greatest risk to subject health is the study medication, clopidogrel, when combined with aspirin.  
These agents have not been tested specifically after TIA and minor ischemic stroke, so rates of 
hemorrhage must be estimated from studies of stroke and acute coronary syndromes.  All subjects in 
the study will receive aspirin.  The benefits of aspirin outweigh its small excess risk of systemic and 
intracranial hemorrhage [64, 65]. 
Clopidogrel in combination with aspirin is likely to be associated with a small excess risk of major 
systemic hemorrhage (estimated at 1% for the study period) but no increased risk of life-threatening 
or intracranial hemorrhage [81, 116, 180].  The absolute increase in risk of life-threatening hemorrhage 
in the MATCH trial, which is most similar to POINT, was 1.3% (2.6% for the combination vs. 1.3% for 
clopidogrel alone), and this risk was spread out over 18 months follow-up.  Subjects are followed for 
90 days and only TIAs and minor ischemic strokes are included, so a 1% excess absolute risk is realistic, 
and is consistent with other trials.  The combination may increase the risk of complications with 
interventions, such as endarterectomy, or may delay the performance of these procedures due to 


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concerns about bleeding risk.  Clopidogrel is also associated with a very small risk of thrombotic 
thrombocytopenic purpura [181], probably less than 1 per 100,000. 
Loss of privacy due to additional contact from investigators not involved directly in the subject’s care is 
another potential risk.  There is also a small risk of loss of confidentiality. 
8.2 
Serious Adverse Events 
The greatest risk to subject health is hemorrhage due to the study drugs.  To reduce this risk, subjects 
will be monitored carefully during the study.  Medications will be stopped if bleeding or other major 
complications occur and before any elective procedure. To mitigate potential risk of dipyridamole, use 
of this drug will be prohibited. 
Unexpected SAEs will be reported to the DSMB in a timely fashion and on a schedule that is 
determined by the DSMB. 
8.2.1 
Management of SAEs/Clinical Outcomes 
WebDCU™ has an integrated web-based SAE/Clinical Outcome Reporting module that provides the 
mechanism by which serious adverse events or clinical outcomes are reported and reviewed.   SAEs/ 
clinical outcomes will then be made available to the appropriate Project Management staff and the 
designated blinded Clinician Event Coordinator (CEC) for review.  Reviews are performed on-line.  If 
additional documentation is required, this will be requested of the site by its overseeing organization 
(NETT or CRC) or the CEC.  Integration of the Clinician Event Coordinator functionality into the data 
entry system facilitates rapid review and reporting of events to the DSMB and regulatory bodies. The 
CRC Medical Monitor is notified when an event is determined to be a serious, unexpected, adverse 
reaction by the CEC.  The CRC Medical Monitor completes the Council for International Organizations 
of Medical Sciences (CIOMS) form and sends it to the country-level Regulatory Manager for sites 
outside the US.  The country level manager submits the form to the country level regulatory agency. 
8.3
Definitions
Adverse Event 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
experimental treatment regardless of whether it is considered related to the treatment (attribution of 
unrelated, unlikely, possible, probable, or definite). Each AE is a unique representation of a specific 
event used for medical documentation and scientific analysis.   
Non-serious AEs are not being collected in the POINT trial, unless they qualify as a Clinical Outcome 
as defined in section 4.6.1. 
Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that is fatal or life threatening, is permanently or 
substantially disabling, requires or prolongs hospitalization, results in a congenital anomaly or requires 
intervention to prevent permanent impairment or damage. 
Unexpected (Unanticipated) Adverse Event 


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An unexpected AE is defined as an event that was “not anticipated” as a risk in the IRB or EC-approved 
protocol, consent form, or package insert, or an event that occurs at a greater frequency or intensity 
than anticipated. 
Anticipated Adverse Event 
Anticipated adverse events in this trial will be those previously described in the package insert for 
clopidogrel and those anticipated based on the natural history of TIA and minor ischemic stroke. 
8.4 
Classification of Adverse Events 
Severity is used to describe the intensity of a specific event.  Severity of SAEs/clinical outcomes will be 
documented using the NCI Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE) (see 
Manual of Procedures).  The CTCAE provides descriptive terminology that will be used for recording 
and reporting SAEs/ clinical outcomes that occur in POINT.  The CTCAE provides a grading (severity) 
scale for each AE term and AEs are listed alphabetically within categories based on anatomy or 
pathophysiology.  The CTCAE (v 4.03) displays Grades 1-5 with unique clinical descriptions of severity 
for each AE based on this general guidance: 
Grade 1:   
Mild AE 
Grade 2: 
Moderate AE 
Grade 3: 
Severe AE 
Grade 4: 
Life-Threatening or Disabling AE 
Grade 5: 
Death related to AE 
Note:  Severity is not equivalent to seriousness.  A serious adverse event (SAE) would be any event in 
category 4 or 5, and any event in category 3 that required or prolonged hospitalization.  Not all grades 
are appropriate for all AEs.  Therefore, some AEs are listed with fewer than five options for Grade 
Selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not an option.    
See also http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
8.5
SAEs/Clinical Outcomes 
 
8.5.1 
SAEs/Clinical Outcomes into the Study Database 
All SAEs/Clinical Outcomes occurring until participation in study has ended are recorded on the online 
SAE/Clinical Outcome Reporting Form (CRF 19) through the WebDCU™. The Site PI or Study 
Coordinator is responsible for entering any and all SAEs into the database and updating the 
information (e.g., date of resolution, action taken), as needed, in a timely manner. Given the vast 
amount of data on AEs associated with clopidogrel, only SAEs/Clinical Outcomes will be recorded; data 
entry must take place within 5 days (within 24 hours for sites in the UK) of discovery of the event.   
The Hub PI for NETT sites and site PI for others are responsible for the monitoring and follow-up of all 
SAEs/Clinical Outcomes until resolution (or end of study for that subject) and appropriate 
documentation in the subject research record. In addition to performing protocol-specified follow-up, 


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the participating PI must review all previously reported ongoing SAEs/Clinical Outcomes to evaluate 
the current status.
Upon completion of the study by the subject, premature withdrawal from the study by the subject, or 
subject’s death, all information regarding each SAEs/Clinical Outcome must be completed, if not done 
so earlier. 
8.5.2 
Reporting Recurrent SAEs/Clinical Outcomes  
If a SAE/Clinical Outcome that was previously reported on the SAE/Clinical Outcome CRF fully resolves 
and then recurs at a later date, the second occurrence is considered a new SAE/Clinical Outcome and a 
new CRF must be completed.  Resolution is the normalization or return to baseline of laboratory 
values, clinical signs or symptoms related to the event. 
8.5.3 
Procedure for Expedited Reporting of SAEs/Clinical Outcomes 
Clinical outcomes may be discovered during the 7-day telephone follow-up, the 30-day phone contact, 
the 90-day follow-up appointment, or at any point during the study period. For subjects considered 
lost to follow-up, efforts should be made for up to 150 days from randomization to determine if an 
outcome event occurred during the subject’s 90 days in the study. When a clinical outcome is 
discovered, the Site PI is responsible for submitting it within 5 days (within 24 hours for sites in the 
UK) of the discovery of the event on the online SAE/Clinical Outcome case report form. 
The Hub PI (for NINDS NETT-CCC Network sites) or Site PI (for POINT Clinical Research Collaboration 
(CRC) sites) are responsible for the monitoring, follow-up and appropriate documentation of all clinical 
outcomes until resolution or the end of study for the subject. The Site/Hub PI will work with the 
appropriate Site Manager to prepare an Event Packet for outcome events, including copies of 
discharge summaries, neurology, cardiology or other consultation notes, head imaging reports, 
appropriate laboratory values, and a narrative summary, plus any supplemental documentation based 
upon adjudication category assigned to the event, with all unique identifiers removed. 
When the SAE/Clinical Outcome CRF is submitted for a fatal SAE or a clinical outcome, the appropriate 
Site Manager is then responsible for reviewing the information for completeness.  If the information is 
deemed insufficient, the Site Manager will request additional information from the site. 
The Site Manager will work with the Site/Hub PI to prepare an Event Packet, as described above. When 
the SAE/Clinical Outcome information is deemed sufficient by the Site Manager, the Clinician Event 
Coordinator (CEC) is charged with performing the Clinical Outcome Review (COR). The COR includes 
review of both Clinical Outcomes and SAEs. 
The CEC, who is blinded, will then review the SAE/Clinical Outcome CRF and the Event Packet 
independently. If clarifications or additional information are required, the CEC will request them from 
the Site Manager (from either the NETT-CCC or POINT CRC), who obtains the information. The CEC can 
also request the information directly from the site. When all information necessary for adjudicating a 
clinical outcome is available and the event requires adjudication (as defined in section 8.5.5) the event 
will be assigned to the appropriate Adjudicators, as described in section 8.5.5.  
A detailed description of the process for adjudication of clinical outcomes is found in the Manual of 
Procedures. 
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The CEC, who will remain blinded throughout the trial, accesses the SAE/Clinical Outcome data. The 
CEC blindly reviews the data independently, but may contact the Clinical Site investigators for 
clarifications and additional information. The CEC designates within 72 hours of notification of the 
SAE/Clinical Outcome occurrence whether the SAE/Clinical Outcome is unexpected and related to the 
study drug. 
The review process closes at the end of the 72 hours. The Clinical Site staff submits SAEs to their 
IRB/EC in accordance with the local guidelines and procedures.  
Timelines for completion of CIOMS Form by the CRC Medical Monitor: 
o 7-day reportable events- within 48 hours of receipt of the notification email (CEC 
assessment). 
o 15-day reportable events- within 7 days of receipt of the notification email (CEC 
assessment).  
Unexpected SAEs will be reported to the DSMB in a timely fashion and on a schedule that is 
determined by the DSMB. 
8.5.4 
Site Monitoring and SAE/Clinical Outcome Reporting 
During a site monitoring visit, the NETT or CRC Site Monitor will verify appropriate documentation and 
reporting of SAE/Clinical Outcomes. In addition, if the site monitor identifies an unreported 
SAE/Clinical Outcome, appropriate documentation and reporting will be initiated as guided by the site 
monitor. 
8.5.5 
Clinical Outcome Event Reporting 
All efficacy and safety clinical outcome events listed in section 4.6.1 will be reported using the identical 
mechanism as described in section 8.5.3 above.  In addition, Event Packets will be prepared by the site 
in conjunction with the NETT CCC or CRC Site Managers.  These will include copies of discharge 
summaries, neurology consultation notes, head imaging reports, and a narrative summary prepared by 
the site, all with unique identifiers removed.  Documents requiring translation will be checked for 
deletion of PHI by the country level manager, and a request for translation will be made to the CRC.  
The CRC will provide the translated documents back to the country level manager for upload.  In 
addition to CRF 19 and the other core documents, additional required documents are available on the 
POINT Clinical Outcome-Specific Checklists for Preparing Event Packets, and must be included as part of 
the Event Packet. The Event Packet will be accessible to the Clinician Event Coordinator (CEC), who will 
review them for completeness.  
Based on the CEC’s judgment, all events will be assigned to two independent Adjudicators:  
The following events will be assigned to two neurologist Adjudicators: ischemic stroke, intracerebral 
hemorrhage (symptomatic or asymptomatic), and other intracranial hemorrhage (symptomatic or 
asymptomatic).  
The following events will be assigned to two cardiologist/internist Adjudicators: myocardial infarction 
(with or without coronary revascularization) and coronary revascularization without myocardial 
infarction. 


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The following events will be assigned to one neurologist and one cardiologist/internist Adjudicator: 
major hemorrhage other than intracranial hemorrhage and other serious adverse events resulting in 
death. 
The assigned Adjudicators will review the reported event and the related Event Packet, and come to 
independent classifications of the event. If clarifications or additional information is/are required, the 
Adjudicators may contact the CEC, who will review requests and ask for additional information or 
clarification when necessary.  
If the Adjudicators disagree with each other on the event classification, a third Adjudicator will be 
assigned to adjudicate the outcome event. If the third Adjudicator’s classification of the event matches 
that of one of the two initial reviewers, this will be the final classification of the event.  
If the third Adjudicator disagrees with both of the original Adjudicators, then there will be a 
conference call to review the discrepant event classification with the Adjudication Committee Chair. 
The Chair will attempt to gain consensus; however, the decision of the Chair will be the final 
classification of the event.  
8.6 
Protocol Violations 
Protocol violations are any unapproved changes, deviations, or departures from the study design or 
procedures of a research project that are under the investigator’s control, have not been reviewed and 
approved by the local or central IRB/Ethics Committee/Committee on Human Research (CHR), and 
have already occurred without prospective review by the IRB/EC/CHR prior to initiation or 
implementation.  
Protocol violations are divided into two categories: major (reportable) or minor (non-reportable; also 
known as deviations) violations. 
Major (reportable) Protocol Violations 
Major protocol violations are any unapproved changes in the research study design and/or procedures 
that are within the investigator’s control and not in accordance with the IRB, EC, or CHR-approved 
protocol that may affect the participant's rights, safety or well-being, or the completeness, accuracy 
and reliability of the study data. All major violations must be reported to the IRB/EC/CHR following 
local guidelines. 
Criteria for defining major violations include any of the following: 
• 
The violation has harmed, or posed a significant or substantive risk of harm, to the research 
participant.  
• 
The violation resulted in a change to the participant’s clinical or emotional condition or status.  
• 
The violation has damaged the scientific completeness or soundness of the data collected for 
the study.  
• 
The violation is evidence of willful or knowing misconduct on the part of the investigator(s).  
• 
The violation involves serious or continuing noncompliance with federal, state or local 
regulations.  
Examples of major protocol violations include, but are not limited to: 
1) Enrollment of participants who did not meet all inclusion/exclusion criteria 


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2) Randomization errors 
3) Failure to obtain informed consent prior to initiation of any study-specific 
tests/procedures 
4)  Failure to follow protocol procedures that specifically relate to primary safety or 
efficacy endpoints of the study 
5)   Study medication dispensing or dosing error 
6)   Receipt of a prohibited concomitant medication 
7)   Incorrectly stored study medications 
Minor (non-reportable) Protocol Violations (also known as Protocol Deviations)  
Minor protocol violations are any unapproved changes in the research study design and/or procedures 
that are within the investigator’s control and not in accordance with the IRB/EC/CHR-approved 
protocol that do not have a major impact on either the participant’s rights, safety or well-being, or the 
completeness, accuracy and reliability of the study data. Minor protocol violations are not reportable 
to the CHR/HRPP, but should be documented in the study files.  
Criteria for minor violations include all of the following: 
• 
The violation did not harm or pose a significant risk of substantive harm to the research 
participant, and  
• 
The violation did not result in a change to the participant’s clinical or emotional condition or 
status, and  
• 
The violation did not damage the completeness, accuracy and reliability of the data collected 
for the study, and  
• 
The violation did not result from willful or knowing misconduct on the part of the 
investigator(s).  
Examples of minor protocol violations (deviations) include, but are not limited to: 
 
1) Data collection that occurs outside the planned time window or location 
2)  Failure to follow approved study procedure that, in the opinion of the PI, does not 
affect subject safety or data integrity 
3) Investigators miss giving a study-required self-administered questionnaire to a 
participant 
9 
STUDY PROCEDURES 
Any patient with a TIA or minor ischemic stroke meeting the inclusion criteria and not having an 
exclusion is a potential candidate for the study. The patient will receive complete information about 
the study, orally and in writing.  
9.1 
Screening Evaluation  
Potential subjects will be identified by neurologists, local emergency departments, and clinic staff in 
conjunction with study personnel.  When a potential candidate is identified, the site PI and/or the 


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Study Coordinator should be contacted to begin the screening process. Patients should be screened 
and randomized as quickly as possible after presentation to the Emergency Department.  
The Eligibility CRF (Form 00) will be completed at this time to determine whether a potential 
participant is eligible; the form captures all the Inclusion and Exclusion criteria for the study, many of 
which are based on tests performed for clinical reasons. 
An electrocardiogram (ECG) will be required to rule out atrial fibrillation.  A head CT or MRI scan will be 
required to rule out hemorrhage, vascular malformation, tumor, abscess, or other TIA mimic.  A CT or 
MRI scan done at a spoke/outside hospital is acceptable as baseline imaging, following review by site 
investigator; an official report is still required. The results are recorded on CRF 11. Local physicians will 
be responsible for interpretation.  Since ECG and head imaging are recommended for all patients 
presenting with TIA and stroke [98, 99], the study will not cover these costs.  
The patient’s presentation history should be taken, evaluating for the possibility that the event was a 
TIA or minor ischemic stroke. Specifics about the event, including time of onset (or time last known 
free from new ischemic symptoms), symptoms, duration of symptoms (if resolved), and pertinent 
review of symptoms should be obtained. 
If the patient has had a TIA, ABCD2 score should be calculated. If the patient has had a stroke, NIHSS 
should be performed. (In the case of a patient with blindness that precedes the onset of a TIA or minor 
stroke, the Manual of Procedures should be consulted for details on scoring the patient using the 
appropriate assessment scale.) 
Certified, trained study personnel will be required to calculate the ABCD2 score and NIH Stroke Scale 
score. The physician (MD or DO), PA or NP investigator must confirm eligibility and review the 
calculation of the NIHSS and the ABCD2 scores, either in person or by phone with a properly trained 
and certified physician, or properly trained and certified study personnel prior to randomization into 
the study. Participants may be randomized by any certified study personnel as long as a site certified 
physician investigator has reviewed and approved eligibility prior to randomization. 
A focused medication history will be taken, as will a focused past medical history. 
Screening laboratories of CBC and creatinine will be reviewed. For a woman premenopausal or 
postmenopausal within 12 months of last menses without a negative pregnancy test or not committing 
to adequate birth without a negative pregnancy test or not committing to adequate birth control (e.g., 
oral contraceptive, two methods of barrier birth control, or abstinence) a pregnancy test will be done.  
Ability to swallow should be assessed. If the patient has had a stroke, swallow evaluation should be 
considered. Swallow evaluation is not a standard component in the evaluation of TIA; TIA patients 
should require no swallow evaluation, unless having a preceding neurological disorder with dysphagia. 
Blood pressure should be taken, and ECG obtained. Brain imaging should be performed with CT or 
MRI, and the results recorded on CRF 11. 
Urgent carotid artery imaging is encouraged but not required. If these studies are done, results should 
be recorded on CRF 13. 
The final inclusion/exclusion criteria checklist should be reviewed after collecting all of the 
information. 
For sites having trouble meeting their enrollment goals, a screen failure log will be completed for all 
patients who are screened but not randomized into the study. This log will not include any personal 


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identifiers and thus will not require consent.  These screen failure logs will be useful in determining 
whether there are modifiable approaches available to increase enrollment.  
Those meeting the eligibility criteria (Section 5.2) will be recruited as trial participants.  Subjects 
already taking aspirin or another antiplatelet agent may be randomized at the discretion of the 
treating physician, as is consistent with current American Stroke Association guidelines [99]. Consent 
will be obtained directly from the patient prior to randomization.  Participants who consent to the 
POINT Trial will be asked to consent to an optional ancillary study consisting of a one-time venous 
blood sample of approximately 10mL collected at the time of enrollment in the trial. Those patients 
who decline the ancillary study will not be prohibited from participating in the POINT Trial. 
Since neurological deficits will have resolved or be minimal at the time of randomization, consent from 
a responsible family member or legal surrogate is not allowed in the study.  
9.2 
Baseline Evaluation 
Inclusion and exclusion criteria will be assessed, including recording the ABCD2 score for patients 
presenting with TIA, and the NIH Stroke Scale Score for subjects presenting with minor ischemic 
stroke.  The baseline evaluation will include subject demographic information, symptoms of the index 
event, prior medications, past medical history, smoking history, blood pressure, and laboratory 
evaluation.  Results of head imaging, laboratories (CBC, INR, glucose), and ECG will be recorded using 
standardized instruments.  Urgent carotid artery imaging will be encouraged but not required.  If 
further diagnostic studies are performed, such as cervicocerebral MRA or CTA, results will be recorded. 
Signed written informed consent will be obtained prior to randomization. Antiplatelet and 
anticoagulant agents other than aspirin will be discontinued prior to randomization. 
9.3 
Randomization 
Upon presentation of a potential subject, the procedure for randomization is as follows: 
1. 
A study subject’s eligibility is determined by site personnel. 
2. 
Qualified site personnel then access (with username and password) WebDCU™.  
3. 
Qualified site personnel complete the Eligibility and Randomization forms in WebDCU™, which 
include protocol-specific eligibility. 
4. 
If the WebDCU™ system deems the subject to be eligible based on the information provided, it 
evaluates the treatment arm distribution and generates a randomization number based on the 
randomization scheme. (The randomization number corresponds to one of the medication 
bottles in inventory at the clinical site). 
5. 
An automatic confirmation e-mail is sent to notify the study team of the randomization.  
6. 
The randomization number generates an ID number that corresponds with a particular study 
drug bottle and with the Study ID pre-printed on the Randomization Verification Form (RVF) 
that matches the study Drug ID. 
7. 
Qualified site personnel obtain the study medication bottle with the corresponding 
randomization number after verifying that the Study Drug ID number on bottle. For complete 
details of the process, see the Manual of Procedures. 


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8.  
Qualified site personnel administer and witness the loading dose. 
9.  
At discharge, the study medication bottle is given to the subject with appropriate instructions 
for daily administration. 
9.3.1 
Treatment Protocols 
Time to treatment is the crucial element in POINT. Therefore, it will be considered a protocol violation 
if a subject is given the initial 600mg loading dose outside of 2 hours following randomization 
After randomization, subjects will be given a medication bottle containing their study drug for the 
duration of the trial.  Qualified site personnel must ensure that the number on the medication bottle 
given to the subject is the same as the randomization number issued by the WebDCU™ study 
database.  Subjects will be provided with a POINT Trial Alert Card  (wallet card) that briefly describes 
the study protocol, identifies an Emergency Contact, the Primary Physician and POINT Trial contact  
(with contact numbers), and lists the UCSF CCC emergency contact number. 
Subjects randomized to clopidogrel will receive clopidogrel 600 mg (eight 75 mg tablets), and will be 
given a bottle containing a supply of clopidogrel 75 mg, with instructions to take one tablet on day 2, 
and 1 additional tablet each day through the 90 day follow up.  Those not randomized to clopidogrel 
will receive eight tablets of an identical-appearing placebo on day 1, and will be given a bottle with 
placebo and instructions to take one tablet each day on days 2 through 90.  All subjects will also take 
50-325 mg of open-label aspirin daily; the dose will be determined by the treating physician but a dose 
of 150-200 mg daily x 5 days, followed by 75-100 mg daily will be strongly recommended.  Use of 
extended-release or regular dipyridamole will be prohibited.  If temporary interruption of study 
medication is required for surgery or other therapy, the subject’s regimen will be resumed as soon as it 
is considered safe by the subject’s neurologist or primary care physician.  Study medications will be 
restarted after carotid endarterectomy (Section 7.5).  If a clear indication for anticoagulation is 
revealed during the 90-day study period (atrial fibrillation, for example), study medications will be 
stopped and anticoagulation will be initiated; under the intent-to-treat principle subsequent events 
will be included in the primary analysis. If patients are already on clopidogrel, they can be enrolled in 
POINT and given the full loading dose. Patients who initially presented at an outside Emergency 
Department and were loaded with clopidogrel can also be evaluated for participation in the study. 
There is uncertainty about whether proton-pump inhibitors (PPIs) interfere with the effectiveness of 
clopidogrel and this has caused regulatory authorities (the European Medicines Agency -EMEA, UK 
Medicines and Healthcare Products Regulatory Agency -MHRA and US FDA) to recommend that 
concomitant use of clopidogrel and PPIs be discouraged unless necessary.   
Clopidogrel is a prodrug that requires conversion to its active metabolite by liver cytochrome P450 
2C19 (CYP2C19). PPIs also are metabolized by CYP2C19 and when taken concomitantly with 
clopidogrel can decrease the antiplatelet effectiveness of clopidogrel. Enzymes other than CYP2C19 
can metabolize one of the PPIs, pantoprazole.  
Some studies have shown that patients on clopidogrel and a PPI have more thrombotic outcomes than 
those on clopidogrel alone. Three explanations for why that might be the case, have been proposed: 
• 
PPIs may interfere with the conversion of clopidogrel to its active metabolite  
• 
PPIs may directly cause harm, and  
• 
The effect may be due to confounding in the reported studies. Patients taking clopidogrel plus 
a PPI were much older and sicker than those taking clopidogrel alone. 


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The studies on which these concerns rest are all observational. Data from clinical trials (CREDO and 
TRITON) have shown no interaction.  
Another point of uncertainty is whether there may be differences between individual PPIs, with some 
pharmacodynamic studies suggesting an interaction with omeprazole but not with pantoprazole. It is 
known that omeprazole is metabolized by the CYP2C19 enzyme, which converts clopidogrel into its 
active metabolite. While pantoprazole can also be metabolized by this enzyme, it also uses other 
routes.  
For these reasons, POINT recommends that H2 antagonists be used when possible in subjects requiring 
gastroesophageal protection and for those not controlled with H2 antagonists and deemed to require 
a PPI, pantoprazole may be the best choice. 
9.3.2 
Risk Factor Evaluation and Management 
To provide optimal care for study subjects and to reduce variability in management, treating clinicians 
will be encouraged to follow standard recommendations on evaluation and management of risk 
factors.  These recommendations are based on published consensus guidelines [97-99].  Key 
recommendations are outlined below. 
Evaluation 
• 
An ECG, a complete blood count, electrolytes, creatinine, glucose, and head CT or MRI are all 
part of routine practice for patients with TIA and minor stroke.  Results of these tests are 
required to assess eligibility for the trial. 
• 
Best practices typically include that if an ultrasound, CT angiography, or MR angiography 
suggest a stenosis greater than 50% , additional carotid imaging to confirm the degree of 
stenosis is warranted. For sites where standard of care includes carotid imaging, it should be 
performed as soon as possible, preferably prior to study entry, and those with >50% internal 
carotid artery stenosis should not be randomized unless the patient declines both carotid 
endarterectomy and endovascular intervention at the time of evaluation for eligibility. 
• 
Fasting cholesterol panel, HbA1c, erythrocyte sedimentation rate, and syphilis serology should 
be considered. 
• 
Cardiac monitoring on a telemetry ward or by Holter monitor should be considered in those in 
whom there is concern for arrhythmia. 
• 
Transthoracic or transesophageal echocardiography should be considered in those with a 
history of cardiac disease, an ECG suggestive of myocardial ischemia, or an abnormal cardiac 
exam. 
• 
Screening for a hypercoagulable state should be considered in those with no apparent risk 
factors for stroke. 
 
Management 
• 
Hypertension should be treated to maintain systolic blood pressure <140 mmHg and diastolic 
blood pressure <90 mmHg; for those with diabetes, blood pressure should be maintained 
<130/85 mmHg. 


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• 
Counseling and treatment to assist with smoking cessation should be offered. 
• 
Cardiac disease should be managed appropriately in consultation with a cardiologist. 
• 
Alcoholism should be treated through formal cessation programs. 
• 
High-dose, high-potency statin (e.g., atorvastatin 80 mg daily) is recommended in all subjects 
unless LDL is < 70 mg/dL or there is a contraindication.   
• 
Tight control of diabetes is recommended to maintain HbA1c < 7%. 
• 
Physical exercise should be encouraged (>30 min for >3 days/week). 
• 
Subjects with atrial fibrillation or an obvious cardiac source of embolus should be discontinued 
from study medications and treated with anticoagulation unless there is a contraindication. 
• 
Subjects with an internal carotid artery stenosis of 70-99% that may have been responsible for 
the index event should be considered for urgent endarterectomy.  If the stenosis is identified 
prior to randomization, the patient is excluded from the trial, unless: 
o the investigator does not consider the subject to be a candidate for either carotid 
endarterectomy or endovascular intervention, OR 
o the patient declines both carotid endarterectomy and endovascular intervention. 
• 
Subjects with an internal carotid artery stenosis 50-69% that may have been responsible for 
the index event should be considered for endarterectomy if risks of surgery are considered 
minimal.  If the stenosis is identified prior to randomization, the patient is excluded from the 
trial, unless: 
o the investigator does not consider the subject to be a candidate for either carotid 
endarterectomy or endovascular intervention, OR 
o the patient declines both carotid endarterectomy and endovascular intervention. 
9.4 
Follow-up 
 
9.4.1 
Follow-up 7 Day Phone Call 
The Site Coordinator will contact subjects by telephone (or in person) at 7 days.  A review of 
SAEs/Clinical Outcomes, concomitant medications and compliance with study medication will be 
assessed. The QVSFS, a screen for stroke-free status questionnaire [155] will also be administered.  If 
subject contact suggests that a possible stroke, TIA or myocardial infarction may have occurred, an 
Outcome Event Visit will be scheduled. 
9.4.1.1 30 Day Phone Contact  
The Site Coordinator will contact subjects by telephone at 30 days to uncover any issues or concerns 
that might impact study drug compliance and retention in the study. 


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While no study data will be collected for the 30-day phone contact, if subject contact suggests that a 
possible stroke, TIA or myocardial infarction may have occurred, an Outcome Event Visit will be 
scheduled. 
9.4.2 
90 Day In-Person or Phone Follow- up 
A review of SAEs/Clinical Outcomes, concomitant medications and compliance with study medication 
(via the Morisky questionnaire) will be assessed. The QVSFS, mRS and NIHSS will also be administered.   
At the 90 Day visit, the study physician will discuss options for antiplatelet therapy.  Unless the 
subject’s treating neurologist or primary care physician has a particular preference for one of the 
proven antiplatelet medications, clopidogrel 75 mg will be prescribed for subjects who can afford 
clopidogrel or have medical coverage for it.  For others, aspirin 75-100 mg will be prescribed, 
consistent with American Stroke Association guidelines.  The physician will confirm that a high-dose, 
high-potency statin is also prescribed [158] and that blood pressure and diabetes are well controlled.  
Diet, exercise, and appropriate action in the event of stroke will also be discussed. 
The 90 Day follow-up should be completed during an in-person visit whenever possible; under limited 
circumstances, for example, if the subject is unable to come in for follow-up, the visit may be 
completed by telephone. CRF completion for the visit will be guided by whether the visit was 
conducted by phone or in person. For visits completed over the phone, the omission of the NIHSS 
assessment will not result in a protocol deviation. The 90-day assessment does not have to be 
completed by the PI. It can be completed by anyone on the study team that has completed the 
appropriate POINT study training and whose certifications are current. 
9.4.2.1 Subjects Considered Lost To Follow-up 
A subject is considered to be lost to follow-up (LTFU) when continued contact with the subject cannot 
be maintained and, despite an active follow-up effort, the site is unable to collect reliable information 
about the outcome event status of the subject up to 150 days following randomization (the 90 day 
enrollment period, and up to 60 days after the projected end of the subject’s enrollment).  
Information about outcome events that occurred during the subject’s 90 day enrollment will be 
considered reliable when Form 14: Questionnaire for Verifying Stroke Free Status and/or Form 19: 
SAE/Clinical Outcome Reporting are completed based on contact with the subject, or the subject’s 
caregiver or alternate contact. Events reported in this way will be adjudicated and included in the 
primary analysis. 
A subject can be considered lost to follow-up when the clinical site can show documented attempts to 
reach the subject, and the period beyond the final scheduled study visit has reached 60 days (i.e., 150 
days after randomization). For any subject who may be lost to follow-up, the POINT Clinical Site must 
discuss the subject with the appropriate NETT or CRC Study Manager and the UCSF Clinical 
Coordinating Center team before assigning that subject lost. 
POINT Clinical Sites will need to demonstrate and document in WebDCU (Form 17 - End of Study: 
General Comments field) at least three (3) attempted telephone contacts by research personnel. A 
progress note, including the time and date of each attempt, should be added to the participant’s study 
file for each contact. After attempts at phone contact are considered unsuccessful, or a subject has 
been reached but fails to appear for the 90 day visit, research personnel at sites must also generate 
and send at least one (1) letter using institutional letterhead and envelope. The letter should be sent 


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using Certified Mail™ with Return Receipt Service (or equivalent in other countries) for evidence of 
delivery to the participant’s address, allowing a week for the subject to respond to the site. The receipt 
should be added to the participant’s file, and a progress note, along with a copy of the letter(s), should 
also be placed in the subject’s study file. When subjects cannot be contacted despite the site team 
implementing these approaches, investigators should attempt to determine the subject’s vital status at 
90 days (i.e., living or deceased) using locally-approved resources. 
9.4.2.2 End of Study  
A subject is considered to have completed the study when the 90 Day Visit is completed. For those 
subjects who fail to complete a 90 Day Visit, subjects are considered to have exited the study at the 
time of withdrawal of consent or death occurring prior to the 90-day visit window, or, for those 
considered lost to follow-up, at 150 days from randomization, when the 90-day visit plus 60 days 
window closes.  
Form 17: End of Study should be completed in the WebDCU™ system for every subject once the 
subject has exited the study.   
9.4.3 
Event Visit 
An Outcome Event Visit should be conducted if a subject experiences an ischemic stroke, TIA, or 
myocardial infarction. Outcome Event Visits should be conducted in person unless the subject 
experiences a myocardial infarction or refuses to come for an in-person visit.  CRF completion for the 
visit will be guided by whether the visit was conducted by phone or in person. Event visits are 
conducted as needed, and can be done more than once for the same subject.  
A listing of data collected during event visits is included in Section 1.2.  SAEs/Clinical Outcomes, 
concomitant medications, mRS, NIHSS, QVSFS, and Morisky Questionnaire will be recorded.  Head 
imaging with CT or MRI will be strongly encouraged to document stroke and after any suspected TIA.  
ECG and cardiac enzyme will be required to document myocardial infarction.  Appropriate laboratory 
testing will be required for documentation of systemic hemorrhage or other systemic complications.  
Autopsy will be encouraged when cause of death is unclear.  If study medications are discontinued due 
to an outcome or SAE, they should be restarted as soon as felt to be safe by the treating physician.  
Event visits may occur on the same day as the 90-day visit since it is expected that clinical outcome 
events may often be identified at the 90 day visit.  Each subject will continue to be followed through 
90 days post randomization.   
9.4.4 
Adherence to Treatment 
Subject adherence with the study drug (clopidogrel and placebo) and aspirin will be assessed by 
administering the Morisky medication adherence questionnaire at the 7 day telephone call, the 90 day 
visit, and at the event visit. The 4-question Morisky scale is a simple, commonly used, validated 
adherence measure (Morisky, DE; Green, LW; Levine, DM. 1986, Medical Care, 24, 1. p.67-74). This will 
serve as the primary measure of adherence. A participant is considered compliant with study 
medication if he/she reported at least medium compliance on the study adherence questionnaire. The 
investigator will be responsible for monitoring subject adherence.  A subject will be counseled on the 
importance of complying with the study medication.   


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In addition, for clopidogrel, compliance with the study drug will be documented at the 90-day visit.  
Those subjects taking more than 80% of tablets on days 2-90 (71 or more tablets) will be considered 
adherent as assessed by pill count and subject/care-giver report.  NOTE: Since the loading dose is 
observed by the study investigator or other member of the study team (see Manual of Procedures 
section 11.4, Study Procedures) and recorded on CRF 7, subjects will be considered to be in compliance 
with the loading dose.  Therefore, a subject is adherent if he/she has taken at least 79 tablets (8 at 
loading dose + 71 on days 2-90). 
The sites identified for the study have reported adherence rates of about 95% in prior stroke trials.  
However, if there are systematic problems with adherence at a particular site, the NETT and CRC will 
know this rapidly and will contact the site to identify possible solutions. 
Concomitant medications will also be recorded at follow-up visits.   
10 
STATISTICAL CONSIDERATIONS 
 
10.1 
Statistical Analysis Plans 
This section is an overview of the statistical considerations. Complete details can be found in the 
Statistical Analysis Plan (SAP). It provides the general specifications for the analysis of the data to be 
collected and presented in the Clinical Study Report. A final SAP will be issued by the SDMC prior to 
database lock and before code breaking. The SAP will define all “pre-specified, planned analyses.” 
10.1.1 Randomization Scheme 
Randomization will be implemented centrally via the WebDCU™ system.  The randomization scheme 
will ensure treatment is balanced within site and overall.  The study will include both TIA and minor 
ischemic stroke, with the latter accounting for no more than 50% of enrollment.   
10.1.2 Sample Size Estimates 
Primary Null Hypothesis 
In patients with high-risk TIA or minor ischemic stroke treated with aspirin 50-325 mg/day, there is no 
difference in the event-free survival at the 90-day follow-up 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 from new ischemic symptoms.  The primary outcome is a composite consisting of 
ischemic stroke, myocardial infarction, or ischemic vascular death; the primary safety outcome is 
major hemorrhage.  
The original maximum sample size to detect a relative risk reduction (RRR) of 23% is 4,150 subjects.  As 
stipulated in the Statistical Analysis Plan, following the first interim analysis, the maximum sample size 
has been re-estimated to be 5,840 subjects.  The original sample size estimation is based on 90% 
power and a two-sided alpha of 0.05, 12% crossovers, and 2% losses to follow-up.  The RRR of 23% 
translates to a hazard ratio of 0.75 assuming the proportion of subjects with events in the placebo 
group to be 15%, and inflation to account for two interim analyses for efficacy at equal intervals using 
O’Brien and Fleming stopping boundaries.   


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10.1.3 Secondary Outcomes  
A number of other secondary outcomes will be evaluated separately, including risk of ischemic stroke, 
intracranial hemorrhage, and major hemorrhage, and the composite of the primary outcome and 
major hemorrhage.  The influence of index event type (TIA vs. minor stroke), sex, and race/ethnicity 
will be evaluated in subgroup analyses.   
10.2 
Statistical Analyses 
 
10.2.1 Primary Outcomes 
The primary analysis will be intention to treat, with inclusion and treatment group defined per the 
randomization assignment.  Missing values will remain missing and subjects will be censored at their 
last follow-up assessment (end of study or last visit prior to loss to follow-up). Kaplan-Meier estimates 
of the cumulative risk of an event will be reported for the maximum 90-day follow-up, and the log-rank 
test will be used to evaluate the statistical significance of the treatment effect.  The Type I error for the 
primary analysis will consider two-sided alpha=0.05 significant. 
10.2.2 Secondary Outcome Events 
The analysis strategy outlined for the primary outcome will be used for most of the secondary 
analyses. Each secondary outcome event at the two-sided alpha of 0.05 will be tested, recognizing the 
dangers of inflating the Type I error probabilities.  These tests will be viewed as exploratory 
hypotheses that may or may not support the results of the primary analysis. 
10.3 
Data and Safety Monitoring Procedure and Plan 
An external Data Safety and Monitoring Board (DSMB) is appointed by and reports to the NINDS.  
Open and closed reports will be prepared by the NETT-SDMC statisticians.  The DSMB will meet 
approximately every 6 months with additional meetings scheduled as they require.  At intervals 
defined by the DSMB, reports of safety events will be submitted to the DSMB by NETT-SDMC 
statisticians.   
A blinded Clinician Event Coordinator will review safety data on SAEs as they become available to the 
UCSF CCC, including adjudicating whether events are serious, related to the study drug, or unexpected 
(in addition to the review of the site investigator). The safety data will be made available to the 
Clinician Event Coordinator on the WebDCU™ system to allow real-time access, review and reporting.  
10.3.1 Interim Analyses and Stopping Rules 
Unacceptable Safety Profile.  The DSMB will be asked to use judgment to weigh evidence of efficacy 
and rates of adverse events.  The committee will meet, as outlined in NINDS guidelines, to assure 
subject safety; additional interim analyses may be requested by the DSMB.  Since frequency, severity, 
and distribution of adverse events, as well as early evidence of benefit, are all likely to affect the 
decision to discontinue a treatment arm, establishing strict criteria for stopping a priori is imprudent; 
rather, careful judgment of the DSMB will be required. 


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Superiority or Inferiority Established Prematurely.  The number of interim evaluations of the primary 
outcome data will be determined by the DSMB and will be described in the Statistical Analysis Plan. 
 
11 
ETHICAL AND REGULATORY STANDARDS 
 
11.1 
Ethical Considerations 
The study will be conducted in accordance with the U.S. Food and Drug Administration’s (FDA) Code of 
Federal Regulations (CFR Title 21), ICH Good Clinical Practice (GCP) guidelines, and the relevant 
regulations for clinical trials for each investigational site. 
11.2 
Regulatory Requirements 
Prior to initiating the study, each site will obtain IRB or Ethics Committee approval for the protocol, 
Informed Consent Forms and materials used to recruit subjects.  In addition, each investigator will sign 
an Investigator Agreement with the study sponsor. IRB/IEC-approved informational videos and quizzes 
designed to inform physicians and supplement the informed consent process may be presented on 
tablet devices and online to study physicians and potential subjects. Signatures of study subjects 
documenting their consent will be collected on paper and/or digitally. Prior to their participation, 
subjects will be provided printed paper copies of the signed consent form, as required by ICH GCP 
4.8.11 and 21 CFR 50.27. Protocol amendments are not allowed by any investigator without prior 
approval from the Executive Committee.  All changes to the protocol approved by the Executive 
Committee must be submitted to the site’s IRB/IEC for review and approval as appropriate.  The trial 
has received a waiver from IND requirements from the FDA. However, each investigator at sites 
outside the U.S. must assure that any necessary approvals, or applicable waiver(s), have been obtained 
from the appropriate regulatory authority and/or national competent health authority, with 
authorization to proceed. 
11.3 
Institutional Review Board (IRB) or Ethics Committee (EC) 
Prior to initiating the study, each Investigator must submit the following to an IRB/IEC: the Informed 
Consent Form, this protocol and materials used to recruit subjects for this clinical trial. No study 
subjects may be recruited until documented IRB/IEC approval (or favorable opinion) is obtained for 
that site. Any addendums or revisions to the above documents must be resubmitted for review and 
approval. Each investigator will follow the requirements of his or her IRB/IEC on periodic reporting of 
the progress of the study, reporting of serious or unexpected adverse events, safety monitoring 
reports, and termination of the study.  
11.4 
Informed Consent 
Each eligible patient who wishes to participate in this study will be required to give written informed 
consent. Written informed consent will include signatures collected on paper and/or digitally and 
subjects will be provided printed paper copies of the consent form.  Before the consent form is signed, 
a trained researcher will explain why the patient was selected for screening and the purpose of the 


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screening and how results of screening are used to determine eligibility. IRB/IEC-approved 
informational videos and quizzes designed to inform physicians and supplement the informed consent 
process may be presented online, and on tablet or similar electronic devices to study physicians and 
patients. The patient will be informed that, if he or she meets all of the inclusion criteria and none of 
the exclusion criteria, and agrees to participate, he or she will be enrolled in a clinical trial of 
clopidogrel and placebo. The consent document explains the risks and potential benefits of the 
therapy, the procedures for the trial, and alternatives to participation.  There will be no surrogate 
consent in the study. Subjects must personally consent to participation and sign the approved consent 
form(s) which will be retained by the investigator and may be reviewed by the sponsor’s authorized 
monitors or auditors, and authorized representatives from regulatory authorities. 
12 
STUDY MONITORING 
 
12.1 
Site Monitoring, Quality Assurance and Remedial Actions 
Quality Assurance activities will be a collaborative effort between the POINT CRC and the NETT CCC.
12.1.1 Site Visits 
The POINT CRC monitoring staff or contractors will perform all site visits to CRC investigators, on a 
jointly acceptable schedule.  Similarly, the NETT-CCC will perform all visits for its sites. The site 
Readiness Call will take place via telephone contact prior to any participants being enrolled.  Required 
regulatory documents will be stored in the regulatory module of WebDCU™.  Subsequent site visits are 
scheduled on an as-needed basis based on recruitment, data quality, or continued noncompliance (for 
cause).  Every site will receive at least one visit during the course of the study.  The visit will include 
review of regulatory documents maintained at the site, verification of the appropriate version and 
completion of Informed Consent Forms, supplemental videos and quizzes, protocol compliance, study 
drug accountability, discussions with the site PI and staff regarding study conduct, and a data audit 
against source documents, as available.  The site visits will follow the CRC and NETT Standard 
Operating Procedures/Monitoring Plan for conducting visits. A site visit report summarizing the 
findings will be issued to the Study PI and the Operations Committee within 28 days of the visit.   
12.1.2 Remedial Action 
Sites that demonstrate difficulty complying with study procedures, recruitment, or maintaining data 
quality will be discussed with the Executive Committee.  Action may include direct phone contact with 
the site PI by the POINT CRC or NETT Site Monitor to discuss the issues and create a corrective action 
plan, subsequent site visit by the Site Monitor, and/or a probationary period until effective corrective 
action has been taken.  If the situation remains unresolved, the Executive Committee may suspend the 
site from the study.  Specifically, with regard to recruitment, sites that are certified to enroll study 
participants but do not enroll a participant in 90 days, will be contacted by the CRC or NETT Site 
Monitor via telephone to determine the site’s continued interest in study participation, and to create a 
plan to increase enrollment of participants. 


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12.2 
Data Management 
 
12.2.1 Data Quality Monitoring 
The POINT CRC monitoring staff will have access to real-time data that describe the quality of the data 
submitted by CRC physicians, and the NETT CCC will do the same for its sites.  These data include 
recruitment, missing values and other data anomalies, missing forms, missed visits, late visits, subject 
ineligibility post enrollment, and other protocol deviations and violations.   
13 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed by the 
Executive Committee.  The trial results will be published as soon as possible after database lockdown.   
This trial will produce detailed data on treatment effects, medical care, and outcomes in a cohort of 
5,840 subjects with TIA or minor ischemic stroke.  Three years after the primary publication associated 
with this work is submitted, a HIPAA-compliant, de-identified version of the database will be made 
available publicly.  POINT biostatisticians will be consulted to assure that it is impossible to uniquely 
identify any participant.  This may mean removing or categorizing certain variables.  A data use 
agreement will not be required for access to this dataset.  Data in comma-delimited text format will be 
sent to parties that express interest, including a data dictionary in a text file. 
The goal of the POINT Trial Publications Policy is to provide guidelines for preparing, reviewing, 
submitting and maximizing productivity of high-quality peer-reviewed publications. In addition to 
overseeing the performance of the trial, the Executive Committee is responsible for encouraging paper 
production, ensuring timely publication of data, maintaining a high standard for the quality of papers 
produced for POINT, and determining appropriate authorship. When the Committee is discussing 
manuscripts associated with ancillary studies, the PI of the ancillary study and his/her designee will 
also join the Executive Committee for that discussion (see Section 14, Ancillary Studies). 
Manuscript proposals will be submitted to the Executive Committee. These proposals will include the 
type (primary, secondary, tertiary and quaternary), list of authors and their qualifications for 
authorship, a statement that no others deserving authorship have been omitted, the scientific 
rationale for the paper, the data needed and a description of the proposed analyses and any deadlines 
for submission of abstracts or presentation dates if applicable. The Publications Policy can be found in 
the Manual of Procedures. 
14
ANCILLARY STUDIES
Proposals for ancillary studies will be reviewed by the Executive Committee; these studies will require 
funding outside the original study grant. The committee will assure that all such studies are hypothesis 
driven, methodologically robust and contain complete and accurate data. Approval will follow the 
ancillary study approval process which defines the standard procedures for proposing, reviewing, and 
approving ancillary studies and/or substudies conducted within the trial. It will meet each month by 
teleconference the first 6 months of enrollment, and every other month for the duration of subject 
enrollment. 


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Pharmaceutical industry representatives have not been involved with the trial design and will not 
participate routinely in the execution of the trial or presentation of the results. Data will be controlled 
by the Executive Committee, which will review requests for access and specific analyses. Monitoring 
during the trial will be dictated by safety and scientific concerns rather than regulatory requirements. 
Publication of the results will be governed by the policies and procedures developed by the Executive 
Committee. Sites will not be required to participate in any ancillary study that requires additional data 
collection, but they will be encouraged to participate in accepted studies. The Ancillary Studies Policy 
can be found in the Manual of Procedures. 
14.1 
Optional POINT Biomarkers Ancillary Study  
Participants who consent to the POINT trial will be asked to consent to an optional ancillary study 
consisting of a one-time venous blood sample of approximately 10 mL, collected at the time of 
enrollment in the trial. Subjects indicating consent to the Biomarkers Study by checking the 
appropriate box will be asked for a one-time sample of approximately 10 mL of peripheral venous 
blood. Consent will be collected for both the blood sample and the optional ancillary study.  Those 
patients who decline the ancillary study will not be prohibited from participating in the POINT Trial. 
Plasma and DNA will be prepared for genotyping analysis and stored at the Neurogenetics Laboratory 
at the Mayo Clinic in Jacksonville, Florida (MCF) as required by Federal and state regulations.  The 
study samples will be used for testing the specific hypothesis as to whether clopidogrel resistant 
genotypes modify the stroke prevention response in high-risk TIA patients.  Subjects will be assigned 
numbers which will be placed on the sample labels and allow researchers to link the sample to the 
encrypted ancillary study database. No personal identifying information will be kept with the samples. 
Results of the genotyping analysis will not be shared with subjects.  
Of primary interest is the relative risk of vascular outcome events for carriers (of specific ABCB1 and 
CYP2C19 genotypes) versus non-carriers amongst those receiving clopidogrel. Of secondary interest is 
a subgroup analysis by the enrolling/index event type (either TIA or minor ischemic stroke cohort) 
performed separately for the TIA cohort and the minor ischemic stroke cohort. 
Genotyping results (raw data and summary data) will be provided to the POINT Trial Principal 
Investigator and lead statistician for incorporation into the existing trial data set into WebDCU. 
Analyses exploring an interaction between genotypes and treatment response will be done jointly, 
including testing of inherited clopidogrel resistance.  This would be the first systematic study of 
clopidogrel resistance in the setting of stroke prevention following TIA.  The stored samples will also be 
a resource for future studies in this patient population. 
 
 
 
 


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` 

SAP_000.pdf: 
 
CONFIDENTIAL 
 
 
 
 
PLATELET‐ORIENTED INHIBITION IN NEW TIA AND 
MINOR ISCHEMIC STROKE 
 (POINT) TRIAL  
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepared by 
Yuko Y. Palesch, Ph.D. (SDMC) 
David V. Glidden, Ph.D. (UCSF) 
Jordan J. Elm, Ph.D. (SDMC) 
 
The Statistical and Data Management Center (SDMC) is part of  
Data Coordination Unit  
Division of Biostatistics & Epidemiology 
Medical University of South Carolina 
Charleston, SC 29425 
 
Version 8 
 
Date: September 2017 
 


CONFIDENTIAL 
POINT Trial Statistical Analysis Plan 
 
Page 1 of 23 
(Version 8: Sept 2017) 
TABLE OF CONTENTS 
 
 
1 
LIST OF ABBREVIATIONS .......................................................................................... 2 
2 
STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS ............................................ 2 
3 
OBJECTIVES OF THE STUDY ...................................................................................... 3 
3.1. 
Efficacy .................................................................................................................... 3 
3.2. 
Safety ...................................................................................................................... 3 
4 
STUDY DESIGN ........................................................................................................ 3 
5 
SAMPLE SIZE CONSIDERATIONS ................................................................................ 3 
5.1 
Sample Size Determination for the primary efficacy Analysis ................................ 3 
5.2 
Re‐estimation of the Sample Size ........................................................................... 5 
6 
DEFINITION OF TARGET POPULATION AND STUDY SAMPLES ....................................... 5 
6.1. 
Target Population ................................................................................................... 5 
6.2. 
Intent‐to‐Treat Sample ........................................................................................... 6 
6.3. 
Safety Analysis Sample ............................................................................................ 6 
7 
RANDOMIZATION ................................................................................................... 6 
8 
BLINDING ............................................................................................................... 6 
9 
MULTIPLICITY ......................................................................................................... 7 
10 
MISSING DATA ........................................................................................................ 7 
11 
MONITORING AND EVALUATION OF CLINICAL CENTER EFFECT .................................... 7 
12 
EFFICACY ANALYSIS ................................................................................................. 7 
12.1. 
Primary Outcome Variable Analysis........................................................................ 7 
12.1.1. 
Primary Outcome .................................................................................................... 7 
12.1.2. 
Statistical Hypothesis .............................................................................................. 8 
12.1.3. 
Primary Efficacy Analysis ........................................................................................ 8 
12.1.4. 
Additional Efficacy Analyses of the Primary Outcome: Adjusting for Clinical 
Centers .................................................................................................................... 9 
12.1.5. 
Additional Efficacy Analyses of the Primary Outcome: Adjusting for Covariates .. 9 
12.1.6. 
Additional Efficacy Analyses of the Primary Outcome: As‐Treated Analyses ........ 9 
12.1.7. 
Additional Efficacy Analyses of the Primary Outcome: Subgroup Analyses ......... 10 
12.2. 
Interim Efficacy Analysis ....................................................................................... 10 
12.3. 
Interim Futility Analysis ........................................................................................ 11 
12.4. 
Interim Monitoring Schematic .............................................................................. 13 
12.5. 
Secondary and Tertiary Clinical Efficacy Outcomes Analyses ............................... 14 
13 
SAFETY ANALYSES ................................................................................................. 15 
13.1 
13.1.  Safety Monitoring ....................................................................................... 15 
13.2 
Summary of Adverse Events ................................................................................. 15 
14 
BIOMARKER ANCILLARY STUDY .............................................................................. 16 
15 
REFERENCES ......................................................................................................... 17 
16 
APPENDIX: SAMPLE SCENARIOS FOR INTERIM STOPPING VERSUS SAMPLE SIZE INCREASE
 ........................................................................................................................... 19 
Table  A.1  Sample  Scenarios  for  Interim  Stopping  versus  Sample  Size  Increase  at  the  First 
Interim Analysis ......................................................................................................................... 19 


CONFIDENTIAL 
POINT Trial Statistical Analysis Plan 
 
Page 2 of 23 
(Version 8: Sept 2017) 
1 
LIST OF ABBREVIATIONS 
AE   
 
Adverse Event 
CRF 
 
Case Report Form 
DCR 
 
Data Clarification Request 
DCU 
 
Data Coordination Unit 
DSMB 
 
Data Safety and Monitoring Board 
FASTER 
 
Fast Assessment of Stroke and Transient ischemic attack to prevent  
 
 
 
 
Early Recurrence 
GCP 
 
Good Clinical Practice 
HR   
 
Hazard Ratio 
ITT   
 
Intent‐to‐Treat 
MI   
 
Myocardial Infarction 
NETT 
 
Neurological Emergencies Treatment Trials 
NIHSS 
 
National Institutes of Health Stroke Score 
NINDS 
 
National Institute of Neurological Disorders and Stroke 
POINT 
 
Platelet‐Oriented Inhibition in New TIA and minor ischemic stroke 
SAE  
 
Serious Adverse Event 
SDMC 
 
Statistical and Data Management Center 
TIA  
 
Transient Ischemic Attack 
 
 
 
2 
STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS 
 
This document provides the details of statistical analyses planned for the POINT Trial, including 
interim analyses for efficacy and evaluation of futility.  In addition, it discusses the statistical 
issues relevant to these analyses (e.g., sample data to be used, missing data, adjustments for 
multiplicity, etc.) 
 
The NETT SDMC will generate Data and Safety Monitoring (DSMB) Reports semiannually or 
more frequently upon request by the DSMB. Each semiannual report provides cumulative 
summary statistics on enrollment; subject status in the study (e.g., number completed day 7 and 
day 90 assessments); baseline characteristics; protocol violations; safety data, including coded 
SAEs, clinical outcomes data (with primary outcomes following the interim analysis schedule 
listed in section 12.2); and data management/quality information (e.g., timeliness and 
completeness of data entry by the clinical centers via the POINT Trial web‐enabled clinical trials 
management system (WebDCU™); number of data queries generated and resolved). For all 
safety data, tables or figures will be stratified according to index event type: either TIA or minor 
stroke.  The statistics for the ‘Closed Session’ DSMB Reports are provided by treatment group 
(partially blinded).  The ‘Open Session’ DSMB report contains aggregated statistics only, i.e., not 
by treatment group. If a semiannual report coincides in timing with a planned interim analysis, 
the analysis results are appended to the report. 


CONFIDENTIAL 
POINT Trial Statistical Analysis Plan 
 
Page 3 of 23 
(Version 8: Sept 2017) 
 
 
3 
OBJECTIVES OF THE STUDY 
 
3.1. Efficacy 
 
The primary objective of the POINT Trial is to determine the effectiveness of clopidogrel (a 
loading dose of 600 mg followed by 75 mg/day) over placebo when initiated within 12 hours 
of time last known free of new ischemic symptoms in patients receiving aspirin therapy at 
50‐325 mg/day.   The primary efficacy hypothesis is that event‐free survival at 90 days is 
higher  in  subjects  treated  with  clopidogrel+aspirin  than  in  subjects  treated  with 
placebo+aspirin, when randomized within 12 hours of time last known free of new ischemic 
symptoms.    The  primary  outcome  measure  for  this  hypothesis  is  the  composite  event  of 
ischemic stroke, MI, or ischemic vascular death. 
 
3.2. Safety 
 
The safety of clopidogrel when compared to placebo is evaluated by comparing rates of all‐
cause death, intracranial hemorrhage, major hemorrhage, minor hemorrhage, and other 
treatment related complications and SAEs (see section 13.2). 
 
The primary safety outcome is major hemorrhage. Major hemorrhage is one that results in 
symptomatic intracranial hemorrhage, intraocular bleeding causing loss of vision, need for 
transfusion of two or more units of red cells or equivalent amount of whole blood, need for 
hospitalization or prolongation of an existing hospitalization, or death. This may include 
bleeding events related to surgical procedures. 
 
4 
STUDY DESIGN 
 
The study is of a two‐arm parallel design whereby eligible subjects are randomized in a 1:1 ratio 
to either the clopidogrel group or to the placebo group.  Each subject is followed for 90 days 
from randomization. 
 
5 
SAMPLE SIZE CONSIDERATIONS 
 
5.1 Sample Size Determination for the primary efficacy Analysis 
 
The minimum necessary sample size in the trial is established by the requirement to detect the 
smallest expected, clinically meaningful treatment difference comparing the treatment with 
placebo.  A relative risk reduction of 23% is the smallest difference felt to be of clinical 
importance.  The total sample size for the study is 4,150 subjects (rounded up from 4,142).   
With a sample size of 4,150 patients, with 530 events, the study will have 90% power to detect a 
relative risk reduction of 23% with a two‐sided alpha of 0.05.  The sample size was estimated 
based on a hazard ratio (HR) of 0.75 (equivalent to RRR of 23%) assuming an exponential 
survival distribution (assuming the proportion of patients with events in the placebo group is 
0.1524 at 90 days), with inflation to account for two interim analysis for efficacy at equal 
intervals using O'Brien and Fleming stopping boundary using the Lan‐Demets spending function 
and inflation for lost‐to‐follow‐up and/or crossover. The intent‐to‐treat (ITT) principle is applied 
to the analysis, and therefore, we inflated the sample size to safeguard against lost‐to‐follow‐up 


CONFIDENTIAL 
POINT Trial Statistical Analysis Plan 
 
Page 4 of 23 
(Version 8: Sept 2017) 
and/or crossover in the actual treatment received, which may dilute the effect size. From 
FASTER there were 12% crossovers and 2% losses to follow‐up [8].  Most events will occur early 
in the follow‐up period and hence a smaller fraction of events will be lost and a smaller total 
correction in sample size is required (5.0%). Details regarding the sample size calculation are 
provided in Table 1.   
 
Table 1. Assumptions and Specifications Used to Calculate Sample Size 
Proportion with events at 90 days in placebo (aspirin) group 
15.24% 
Relative risk reduction  (reference: placebo+aspirin group) 
0.23 
Hazard Ratio 
0.75 
Delay between symptom onset and enrollment 
12 hour 
   Loss to follow‐up at 90 days (from FASTER) 
2% 
   Crossovers at 90 days (from FASTER, non‐event related) 
12% 
   Impact of crossover on events 
29% 
   Inflation factor for crossovers and losses if events at 90 days 
31% 
Modeled inflation factor to account for crossovers/losses 
5.0% 
Power 
0.90 
Total alpha (2‐sided) with 2 interim analyses 
0.05 
 
Given the uncertainty in the assumptions used to predict effect size and event rates, we have 
chosen  a  sample  size  to  provide  90%  power.    With  this  sample,  we  will  have  80%  power  to 
detect a relative risk reduction of 19%.  Further, we will have 80% power if the placebo event 
rate is 23% lower than projected (see Figure 2) or early losses to follow‐up are 4‐times more 
frequent than anticipated.  Power curves are shown below: 
 
 
 
Figure 1. Minimum Detectable Relative Risk Reduction for 90% Power by Placebo Event Rate by 
Total Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2. Total Sample Size Needed by Placebo Event Proportion by Power 
Power Curves
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0.08
0.1
0.12
0.14
0.16
0.18
Placebo Event Proportion
Total Sample Size
90%
85%
80%
75%
70%
65%
 
 
5.2 Re‐estimation of the Sample Size  
If after 4,150 patients have been enrolled, less than 530 events have been observed, then power 
will be reduced. This could happen, for example, if the event rate is lower than expected in the 
minor stroke cohort. The power is defined by the total number of events, which depends only 
on the hazard ratio. For a given sample size, a decrease in event rates (overall), assuming a fixed 
hazard, will decrease power.    
 
The sample size re‐estimation should be based solely on the placebo event rate (not the 
observed difference in treatment groups). The assumed placebo rate is 15.24% with a 95% CI 
(13.63%, 16.85%) based on a sample of 1907 TIA patients from KPNC. At the time of the first 
interim analysis when approximately 1/3 of the expected number of events (177) are observed, 
if the one‐sided upper 99% confidence limit around the observed placebo rate does not overlap 
with those of the assumed rate (Lower 13.63%, Upper 16.85%), then the maximum sample size 
will be re‐estimated based on the observed placebo event rate (given a RRR of 23% as originally 
assumed).  
 
Figure 2 gives the total sample size needed for a given placebo event rate at various powers. 
Some scenarios for stopping the trial early versus increasing the sample size are given in section 
12.5 as a guide for the DSMB. The DSMB’s decision to recommend an increase in the total 
sample size would take into account the likelihood of success of the trial using the other interim 
monitoring criteria (see section 12.4 for a flow chart) as well as the safety profile. 
 
5.3 Re‐estimation of the Sample Size Result 
 
As stipulated in section 5.2, following the first interim analysis, the maximum sample size has 
been re‐estimated to be 5,840 subjects. 
 
6 
DEFINITION OF TARGET POPULATION AND STUDY SAMPLES 
 
6.1. Target Population 
 


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The  target  population  to  which  the  clopidogrel  treatment  regimen  may  be  applied  are 
patients 18 years of age or older with high‐risk TIA (defined as an ABCD2 score > 4) or minor 
ischemic stroke (with NIHSS < 3) who can be randomized within 12 hours of time last known 
free from new ischemic symptoms. 
 
6.2. Intent‐to‐Treat Sample  
 
As the primary analysis, all efficacy and safety outcome measures are analyzed under the 
intent‐to‐treat  (ITT)  principle.  Under  this  principle,  the  evaluable  sample  includes  all 
randomized subjects, except for re‐enrollers. Re‐enrollers are patients who are determined 
to have been enrolled into the POINT trial more than once. For re‐enrollers, only the data 
associated with the first enrollment will be counted in the primary analysis. 
 
6.3. Safety Analysis Sample 
 
All randomized subjects are included in the safety analysis sample, regardless of the amount 
of treatment administered.   
 
 
7 
RANDOMIZATION 
 
The  randomization  will  take  place  centrally  via  WebDCU™.  Subjects  will  be  randomized  1:1 
(clopidogrel: placebo), controlling for clinical site using the blocked‐urn method.  
 
 
The  detailed  randomization  scheme  and  source  codes  will  be  provided  in  the  Randomization 
Plan document. Although a randomization scheme with any constraints would yield some bias in 
the inferences from using standard analytic methods, Efron (1971) shows the appropriateness of 
standard statistical tests under the biased coin randomization in large studies.  Friedman et al 
(1998 p. 72) note that the variance terms under the biased coin design tend to be larger than 
under simple randomization.  The consequence is that it would be more difficult to reject the 
null hypothesis, and therefore, we would be more conservative in determining the significance 
of the effectiveness of the treatment. 
 
A “Real‐Time” randomization procedure is implemented via the WebDCUTM system where the 
clinical  center  staff  enters  the  eligibility  information  of  a  subject  prior  to  enrollment.    If  the 
subject’s  eligibility  status  is  confirmed,  the  computer  program  on  the  WebDCUTM  server  will 
evaluate  the  treatment  arm  distribution  and  generate  a  study  number  based  on  the 
randomization scheme.  The study number will correspond to a specific medication bottle that 
will be already at the clinical center.   
 
8 
BLINDING  
 
The study is conducted in a double‐blind manner.  The placebo for clopidogrel will be identical in 
appearance  and  taste.    Minor  side  effects  are  unusual  with  the  medication,  so  it  is  not 
anticipated that either subjects or clinicians will be able to differentiate the placebo from the 
active drug.  Standard laboratory tests cannot detect the effects of clopidogrel.   
 
 


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9 
MULTIPLICITY 
 
The primary efficacy hypothesis is tested with the log‐rank test for equality of survival curves.  
This hypothesis is tested with a two‐sided 0.05 level of significance.   
 
For  secondary  outcomes,  we  will  not  account  for  multiplicity.    These  analyses  are  merely 
supportive  and  exploratory  and  will  be  interpreted  as  such.    The  overall  trial  hinges  on  the 
primary analysis and interpretation of secondary results is already tempered by their placement.  
Accounting for multiple testing would also increase the risk that an interesting finding is not 
subsequently pursued. 
 
 
10 
MISSING DATA 
 
Based on the FASTER (Fast Assessment of Stroke and Transient ischemic attack to prevent Early 
Recurrence) trial, it is anticipated that there would be minimal (2%) loss to follow up for the 90‐
day  assessment  of  the  primary  outcome.    All  efforts  should  be  put  forth  to  ensure  near 
complete  follow‐up,  in  particular  with  the  assessment  of  the  primary  outcome  (time  to  the 
composite  event  of  ischemic  stroke,  myocardial  infarction,  or  ischemic  vascular  death)  and 
occurrence of death.   
 
Nevertheless,  minimal  missing  data  may  be  inevitable.    Since  all  randomized  subjects  are 
included  in  the  primary  efficacy  outcome  analysis,  subjects  missing  outcome  data  will  be 
censored at the last follow‐up assessment time (end of study or last visit preceding loss to follow 
up).    Missing  mRS  data  will  be  imputed  by  carrying  forward  mRS  from  event  visits  or  by 
regression imputation. 
 
 
11 
MONITORING AND EVALUATION OF CLINICAL CENTER EFFECT 
 
On a semiannual basis, the HR of the treatment effect on outcome measures (efficacy or safety) 
and its 95% CI are calculated for each clinical center and for all sites combined, and they are 
graphed in one figure to determine whether any sites are uniquely different from the others or 
from the overall group.  Furthermore, a plot of HRs (y‐axis) by number of subjects enrolled at 
each  site  (x‐axis)  is  generated.    The  expectation  is  that  the  plot  should  appear  like  a  funnel 
where the smaller the number of subjects enrolled, the greater the variability.  This graph also 
assists us in determining where, if any, outliers are with respect to the sites. If any outliers are 
detected, further investigation into the reasons is made to ensure that the trial conduct at those 
sites  is  in  accordance  with  the  protocol  and  GCP  Guidelines.    These  figures  and  graphs  are 
included in the closed DSMB reports. 
 
Inclusion of clinical center effect in the efficacy analysis is discussed in Section 12.1.4 below. 
 
 
12 
EFFICACY ANALYSIS 
 
12.1. 
Primary Outcome Variable Analysis 
 
12.1.1. 
Primary Outcome 


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The  primary  efficacy  outcome  measure  is  the  composite  event  of  ischemic  stroke, 
myocardial infarction, or ischemic vascular death within 90 days.  These events will be 
adjudicated by the Adjudications Committee. 
  
12.1.2. 
Statistical Hypothesis 
 
The set of statistical hypotheses can be stated in terms of hazard functions as: 
 
H0: hc(t)= hp(t)    
versus   
HA: hc(t)≠ hp(t) 
 
where  hc(t)  and  hp(t) are  the  hazard  rates  for  the  clopidogrel  and  placebo  groups, 
respectively.  The  minimum  effect  size  of  clinical  interest  is  a  relative  hazard  rate 
reduction  of  25%,  or  relative  risk  reduction  of  23%.  The  hazard  rate  for  the  placebo 
group is assumed to be 16.5%.  
 
 
12.1.3. 
Primary Efficacy Analysis (ITT) 
 
The primary efficacy null hypothesis of the equality of survival curves is tested with the 
log‐rank test. The overall Type I error for the primary analysis will consider two‐sided 
alpha=0.05 significant. 
 
The  primary  analysis  will  be  intention  to  treat,  with  inclusion  and  treatment  group 
defined  at  the  randomization  assignment.  Missing  values  will  remain  missing  and 
patients  will  be  censored  at  their  last  follow‐up  assessment;  based  on  projected  loss 
rates, it is expected that only 5 subjects will be lost at 7 days and 70 subjects lost at 90 
days, so the problem is relatively minor. Kaplan‐Meier estimates of the cumulative risk 
of an event during maximum 90‐day follow‐up will be reported, with HRs and 95% CI 
calculated using Cox proportional hazards methods (to provide an estimate of treatment 
effect) and the log‐rank test to evaluate the treatment effect. This approach is being 
taken to maximize the time dependent information in the trial while still acknowledging 
the ease of interpretation of risks. For the Cox proportional hazards method, the Efron 
method will be used when there are ties since this method closely approximates the 
exact method, but requires less computing resources. 
 
The primary outcome is composite of ischemic stroke, MI, or ischemic vascular death 
occurring up to 90 days. However, the 90 day visit may occur within +‐14 days of the 
target visit. For patients with an event, the time to event will be the days from 
randomization to the first adjudicated primary outcome event (if it occurred before 90 
days).  Events occurring after 90 days (e.g. day 91) will not be counted in the primary 
analysis. Patients for whom there was no event and whose follow‐up visit occurred after 
day 90 will be censored at exactly 90 days. For patients without a 90 day visit, the 
censoring date will be determined by the last collected QVSFS (censoring time will be 
the actual days from randomization). The Kaplan Meier curves will use the actual days 
up to day 90. For this figure, the “# at risk” will be reported at baseline, 7 days, and 90 
days.  
 


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Likewise, the ITT analysis will be repeated for the primary and secondary efficacy and 
safety outcomes. 
 
 
12.1.4. 
Additional Efficacy Analyses of the Primary Outcome: Adjusting for Clinical 
Centers (Tertiary Analysis) 
 
Ideally, all prognostic variables used in the randomization scheme should be accounted 
for in the analysis of the primary efficacy outcome measure.  For the POINT Trial, clinical 
center is included in the randomization scheme; as a result, clinical center should be 
accounted  for  in  the  analysis.    However,  due  to  the  large  number  of  participating 
centers  (150),  a  statistical  analysis  model  with  center  as  a  fixed  effect  would  yield 
unstable estimates of the treatment effect, especially if some centers contribute a small 
number of subjects.  Therefore, the center effect is omitted in the primary analysis of 
the composite event.  However, as a secondary analysis, at the end of the study, we 
plan  to  analyze  the  primary  efficacy  outcome  variable  adjusted  for  clustering  within 
center  using  a  robust  sandwich  covariance  matrix  estimate  to  account  for  the 
intracluster dependence (proc phreg data=DATA covs(aggregate); id SiteID;).  Sites with 
only 1 enrollment may be collapsed into a single category. 
 
 
12.1.5. 
Additional  Efficacy  Analyses  of  the  Primary  Outcome:  Adjusting  for 
Geographic Region (Tertiary Analysis) 
The geographic region of clinical site (classified as US vs Outside US) will be assessed. 
 
 
12.1.6. 
Additional  Efficacy  Analyses  of  the  Primary  Outcome:  Adjusting  for 
Covariates (Tertiary Analysis) 
 
For other exploratory analyses of the primary outcome variable, the composite event is 
assessed for treatment differences adjusting for a variety of covariates deemed clinically 
or  prognostically  important,  such  as  age  and  time  between  symptom  onset  and 
randomization,  whether  a  brain  infarction  is  demonstrated  on  an  initial  scan.    These 
adjustments are made in the form of a Cox proportional hazards model.  Each covariate 
is evaluated individually first with a model that includes an interaction effect with the 
treatment  (clopidogrel  or  placebo).    If  a  significant  interaction  (p<0.10)  is  observed, 
subgroup analyses may be considered (see Section 12.1.7).  Quantitative and qualitative 
interaction  between  the  treatment  and  each  covariate  also  are  visually  assessed  by 
graphical  methods.    A  multivariable  model  that  includes  covariates  that  contributed 
significantly (p<0.05) as treatment modifiers individually may then be constructed. 
 
 
12.1.7. 
Additional  Efficacy  Analyses  of  the  Primary  Outcome:  On‐Treatment 
Analyses (Secondary Analysis) 
 
To account for study treatment discontinuations prior to 90 days, the primary efficacy 
outcome variable will be analyzed while on‐treatment only, i.e., those who are known to 
have permanently discontinued the study drug will be censored one day after the date 
known  to  have  permanently  discontinued  the  study  drug.  Furthermore,  this  survival 


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analysis of the composite events outcome will analyze all randomized subjects according 
to the treatment that they actually received (i.e., if they were assigned to receive study 
drug bottle containing drug A, but due to administrative/enrollment error, received a 
study  drug  bottle  containing  drug  B,  they  would  be  analyzed  with  the  group  they 
actually received). For the interim analyses, to be included the subject must have been 
randomized at least 90 days prior to the data freeze.   
The treatment effect in this analysis is tested at the two‐sided alpha level of 0.05. 
 
Likwise, the As‐Treated analysis will be repeated for the primary and secondary efficacy and 
safety outcomes. 
12.1.8. 
Additional  Efficacy  Analyses  of  the  Primary  Outcome:  Subgroup  Analyses 
(Tertiary Analysis) 
 
The primary efficacy outcome variable is analyzed by the following subgroups, assuming 
sufficient numbers of subjects are enrolled in the subgroups (~10%): 
 
 
Index event type: either TIA or minor stroke 
 
Age (<65 or≥65) 
 
Gender 
 
Race/ethnicity 
 
Hypertension 
 
Aspirin use prior to randomization 
 
Statin use prior to randomization 
 
Imaging evidence of infarction on initial assessment 
 
Geographic region of clinical site (US versus all other countries) 
 
Current Smoker (at time of Index Event) versus former/non‐smoker 
 
Severity  of  index  ischemic  stroke  among  those  with  index  ischemic  stroke 
(baseline NIHSS 0,1 vs. 2,3) 
 
Risk of index TIA among those with TIA (ABCD2 score >5 vs. <=5) 
 
Time from index event to randomization (<6 hours, >=6 hours) 
 
  
 
Prevailing aspirin dose (This subgroup analysis will be performed for the primary 
efficacy and primary safety outcome.) 
 
The treatment effect in each of the subgroups is tested at the two‐sided alpha level of 
0.05.  
 
12.2. 
Interim Efficacy Analysis 
 
For the interim analyses of the composite event for the primary efficacy analysis, O'Brien 
and  Fleming  (1979)  stopping  boundaries  are  adopted.  Assuming  that  the  two  interim 
analyses occur after approximately 177 (1/3 of 530 total events) and 353 (2/3) events have 
been observed and adjudicated, the nominal alpha levels to reject the null hypotheses for 
overwhelming efficacy are as follows: 
 
 
 


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Table  2.  Nominal  Critical  values  and  Alpha  Levels  for  Three  Interim 
Analysis for Overwhelming Efficacy (O’Brien‐Fleming, =0.05 two‐sided) 
 
Analysis Order 
Number of Events 
Nominal critical point  
(Z‐value scale)  
Alpha level  
1 
177 
±3.710 
0.0002 
2 
353 
±2.511 
0.012 
Final 
530 
±1.993 
0.0463 
 
 
Depending  upon  the  DSMB  request,  additional  interim  analyses  may  be  conducted.  The 
spending function approach gives flexibility in the timing and frequency of interim analyses. 
The most current version of the EAST® software (Cytel Corporation) is used as the interim 
monitoring tool. 
 
At  any  interim  analysis,  if  we  cross  the  stopping  boundary,  the  DSMB  may  recommend 
stopping the study for overwhelming efficacy of one treatment over the other, although the 
better treatment may not necessarily be clopidogrel.  If and only if the stopping boundary is 
crossed,  prior  to  making  the  final  decision  for  recommendation  to  stop  the  study,  it  is 
expected  that  the  DSMB  would  request  thorough  analyses  of  secondary  outcomes  and 
subgroup analyses to confirm the findings of the primary outcome results.   
 
12.3. 
Interim Futility Analysis 
 
Futility  analyses  are  planned  to  be  conducted  to  coincide  in  timing  with  the  tentatively 
scheduled interim analyses for efficacy (at three equal intervals of information).  However, if 
the recruitment is much slower than anticipated or if new information from sources external 
to the study about the clopidogrel treatment becomes available, the futility of the therapy 
may be assessed earlier or in between planned intervals of interim analyses. 
 
The stochastic curtailment method is adopted based on conditional power (Lan KKG et al, 
1982). The informal criterion for determination of futility is that at each interim look, if the 
conditional power (defined as the probability of rejecting the  null hypothesis at the final 
analysis given the data accumulated so far and under the assumption that the alternative 
hypothesis under the original design is true) falls below 20%, then the DSMB evaluates all 
study  information  (such  as  overall  recruitment  rate  and  secondary  outcome  assessment 
data) to consider stopping the study for futility. The evaluation is conducted in a blinded 
manner.   
 
Evaluation of futility using conditional power allows flexibility in that it can be calculated and 
assessed at anytime during the study without inflation of the Type I error probability and 
that the threshold does not necessarily have to be pre‐specified.  The drawback is that the 
overall Type II error probability may not be preserved, whereas a formal but less flexible 
hypothesis  testing  approach  using  the  beta‐spending  function  for  futility  boundaries 
(Pampallona S et al, 2001) does preserve power.  However, for the POINT Trial, the flexibility 


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of  this  informal  approach  to  assessing  futility  holds  more  appeal  because  it  allows  other 
information  to  be  taken  into  consideration,  such  as  recruitment  and  safety  data  and 
conditional power at other alternative effect sizes (Freidlin B and Korn EL, 2002).  
 
An  interim  monitoring  tool,  the  most  current  version  of  the  EAST®  software  is  used  to 
estimate the conditional power. 
 
 


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12.4. 
Interim Monitoring Schematic 
 
 
 
177 adjudicated 
primary events 
are observed 
353 adjudicated 
primary events 
are observed
530 adjudicated 
primary events 
are observed 
Z > ±3.71
Conditional Power 
<0.20 
Current and Assumed placebo 
rates have non‐overlapping CI 
Stop for 
treatment group 
difference
Stop for futility 
Recommend  
sample size 
increase
Z > ±2.511
Stop for 
treatment group 
difference
Stop for futility 
Z > ±1.993 
Significant 
treatment group 
difference
Failed to show 
treatment group 
difference
Conditional Power 
<0.20 


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12.5. 
Secondary and Tertiary Clinical Efficacy Outcomes Analyses  
 
12.5.1. Secondary Analyses  
 
Several secondary analyses will be performed to evaluate of the impact of therapy. Prior to these 
analyses, univariate analyses of covariates, identified from previous studies as having confounding 
effect  on  the  outcome  measurements,  are  conducted  to  determine  their  inclusion  in  the 
multivariable models.  In addition, stepwise regression methods may be applied to assess the best 
set of covariates to include in a particular model.  Some of the suspected significant confounders 
are:  age, time from symptom onset to randomization, African Americans, those previously taking 
aspirin, those with index TIA vs. minor ischemic stroke.   
 
The  usual  verification  of  variable  and  model  assumptions  and  goodness  of  fit  assessments 
accompany each analysis.  Time to event outcomes will be assessed via log rank test (unadjusted) 
and via cox proportional hazard model adjusting for covariates.  A Wilcoxon log‐rank test will be 
used  for  ordinal  outcomes  (mRS).  A  logistic  regression  will  be  used  for  binary  outcomes  (90  day 
mRS).  The significance of each test is set at a two‐sided alpha of 0.05.  
 
ITT analyses and As‐treated analyses will be performed for the following secondary outcomes for 
efficacy/net‐benefit: 
 
Composite event of ischemic stroke, MI, ischemic vascular death, or major hemorrhage  
 
Ischemic stroke 
 
Ischemic vascular death 
 
MI 
 
Composite event of ischemic stroke and hemorrhagic stroke 
 
ITT analyses and As‐treated analyses for efficacy/net‐benefit will be performed for the following 
secondary outcomes for safety/tolerability: 
 
 
Primary efficacy outcome from day 0 to 7 and day 8 to 90, and from day 0 to 30 and day 
31 to 90 (HR and 95% CI will be calcuated via cox model for each time point stratified) 
 
Primary safety outcome from day 0 to 7 and day 8 to 90, and from day 0 to 30 and day 
31 to 90 (HR and 95% CI will be calcuated via cox model for each time point stratified) 
 
All‐cause Death 
 
Hemorrhagic stroke 
 
Symptomatic intracerebral hemorrhage 
 
Other symptomatic intracranial hemorrhage (SAH, SDH or IVH) 
 
Major Hemorrhage other than Intracranial Hemorrhage 
 
All minor hemorrhage (including asymptomatic intracranial hemorrhage) 
 
 
12.5.2. Tertiary  Analyses  (given  sufficient  number  of  events,  >15  events  in  total  for  both 
treatment arms, are available for analyses to be meaningful) 
 
Composite of ischemic stroke, MI, all‐cause death, or major hemorrhage 
 
Composite ischemic stroke, TIA, MI, or ischemic vascular death 
 
TIA (as outcome)  


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 
Coronary Revascularization 
 
Vascular death  
 
SAEs together and by major class (MedDRA Body System) 
 
New handicap/disability defined as 90 day mRS  (>=2) 
 
 90 day mRS (ordinal) 
 
Asymptomatic intracranial hemorrhage (ICH, SAH, SDH or IVH) 
 
 
These analyses are used to confirm or support the findings based on the primary outcome analysis.  
If most of the secondary outcomes show a change in the opposite direction from the primary or no 
change, we might have less confidence in the primary outcome.   
 
 
13 
SAFETY ANALYSES 
 
13.1 
13.1.  Safety Monitoring 
 
The  detailed  guidelines  for  monitoring  for  safety  by  the  Medical  Monitor  and  the  DSMB  are 
provided  in  the  NINDS  Guidelines  for  Data  and  Safety  Monitoring  in  Clinical  Trials 
(http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm). 
 
To expedite review, safety data will be analyzed by the DSMB as reported by the site investigator, 
prior to adjudication.  The unblinded statistician at the NETT SDMC will produce the reports on a 
regular basis and at the request of the DSMB.   
 
The DSMB may request an additional interim analysis of efficacy if safety concerns must be balanced 
against efficacy and may recommend stopping the study prior to the planned interim analysis if, in 
their  judgment,  the  risk  to  patients  outweighs  the  benefit  of  treatment.    The  final  decision  to 
terminate the study will be made by the NINDS, based on the DSMB recommendation. 
 
 
13.2 
Summary of Adverse Events 
 
All SAEs are summarized by “preferred term” and associated system‐organ class according to the 
MedDRA adverse reaction dictionary and by treatment group in terms of frequency of the event, 
number of subjects having the event, timing relative to randomization, severity, and relatedness to 
the study drug.  
 
For the following specific events, the proportions and their 95% confidence intervals by treatment 
group are provided: 
 
 
Death from any cause within 90 (± 14) days of randomization  (expected rate 3%) 
 
Intracranial hemorrhage within 90 days  (expected rate 0.5%) 
 
Major hemorrhage within 90 days  (expected rate 2%) 
 
Minor hemorrhage within 90 days (expected rate 2%) 
 


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Expected rates of these events are based on historical data from the clopidogrel treated patients 
from pilot cohort studies (Johnston, et al., 2000; 2007), and these expected rates will be presented 
alongside the actual rates.   
 
Other  serious  adverse  events  will  be  reported  by  treatment  group.  At  the  end  of  the  study,  the 
cumulative  incidences  of  these  events  are  compared  between  the  two  treatment  groups  using 
Fisher’s exact test at the two‐sided alpha level of 0.01.   
 
14 
BIOMARKER ANCILLARY STUDY 
 
As an ancillary study to the POINT Trial, participants will be asked to donate a one‐time blood sample 
collected at time of enrollment in trial; no follow up is conducted. The objective is to determine whether 
clopidogrel‐resistant  genotypes  modify  the  stroke  prevention  response  in  high‐risk  TIA  and  minor 
ischemic stroke patients. 
 
(1) 
PRIMARY  OUTCOME:  Relative  risk  of  vascular  outcome  events  for  carriers of  specific 
ABCB1 and CYP2C19 genotypes vs. non‐carriers among subjects receiving clopidogrel.  
(2) 
SECONDARY  OUTCOME:  Subgroup  analysis  by  enrolling/index  event  type,  performed 
separately for TIA and  minor ischemic stroke cohorts. 
 
Approximately one‐quarter to one‐third of subjects are expected to be carriers of the CYP2C19 poor 
metabolizer  allele,  which  has  been  associated  with  an  increased  risk  of  vascular  events  with  hazard 
ratios  (HR)  ranging  from  1.5  to  3.6  across  studies.  Of  primary  interest  is  the  relative  risk  of  vascular 
outcome  events  for  carriers  versus  non‐carriers  amongst  those  receiving  clopidogrel.  Assuming 
approximately 80% of the remaining POINT patients consent to participate in this proposal, then the 
total sample contributing to the repository is approximately 2,534 (anticipating that this substudy will 
start  enrolling  August  2012).    Cox  proportional  hazard  regression  will  be  used  to  model  the  time  to 
composite  event  of  ischemic  stroke,  MI,  or  ischemic  vascular  death.  The  model  will  be  fit  using  all 
available data from both treatment groups and will adjust for treatment group (clopidogrel or placebo), 
allele type (carrier vs non‐carrier), and the interaction of carrier and treatment group. From this model, 
the  relative  risk  (hazard  ratio)  for  carriers  receiving  clopidogrel  relative  to  the  noncarriers  receiving 
clopidogrel  (reference  group)  will  be  estimated.  This  model  will  also  adjust  for  other  covariates  as 
specified  in  section  12.1.5.  The  following  suspected  significant  confounders  are:  age,  time  from 
symptom onset to randomization, African Americans, those previously taking aspirin, those with index 
TIA vs. minor ischemic stroke. A model building approach will be used, considering first the univariate 
association of each potential confounder. The allele type should have no affect on outcome rates for the 
placebo group, but the model will be fit with all available data to improve the variance estimates and 
thus improve statistical power.   
Of  secondary  interest  is  a  subgroup  analysis  by  the  enrolling/index  event  type  (either  TIA  or  minor 
ischemic  stroke  cohort).  The  same  analysis  will  be  performed  separately  for  the  TIA  cohort  and  the 
minor ischemic stroke cohort. 
Given  a  sample  size  of  approximately  2,534  total,  there  will  be  1,267  patients  (1/2)  randomized  to 
clopidogrel.  Given  the  expected  event  rate  of  12%  in  the  clopidogrel  group,  a  total  of  149  ischemic 
outcome events are anticipated in the clopidogrel group. Assuming 30% of subjects are carriers of the 
CYP2C19  poor  metabolizer  allele,  a  0.05  alpha  level  two‐sided  log‐rank  test  for  equality  of  survival 
curves will have at least 80% power to detect a difference between the relative risk for carriers receiving 


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clopidogrel  relative  to  the  noncarriers  receiving  clopidogrel  (reference  group)  when  the  true  hazard 
ratio is 1.64. Table 3 below gives the minimum detectable hazard ratio under various assumptions about 
the total number of samples available and the proportion of carriers. 
 
Table 3. Minimum Detectable Hazard Ratios with 80% Power 
Total number 
of samples in 
biomarker 
study 
Expected N in 
clopidogrel 
group 
Proportion 
of  
Carriers 
Expected
number 
of vascular
outcome
events 
Hazard Ratio 
(HR) 
2534 
1267
0.2
152
1.76 
2534 
1267
0.3
152
1.64 
2534 
1267
0.4
152
1.59 
2534 
1267
0.5
152
1.58 
 
 
15 
REFERENCES 
 
Efron B. Forcing a sequential experiment to be balanced.  Biometrika 1971; 58: 403‐417. 
Freidlin B, Korn EL. A comment on futility monitoring.  Controlled Clinical Trials 2002; 23: 355‐366. 
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials, 3rd ed.  1998; New York: Springer‐
Verlag. 
Glidden DV, Vittinghoff E. Modeling clustered survival data with application to multicenter clinical trials: 
the frailty approach.  Statistics in Medicine 2004; 23: 369‐388. 
Holm S. A simple sequentially rejective multiple test procedure.  Scandinavian Journal of Statistics 1979; 
6: 65‐70. 
Johnston, S.C., et al., Short‐term prognosis after emergency‐department diagnosis of transient ischemic 
attack. JAMA, 2000. 284: p. 2901‐2906. 
 
Johnston, S.C., et al., Validation and refinement of scores to predict very early stroke risk after transient 
ischaemic attack. Lancet, 2007. 369(9558): p. 283‐92. 
Lan KKG, Simon R, Halperin M. Stochastically curtailed tests in longterm clinical trials.  Communications 
in Statistics – Sequential Analysis 1982; 1: 207‐219. 
The NINDS rt‐PA Stroke Study Investigators. The National Institute of Neurological Disorders and Stroke 
rt‐PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 
1995;333:1581–1587. 
 
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics 1979; 35: 549‐556. 


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Pampallona S, Tsiatis AA, Kim K. Interim monitoring of group sequential trials using spending functions 
for  the  type  I  and  type  II  error  probabilities.    Drug  Information  Journal  2001;  35:  1113‐1121.


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16 
APPENDIX: SAMPLE SCENARIOS FOR INTERIM STOPPING VERSUS SAMPLE SIZE INCREASE 
 
Table A.1 Sample Scenarios for Interim Stopping versus Sample Size Increase at the First Interim Analysis 
SCENARIO 
Observed 
Placebo Rate 
(Hypothetical 
Values) 
Upper 99% CL 
(for observed 
placebo rate) 
Observed 
Trt Rate
(Hypothet
ical 
Values) 
N at first 
interim 
analysis  
Number 
at risk 
Z‐value 
at 1st 
Interim 
Analysis
(Stop if 
|Z| > 
3.71) 
Conditional 
Power 
(1/3) under
 the 
original 
design 
Re‐
estimated 
N at final 
analysis 
(530 
events) for 
90% Power 
(HR=0.75) 
DSMB  
Recommendations  
at 1st Interim Analysis 
Conditional 
Power 
(2/3) under
 the 
original 
design 
DSMB  
Recommendations
at 2nd Interim 
Analysis 
1
15.24% 
18.4%
11.73%
1383
1.89
0.94
N/A Continue as planned 
0.99
Continue as 
planned 
2
14.0% 
17.1%
14.0%
1332
0.00
0.59
N/A Continue as planned 
0.06Stop for futility 
3
14.0% 
17.0%
12.0%
1435
1.10
0.84
N/A Continue as planned 
0.74
Continue as 
planned 
4
12.0% 
14.6%
10.0%
1696
1.32
0.88
N/A Continue as planned 
0.86
Continue as 
planned 
5
10.0% 
12.4%
12.5%
1658
‐1.63
0.18
6,311 Stop for futility 
N/A N/A 
6
10.0% 
12.2%
8.5%
2017
1.15
0.85
6,311 
Consider safety profile, 
Perform another interim analysis
sooner than planned, 
discuss increasing N 
0.77
Continue as 
planned (with 
increased sample 
size) 
 The assumed placebo rate of the original design was 15.24% with a 95% CI (13.63%, 16.85%).


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Scenario 1 assumes the observed placebo and treatment groups are as hypothesized under the 
original design. 
 
Scenario 2 
177 primary events are observed and the first interim analysis is performed. The observed 
placebo rate is 14%.  Although 14% is less than the expected placebo event rate of 15.24%, the 
99% upper confidence limit overlaps with those of the assumed rate (13.63%, 16.85%). A sample 
size increase is not warranted. The log rank test is performed and the corresponding Z value is 0. 
Since 0 is less than 3.71 (the critical value for the O’brien‐Flemming stopping boundary at look 
1), the trial is not stopped for overwhelming efficacy. The conditional power under the original 
design is 0.59 at the time of the 1st interim analysis which does not meet the criteria to stop for 
futility (>0.20). The DSMB recommends the trial be continued. After 353 events are observed, 
second interim analysis is performed. At this time the conditional power is 0.06 (which is < 0.20). 
The trial is stopped for futility. 
 
Scenario 4 
177 adjudicated primary events are observed and the first interim analysis is performed. The log 
rank test is performed and the corresponding Z value is 1.32. Since 1.32 is less than 3.71 (the 
critical value for the O’brien‐Flemming stopping boundary at look 1), the trial is not stopped for 
overwhelming efficacy. The conditional power is computed to be 0.88 under the design 
alternative which is greater than the criteria to stop for futility (>0.20). The observed placebo 
rate is 12%. Although 12% is less than the expected placebo event rate of 15.24%, the 99% 
upper confidence limit (14.6%) overlaps with those of the assumed rate (13.63%, 16.85%). The 
trial is continued and the next interim look is planned after 2/3 of events have been observed. 
 
Scenario 6 
177 primary events are observed and the first interim analysis is performed. The log rank test is 
performed and the corresponding Z value is 1.15. Since 1.15 is less than 3.71 (the critical value 
for the O’brien‐Flemming stopping boundary at look 1), the trial is not stopped for 
overwhelming efficacy. The conditional power is computed to be 0.85 which is greater than the 
criteria to stop for futility (0.85>0.20). Thus, no formal stopping criteria have been met. 
 
However, the observed placebo rate is 10%. The 99% upper confidence limit around the current 
placebo estimate (12.2%) does not overlap with those of the assumed rate (13.63%, 16.85%).  
This suggests a sample size increase is needed. The sample sizes under various placebo event 
rates are given in Figure 2. To achieve at least 90% power, more than 6,300 patients would be 
needed to observe 530 events given the current estimate of the placebo event rate (10%). 
However, given the substantial increase in sample size required to attain 90% power, the DSMB 
decides to look again sooner than planned after 50% of events (or 265 events) have been 
observed.   
 


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Table A.2 Conditional Power given RRR of 23% and 10% for various placebo proportions 
RRR 
Hazard 
Ratio 
Placebo 
Rate 
Trt 
rate 
Expected N at 
first interim 
analysis  
Number at risk
Z Log‐
Rank 
Test 
p‐value 
t 
(177 
events)
Conditional Power 
under the null 
Conditional 
Power  
under 
 the original 
design 
Conditional 
Power  
under 
 current trend
0.23 
0.75 15.24%11.73%
1383
1.89
0.0586
0.33
0.13 
0.94
0.94
0.23 
0.75
14%10.78%
1506
1.88
0.0602
0.33
0.13 
0.94
0.94
0.23 
0.75
12% 9.24%
1756
1.86
0.0628
0.33
0.13 
0.94
0.93
0.23 
0.75
10% 7.70%
2108
1.84
0.0654
0.33
0.13 
0.94
0.93
0.10 
0.9 15.24%13.72%
1288
0.79
0.4281
0.33
0.03 
0.79
0.22
0.10 
0.9
14%12.60%
1403
0.79
0.4313
0.33
0.03 
0.78
0.22
0.10 
0.9
12%10.80%
1636
0.78
0.4362
0.33
0.03 
0.78
0.21
0.10 
0.9
10% 9.00%
1964
0.77
0.4410
0.33
0.03 
0.79
0.21
The table A.2 shows the conditional power when the difference in treatment groups is equivalent to a RRR of 23% (HR=0.75) for various placebo 
rates. The Conditional power is constant given a constant RRR (rows 1‐4). Decreasing the RRR to 10% results in a decrease in conditional power, 
but again the conditional power is constant for a fixed RRR (rows 5‐8). 
 
 
 


Table A.3 Coding of Composite Outcomes 
POINT Trial Statistical Analysis Plan 
 
Page 22 of 23 
 
 
webDCU 
Code 
Group 
556 
Major Hemorrhage 
Hemorrhagic stroke 
Major Hemorrhage other 
than Intracranial Hemorrhage 
(a.k.a. Major systemic hemorrhage) 
Coronary 
 Revascularization 
Ischemic 
 stroke 
Asymptomatic 
intracranial 
hemorrhage (ICH, 
SAH, SDH or IVH) 
All minor hemorrhage 
(including 
asymptomatic 
intracranial 
hemorrhage) 
1 
  
  
  
  
Ischemic stroke  
2 
Symptomatic hemorrhagic 
transformation of an 
ischemic stroke 
Symptomatic hemorrhagic 
transformation of an ischemic 
stroke  (OF INDEX EVENT OR 
FOLLOW‐UP EVENT) 
  
  
Symptomatic hemorrhagic 
transformation of an 
ischemic stroke  (NOT OF 
INDEX EVENT) 
3 
  
  
  
  
Asymptomatic 
hemorrhagic 
transformation of an 
ischemic stroke  (NOT OF 
INDEX EVENT) 
4 
Symptomatic 
intracerebral hemorrhage  
Symptomatic intracerebral 
hemorrhage  
  
  
  
5 
  
  
  
  
  
Asymptomatic 
intracerebral 
hemorrhage 
Asymptomatic 
intracerebral 
hemorrhage 
6 
Other Symptomatic 
intracranial hemorrhage 
Other Symptomatic intracranial 
hemorrhage If 
7 
  
  
  
  
 
Other Asymptomatic 
intracranial 
hemorrhage 
Other Asymptomatic 
intracranial 
hemorrhage 
9 
  
  
  
Myocardial infarction 
with Coronary 
Revascularization  
  
10 
  
  
  
  
  
11 
  
  
  
Coronary 
Revascularization 
without Myocardial 
Infarction  
  
12 
Major Hemorrhage other 
than Intracranial 
Hemorrhage  
  
Major Hemorrhage other than 
Intracranial Hemorrhage 
13 
 
 
Minor hemorrhage 
other than intracranial 
hemorrhage