Clinical trial NCT01742117
Conditions: Coronary Artery Disease Acute Coronary Syndrome Stenosis
Keywords: percutaneous coronary intervention angioplasty
Sponsor: Mayo Clinic
Start date: 2013-05-01; Completion date: 2020-10-31
Enrollment: 5276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Clopidogrel is an anti-platelet medication approved by the U.S. Federal Drug Administration (FDA) for use in patients who undergo Percutaneous Coronary Intervention (PCI) with coronary stent implantation. Anti-platelet medications work to prevent blood clots from forming. Some studies have suggested that patients who have a certain genetic liver enzyme abnormality (known as cytochrome P450 2C19 \[CYP2C19\] \*2 or \*3 allele) may have a reduced ability to activate clopidogrel, and therefore may have a lowered response to clopidogrel. It is thought that perhaps people who have a coronary stent procedure may have this genetic liver enzyme abnormality. There is a research genetic test available to determine whether or not someone has this genetic liver enzyme abnormality. Ticagrelor, is a newer anti-platelet drug that is not dependent on the CYP2C19 liver enzyme for its activation and hence in poor clopidogrel metabolizers, alternative drugs like Ticagrelor have been recommended for use as an anti-platelet agent after PCI. The purpose of this study is to determine if genetic testing can identify the best anti-platelet therapy, for patients who undergo a coronary stent placement and do not activate clopidogrel very well.

Detailed description:
TAILOR-PCI is a multi-site, open label, prospective, randomized trial testing the hypothesis that after percutaneous coronary intervention (PCI), using a genotyping strategy ticagrelor 90 mg twice per day is superior to clopidogrel 75 mg per day in reducing a composite endpoint of major adverse cardiovascular events (MACE), i.e., non-fatal myocardial infarction, non-fatal stroke, severe recurrent ischemia, cardiovascular (CV) death, and stent thrombosis (primary endpoints) in CYP2C19 reduced function allele patients. Patients who undergo PCI will be randomized to a conventional therapy arm (i.e., to receive clopidogrel 75 mg once daily without prospective genotyping guidance) versus a prospective CYP2C19 genotype-based anti-platelet therapy approach (ticagrelor 90 mg bid in CYP2C19 \*2 or \*3 reduced function allele patients, clopidogrel 75 mg once daily in non-\*2 or -\*3 CYP2C19 patients). Buccal swabs will be obtained for those subjects randomized to the prospective genotyping arm. All subjects will have a blood sample drawn for DNA analysis but genotyping using these DNA samples will be performed only after completion of the duration of anti-platelet therapy (i.e., after one year). The primary endpoints will be assessed prospectively and will be compared between the conventional arm and the prospective genotyping arm among those identified as reduced function CYP2C19 allele carriers according to the 1-year genotype results.

Arms: arm 1: Subjects will be genotyped prospectively for CYP2C19\*2, \*3 and \*17 alleles and will receive treatment based on their genotype. In this group, patients who have the CYP2C19 reduced function allele \[i.e., \*2 allele (heterozygous or homozygous) or \*3 allele (heterozygous or homozygous)\] patients will receive ticagrelor 90 mg bid. The WT YP2C19 patients will receive clopidogrel 75 mg once daily. arm 2: Subjects will receive clopidogrel once daily after the index PCI and will be retrospectively genotyped for CYP2C19\*2, \*3 and \*17 alleles after completion of one year of treatment with clopidogrel.
Interventions: intervention 1: Clopidogrel intervention 2: Ticagrelor
Intervention descriptions: intervention 1: One 75 mg tablet per day by mouth for one year intervention 2: One 90 mg tablet twice per day by mouth for one year

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Tailored Antiplatelet Initiation to Lesson Outcomes 
Due to Decreased Clopidogrel Response After 
Percutaneous Coronary Intervention (TAILOR-PCI) 
 
 
NCT01742117 
 
September 13, 2019 


 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL 
Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel 
Response after Percutaneous Coronary Intervention: TAILOR-PCI 
 
 
 
 
Document History 
Effective Date 
Version 1 
08 Nov 2012 
Version 2 
10 Dec 2012 
Version 3 
13 Feb 2013 
Version 4 
20 Sept 2013 
Version 5 
05 May 2014 
Version 6 
01 Oct 2014 
Version 7 
19 May 2015 
Version 8 
Version 9 
20 Jun 2017 
05 Apr 2018 
                                                     Version 10                         08 Nov 2018 
 
 
 
 
 Version 11 
 
    19 Dec 2018 
 
 
 
 
 Version 12 
 
    18 Jun 2019 
 
 
 
 
 Version 13 
 
    11 Jul 2019 
 
 
 
 
 Version 14 
 
    13 Sep 2019


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Study Sponsor 
Center for Individualized Medicine (CIM), Mayo Clinic 
Division of Cardiovascular Diseases, Mayo Clinic 
 
 
Principal Investigators 
Naveen Pereira, MD 
Mayo Clinic 
200 First Street, SW 
Rochester, MN 55905 
 
 
Michael Farkouh, MD 
Toronto General Hospital 
585 University Avenue, 4N474 
Toronto, Ontario M5G 2N2 CAN 
 
 
Contract Research Organizations 
Applied Health Research Centre (AHRC), Toronto, Canada 
DreamCIS, Inc. (DCIS), Seoul, Korea 


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Table of Contents 
1. GLOSSARY OF TERMS ........................................................................................................... 7 
2. SPECIFIC AIMS AND OBJECTIVES / HYPOTHESES ......................................................... 8 
2.1 Primary Hypotheses .............................................................................................................. 8 
2.2 Secondary Aims and Objectives ........................................................................................... 8 
2.3 Exploratory Pre-specified Outcomes .................................................................................... 8 
3. BACKGROUND AND SIGNIFICANCE.................................................................................. 9 
4. PRELIMINARY STUDIES ..................................................................................................... 10 
5. BASIC STUDY DESIGN ........................................................................................................ 11 
6. STUDY POPULATION AND ELIGIBILITY CRITERIA ..................................................... 15 
6.1 Study Population and Source of Participants ...................................................................... 15 
6.2 Inclusion/Exclusion Criterion ............................................................................................. 15 
6.2.1 
Inclusion ..................................................................................................................... 15 
6.2.2 
Exclusion .................................................................................................................... 15 
7. STUDY INTERVENTIONS .................................................................................................... 16 
7.1 Intervention ......................................................................................................................... 16 
7.2 Randomization .................................................................................................................... 16 
7.3 Concomitant Therapies ....................................................................................................... 17 
7.4 Dose Justification ................................................................................................................ 17 
7.5 Side Effects ......................................................................................................................... 17 
7.6 Summary of the Risks and Benefits .................................................................................... 17 
7.6.1 
Potential Benefits: ....................................................................................................... 17 
7.6.2 
Potential Risks ............................................................................................................ 17 
8. RECRUITMENT PROCEDURES ........................................................................................... 20 
8.1 Common Recruitment Procedures ...................................................................................... 20 
8.2 Informed Consent................................................................................................................ 21 
8.3 Confidentiality and HIPAA/Privacy Requirements ............................................................ 21 
9. SCREENING PROCEDURES ................................................................................................. 21 
10. BASELINE EVALUATIONS AND RANDOMIZATION ................................................... 22 
10.1 Evaluations Performed During the Baseline Period ......................................................... 22 
10.2 Randomization Procedures ............................................................................................... 23 
10.3 Genomic Research ............................................................................................................ 23 
11. FOLLOW-UP EVALUATIONS ............................................................................................ 23 
11.1 Evaluations Performed During the Follow-up Period....................................................... 23 


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11.2 Evaluations for Study Completion, Study Withdrawals, and Treatment Discontinuation 24 
11.3 Study Schedule of Assessments ........................................................................................ 24 
Table 1. Schedule of Assessments to be performed during the study....................................... 25 
11.4 Digital Registry Sub-Study………………………………………………………………25 
Table 2.  Schedule of Assessments to be performed during the sub-study…………………...27 
12. OUTCOME DETERMINATIONS ........................................................................................ 30 
12.1 Primary Outcome .............................................................................................................. 30 
12.2 Secondary and Exploratory Pre-specified Outcomes ........................................................ 30 
12.3 Clinical Event Definition and Adjudication ..................................................................... 31 
13. QUALITY CONTROL ACTIVITIES ................................................................................... 33 
13.1 Training Sessions and Certification Procedures ............................................................... 33 
13.1.1 
Genotyping via SPARTAN® Bioscience .................................................................... 34 
13.1.2 
Genotyping via ABI TaqMan ..................................................................................... 34 
13.1.3 
Database Training ....................................................................................................... 34 
14. PARTICIPANT SAFETY, ADVERSE EVENTS, CLINICAL ENDPOINTS, AND OTHER 
REPORTING ................................................................................................................................ 34 
14.1 Institutional Review Boards .............................................................................................. 34 
14.2 Adverse Events ................................................................................................................. 34 
14.3 Clinical Endpoints ............................................................................................................. 35 
14.4 Other ................................................................................................................................. 35 
15. STATISTICAL CONSIDERATIONS ................................................................................... 35 
15.1 Study Design ..................................................................................................................... 35 
15.2 Sample Size and Power Considerations ............................................................................ 36 
15.2.1 
Primary Endpoint ........................................................................................................ 36 
15.2.2 
Revised Sample Size Calculations.............................................................................. 37 
15.2.3 
Secondary Endpoint .................................................................................................... 38 
15.3 Randomization .................................................................................................................. 38 
15.4 Statistical Comparisons of Baseline Factors ..................................................................... 39 
15.5 Specification of the Primary Analyses .............................................................................. 39 
15.6 Specification of the Secondary Analyses .......................................................................... 40 
15.7 Subgroup Analyses ........................................................................................................... 40 
15.7.1 
Interaction Between CAD Presentation and Genotype-guided Therapy .................... 40 
15.7.2 
Interaction Between *17 Carriers and *2/*3 and Antiplatelet Therapy ..................... 40 
15.7.3 
Additional Subgroup Analyses ................................................................................... 40 
15.8 Monitoring for Futility and Efficacy ................................................................................. 40 


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15.9 Assumptions Monitoring .................................................................................................. 41 
15.9.1 
Event Rate in the Stable CAD Patients ...................................................................... 41 
15.9.2 
Event Rate in Subjects Enrolled at Korean Sites ........................................................ 42 
15.9.3 
Cross-over Monitoring ............................................................................................... 43 
15.9.4 
Spartan Performance Monitoring ............................................................................... 43 
16. TRIAL MANAGEMENT ...................................................................................................... 43 
16.1 Data Management Oversight ............................................................................................ 43 
16.2 Quality Assurance ............................................................................................................. 44 
16.3 Quality Control Procedures ............................................................................................... 45 
16.4 Site Monitoring ................................................................................................................. 45 
16.5 Study Completion and Closeout Procedures ..................................................................... 45 
16.6 Hardware and Software Configuration ............................................................................. 46 
16.6.1 
Hardware and Database Software ............................................................................... 46 
16.6.2 
Statistical Software ..................................................................................................... 46 
16.6.3 
Access Control and Confidentiality Procedures ......................................................... 46 
16.6.4 
Security ....................................................................................................................... 46 
16.6.5 
Back-up Procedures .................................................................................................... 46 
16.6.6 
Virus Protection .......................................................................................................... 46 
16.6.7 
Data Management Activities ...................................................................................... 46 
16.6.8 
Reports and Summaries .............................................................................................. 47 
16.7 Biological Sample Management ....................................................................................... 47 
17. STUDY ADMINISTRATION ............................................................................................... 48 
17.1 Cooperative Agreement Mechanism ................................................................................. 48 
17.2 Steering Committee .......................................................................................................... 49 
17.3 Executive Committee ........................................................................................................ 49 
17.4 Publications Committee .................................................................................................... 49 
17.5 Data and Safety Monitoring Board ................................................................................... 49 
17.6 Adjudication Committee ................................................................................................... 49 
17.6.1 
Adverse Event and Clinical Endpoint Reporting ....................................................... 49 
17.7 Monitoring ........................................................................................................................ 50 
17.8 Informed Consent Procedures ........................................................................................... 50 
17.9 Confidentiality .................................................................................................................. 50 
18. REFERENCES ....................................................................................................................... 50 
APPENDICES .............................................................................................................................. 54 


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A. Ticagrelor and Clopidogrel Dose Justification and Side-effects.......................................... 54 
Ticagrelor Dose Justification (normal dosage, oral route) ........................................................ 54 
Clopidogrel Hydrogen Sulfate Dose Justification (normal adult dosage, oral route) ............... 54 
Dosage in Hepatic Insufficiency ............................................................................................... 55 
Dosage in Geriatric Patients ...................................................................................................... 55 
18.1.1 
Ticagrelor Side Effects ............................................................................................... 56 
18.1.2 
Clopidogrel Side Effects (<2% unless otherwise stated)............................................ 56 
B. Clinical Trial Management Systems (CTMS) ...................................................................... 57 
Electronic Data Capture ............................................................................................................ 57 
Medidata Balance ...................................................................................................................... 57 
C. Statistical Considerations…..................................................................................................58 
D. Site Monitoring…………………………………………………………………………….60 
E. Steering Committee Membership………………………………………………………….61 
F. Publications Committee…………………………………………………………………....61 
G. Data and Safety Monitoring Board………………………………………………………...61 
H. Monitoring…………………………………………………………………………………61 
 


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1. GLOSSARY OF TERMS 
 
 
 
ACC 
American College of Cardiology 
AHA 
American Heart Association 
ACS 
acute coronary syndrome 
AHRC 
Applied Health Research Center 
BAP 
Biospecimens Accessioning and Processing Lab 
bid 
twice daily 
CABG 
Coronary Artery Bypass Graft 
CAD 
coronary artery disease 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
case report form 
CV 
cardiovascular 
DCIS 
DreamCIS, Inc. 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
HHS 
Health & Human Services 
FDA 
Food and Drug Administration 
HR 
Hazard Ratio 
MACE 
major adverse cardiovascular event 
MI 
myocardial infarction 
NSTEMI 
non-ST elevation myocardial infarction 
PCI 
percutaneous coronary intervention 
PHS 
Public Health Service 
PI 
Principal Investigator 
qd 
every day 
SCAI 
Society for Cardiovascular Angiography and Interventions 
STEMI 
ST-elevation myocardial infarction 
WT 
wild type 


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2. SPECIFIC AIMS AND OBJECTIVES / HYPOTHESES 
TAILOR-PCI is a prospective, randomized trial testing the hypothesis that after percutaneous coronary 
intervention (PCI), ticagrelor 90 mg bid is superior to clopidogrel 75 mg qd in reducing a composite 
endpoint of major adverse cardiovascular events (MACE), i.e. non-fatal myocardial infarction, non-fatal 
stroke and cardiovascular (CV) death, severe recurrent ischemia, and stent thrombosis (primary 
endpoints) in CYP2C19 reduced function allele patients. Patients who undergo PCI will be randomized to 
a conventional therapy arm (i.e. to receive clopidogrel 75 mg once daily without prospective genotyping 
guidance) versus a prospective CYP2C19 genotype-based anti-platelet therapy approach (ticagrelor 90 mg 
bid in CYP2C19*2 or *3 reduced function allele patients, clopidogrel 75 mg once daily in non-*2 or -*3 
CYP2C19 patients). Buccal swabs will be obtained for those subjects randomized to the prospective 
genotyping arm. All subjects will have a blood sample drawn for DNA analysis but genotyping using 
these DNA samples will be performed only after completion of the duration of anti-platelet therapy (i.e. 
after one year). In cases where the initial sample collected to analyze the DNA at the one year time point 
is found to be an unviable sample, the subject will be contacted and asked to provide another DNA 
sample via a blood sample or saliva sample. The primary endpoints will be assessed prospectively in the 
retrospectively identified reduced function CYP2C19 allele patients receiving clopidogrel 75 mg once 
daily and compared with the prospectively identified reduced function CYP2C19 allele group receiving 
ticagrelor 90 mg bid. A total of 5,270 patients will be enrolled. 
 
2.1 Primary Hypotheses 
Hypothesis 1A: As compared with clopidogrel, treatment with ticagrelor will result in significantly 
reduced risk of MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, CV death, severe recurrent 
ischemia, and stent thrombosis if not captured in other events, in patients with reduced function CYP2C19 
allele(s) (as identified retrospectively by the ABI TaqMan platform) who undergo PCI. This hypothesis 
will be tested with a two-sided test at a Type I error rate of 0.05. 
Hypothesis 1B: In patients undergoing PCI who are wild type with respect to CYP2C19 (by TaqMan), 
and who receive clopidogrel, prospective knowledge of their genotype (according to the Spartan® 
platform results) does not alter the risk of MACE. This hypothesis will be tested formally only if the null 
hypothesis for Hypothesis 1A is rejected. 
 
2.2 Secondary Aims and Objectives 
To assess the incidence of major or minor bleeding in patients with reduced function CYP2C19 
allele(s) receiving ticagrelor versus clopidogrel 
 
2.3 Exploratory Pre-specified Outcomes 
1. The individual components of the primary outcome. 
2. To assess the effect of CYP2C19*17 on bleeding risk and MACE. 
3. The effect of CYP2C19*2 or *3 genotype on multiple recurrent MACE events in the individual 
subject. 
4. To compare the occurrence of MACE in patients with reduced function CYP2C19 allele(s) 
receiving clopidogrel to those with wild type (WT) genotype receiving clopidogrel. 
5. To compare the occurrence of MACE in patients with reduced function CYP2C19 allele(s) 
receiving ticagrelor to those with WT genotype receiving clopidogrel. 
6. To assess the effect of coronary artery disease (CAD) presentation: a) Stable coronary artery 
disease b) Unstable angina or non-ST elevation myocardial infarction (NSTEMI), and c) ST- 
elevation myocardial infarction (STEMI) on the effectiveness of ticagrelor in patients with 
reduced function CYP2C19 allele(s) and on the association of CYP2C19 genotype and occurrence 
of MACE. 


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7. To assess the mechanism of coronary stent thrombosis in patients with reduced function 
CYP2C19 allele(s) receiving ticagrelor versus clopidogrel. 
8. To compare MACE and bleeding outcomes in all patients randomized to the conventional therapy 
arm versus the prospective genotyping arm. 
9. To assess implementation of a CLIA-approved CYP2C19 pharmacogenetic testing on the 
Spartan® platform (accuracy of genetic testing by sequence analysis and genotype failure rates). 
10. To assess compliance with dual anti-platelet therapy by phone survey. 
11. Performing a pharmacoeconomic analysis of the conventional therapy approach as compared with 
the genotype based approach in subjects who undergo PCI. 
12. To assess patients’ attitudes towards genotyping and the results of genotyping by survey. 
 
3. BACKGROUND AND SIGNIFICANCE 
Several studies have suggested that CYP2C19*2 (rs4244285) and *3 (rs4986893) allele carriers may have 
a reduced ability to metabolize clopidogrel and hence have an impaired response to clopidogrel as 
measured by platelet function (1,2,3,4). The Food and Drug Administration (FDA) has advised practitioners 
to “consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor 
metabolizers” and who are to receive clopidogrel. The FDA based this boxed warning on a small, 
crossover trial that evaluated pharmacokinetics and antiplatelet responses to clopidogrel in 40 healthy 
subjects(5). The use of platelet function studies as an endpoint in this and other larger clinical studies limits 
the clinical relevance of genotyping since the relationship between cardiovascular endpoints and platelet 
function studies is unclear and confounding. 
 
There are several studies that suggest that CYP2C19*2 and *3 allele carriers may have increased major 
adverse cardiovascular events with the use of clopidogrel after coronary stent implantation and in acute 
coronary syndromes(1,2,6). However, in none of these trials was genotyping performed comprehensively 
and prospectively and were hence prone to bias. Furthermore, pharmacogenetic analysis was performed  
in a sub-group of patients who had DNA collected and not in the entire cohort of patients. 
 
Both clopidogrel and ticagrelor are FDA approved for use in patients who undergo PCI and coronary stent 
implantation. Ticagrelor has been shown to be superior to clopidogrel in a large trial involving 18,624 
patients with acute coronary syndrome in reducing cardiovascular deaths, stroke and myocardial 
infarction (hazard ratio 0.84, 95% CI, 0.77-0.92)(7). Ticagrelor has also been shown to be safer in patients 
undergoing coronary artery bypass graft (CABG) and has the additional benefit of reversible inhibition. 
However, ticagrelor caused an increased risk of non-CABG-related bleeding. In addition, prasugrel 
(another anti-platelet drug that irreversibly inhibits the P2Y12 receptor) has been shown to be superior to 
clopidogrel in reducing the risk of cardiovascular death, myocardial infarction (MI), and stroke in a large 
trial involving 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI 
(HR 0.81, 95% CI, 0.73-0.90)(8). However, prasugrel also led to significantly higher rates of bleeding, 
including life-threatening and fatal bleeding. The findings from these 2 trials have been inconsistently 
adopted into routine use post-PCI, and the recent availability of generic clopidogrel has also contributed 
to the delayed uptake of prasugrel and ticagrelor into routine clinical practice of acute coronary syndrome 
(ACS) and post-PCI in the United States and Canada. 
 
Routine clinical use of genotyping for CYP2C19 in patients who undergo coronary stent implantation is 
not recommended due to lack of evidence as per recent guidelines published by the American College of 
Cardiology (ACC), American Heart Association (AHA), and Society for Cardiovascular Angiography 
and Interventions (SCAI)(9). Hence, the standard of care at present is to treat all patients who undergo  PCI 
with standard dose of clopidogrel without preemptive genotyping. If genotyping is performed and patients 
are preemptively identified as being predisposed to potentially inadequate platelet inhibition based on 
their genotype, treating these patients with a P2Y12 inhibitor (prasugrel or ticagrelor) would be a 


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Class IIb (level of evidence C) indication(9) and treating these patients (who presumed to be poorer 
metabolizers) with an alternative anti-platelet agent to clopidogrel is implied in the FDA boxed warning. 
However, there appears to be adequate equipoise in the cardiovascular community as to the best approach 
in treating these patients. Hence, the purpose of this study is to determine the optimal anti-platelet  
therapy for patients with CYP2C19 reduced function alleles who undergo PCI. 
 
4. PRELIMINARY STUDIES 
Mega(1) explored the effect of CYP2C19 reduced function allele in a separate cohort of 1,477 subjects 
with acute coronary syndromes who were treated with clopidogrel in the TRITON-TIMI 38. The 
pharmacogenetic cohort receiving clopidogrel represented approximately 10% of the total original study 
population. Among the clopidogrel-treated subjects there was a 12.1% composite event rate of death  
from cardiovascular causes, myocardial infarction, and stroke as compared with 8% of patients with WT 
CYP2C19 genotype (i.e. relative 53% increased risk). The risk of stent thrombosis in the carriers was 
2.6% as compared with 0.8% in the WT group. 
 
Simon(3) observed similar results in their analysis of 2,208 patients in the FAST-MI cohort. They 
observed a higher event rate in carriers of two CYP2C19 reduced function alleles (21.5% vs. 13.3%, 
adjusted hazard ratio (HR), 1.98; 95% CI, 1.10-3.58). In patients undergoing PCI (n=1535), the adjusted 
risk of death, MI, or stroke was 3.58 times higher in patients with 2 CYP2C19 reduced function alleles 
(95% CI, 1.76-7.51, p=0.005). 
 
In a collaborative meta-analysis, with data extracted from 9 previous studies(10) involving 9,685 study 
participants receiving clopidogrel (91.3% with PCI, 54.5% with ACS), carriers of 1 (HR, 1.55; 95% CI, 
1.11-2.17) or 2 (HR, 1.76; 95% CI, 1.24 – 2.50, p=0.002) reduced function CYP2C19 alleles had a 
significantly increased risk of composite end point (CV death, MI, or stroke). Furthermore, a  
significantly increased risk in stent thrombosis was observed with carriers of 1 (HR, 2.67; 95% CI, 1.69- 
4.22, p<.0001) or 2 (HR, 3.97; 95% CI, 1.75-9.02, p=.001) reduced function CYP2C19 alleles. Similarly, 
a study by Hulot(11) of 4,905 patients with PCI showed an odds ratio of 3.45 for stent thrombosis for 
individuals carrying a CYP2C19*2 allele. 
 
Shuldiner(2) reported a genome-wide association study that identified CYP2C19 to be significantly 
associated with platelet aggregation response to clopidogrel. The CYP2C19*2 variant was shown to 
account for 12% of the variation in platelet aggregation to ADP. The relationship of CYP2C19*2 
genotype to cardiovascular outcomes was analyzed in 227 patients undergoing PCI; carriers of the 
reduced function allele were found to have a composite event rate (myocardial infarction, ischemic stroke, 
stent 
thrombosis, 
unplanned 
target 
vessel 
revascularization, 
unplanned 
non-target 
vessel 
revascularization, hospitalization for coronary ischemia, and death secondary to any cardiovascular cause) 
of 20.9% as compared with 10% event rate in non-carriers. 
 
In contrast, a pharmacogenetic analysis of two large trials by Pare(12) comparing the effects of clopidogrel 
versus placebo, the CURE study in acute coronary syndromes and the ACTIVE A study in atrial 
fibrillation of 6,215 patients combined, showed similar benefit of clopidogrel as compared with placebo 
in both carriers and non-carriers of the reduced function allele. Hence, the beneficial effect of clopidogrel 
as compared with placebo was maintained irrespective of reduced function CYP2C19 carrier status. 
However, only 14.5% of the participants in this study underwent PCI with stent as compared with >70% 
in other studies that have demonstrated a positive correlation between CYP2C19 carrier status and 
response to clopidogrel. The genetic sub study of CHARISMA also did not find any interaction between 
clopidogrel and CYP2C19 status(13). Similar to CURE and ACTIVE A, this study did not include a post- 
PCI population. 


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The PLATO study evaluated patients with acute coronary syndrome who were treated with ticagrelor or 
clopidogrel(7). Amongst the 18,624 patients enrolled in PLATO, 10,285 patients had provided samples  for 
genetic analysis(14). The primary event rate of the composite of cardiovascular death, myocardial 
infarction, or stroke after 12 months of treatment was 8.6% in patients treated with ticagrelor versus 
11.2% in the patients treated with clopidogrel when analyzed for all patients with any loss of function 
allele, including CYP2C19 genotype. However, CYP2C19 genotype did not play a role in influencing 
response to ticagrelor. In patients who were treated with clopidogrel, although a significant difference in 
event rate was observed in the first 30 days of treatment for those with any loss of function allele as 
compared with WT, this difference in outcome was not observed when the full follow-up period of 12 
months was analyzed. This reduced interaction of  CYP2C19 polymorphisms was explained in part by  
just 64% of the genetic cohort having had percutaneous coronary intervention stent procedure. The event 
rate in patients receiving clopidogrel who had reduced function CYP2C19 genotype was 11.2% while 
those receiving clopidogrel with no loss of function CYP2C19 allele was 10%. 
 
In a more recent meta-analysis by Holmes(15), evaluating 32 studies of 42,016 patients, a treatment-only 
analysis revealed that carriers of one or two reduced function CYP2C19 alleles were at a higher risk for 
cardiovascular events (relative risk 1.18, absolute risk increase of 8-12 events per 1000 individuals). 
However, there was a significant small study bias. When this analysis was restricted to studies with 200  
or more events, the relative risk of increased events was not significant, and when confined to genetic 
studies nested within randomized trials, the CYP2C19 genotype was not significantly associated with 
cardiovascular events. A limitation of this meta-analysis was the lack of specific analysis for patients 
undergoing stenting compared with other medical treatments, including the inclusion of a large number of 
patients whom were being treated for reasons other than stenting (e.g. atrial fibrillation, STEMI). 
 
Overall, preliminary studies have demonstrated an association between CYP2C19 reduced function 
alleles, clopidogrel response, and outcomes in patients undergoing PCI. These studies have all been 
retrospective in nature and a recent large meta-analysis suggests no significant association between 
CYP2C19 genotype and cardiovascular events with clopidogrel use. Whether such patients with 1 or 2 
CYP2C19 reduced function alleles might benefit from alternative anti-platelet therapy is controversial and 
has not yet been studied in a prospective, randomized fashion. 
 
The RAPID GENE study randomized 187 patients undergoing PCI for ACS or stable coronary disease to 
a strategy of rapid point-of-care genotyping or to standard treatment. For patients assigned to the rapid 
genotyping strategy, those that were identified as carriers of the CYP2C19*2 allele were switched to 
prasugrel, while non-carriers and those in the standard treatment group received clopidogrel 75mg daily. 
The strategy of rapid genotyping in conjunction with personalized antiplatelet therapy, led to a reduction 
in HPR in CYP2C19*2 carriers compared to those in the standard group (0% vs. 30.4%). In the study, the 
point-of-care genetic test demonstrated a sensitivity of 100% and a specificity of 99.3%. These results 
provided the proof-of-concept that bedside genotyping was feasible and accurate(16). 
 
5. BASIC STUDY DESIGN 
This will be a multi-site, open label, prospective randomized trial involving ACS and stable CAD patients 
who come to the cardiac catheterization laboratory at Mayo Clinic, Mayo Clinic Health System (MCHS), 
and other U.S.A., and international sites. 
 
Only ACS patients who come to the cardiac catheterization laboratory at the international sites, and both 
ACS and Non-ACS patients who come to the cardiac catheterization laboratory at Mayo Clinic, MCHS, 
and other U.S.A. sites will be considered for recruitment. The anticipated number of patients amongst the 
U.S.A. sites will be over 4,000 patients who undergo PCI per year and amongst the international sites, 
over 6,000 ACS patients who undergo PCI per year. Eligible, consented patients will undergo 


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randomization after PCI to either a conventional therapy arm or prospective genotyping arm. The 
conventional therapy arm patients will receive clopidogrel once daily after the index PCI and will be 
retrospectively genotyped for CYP2C19*2, *3 and *17 alleles after completion of one year of treatment 
with clopidogrel. The prospective genotyping arm patients will be genotyped prospectively for 
CYP2C19*2, *3 and *17 alleles and will receive treatment based on their genotype. In this group,  
patients who have the CYP2C19 reduced function allele [i.e. *2 allele (heterozygous or homozygous) or 
*3 allele (heterozygous or homozygous) patients will receive ticagrelor 90 mg bid. The WT CYP2C19 
patients will receive clopidogrel 75 mg once daily. If ticagrelor is discontinued prematurely in  the 
reduced function CYP2C19 allele patient due to intolerance and there is no contraindication for continued 
dual anti-platelet therapy, the patients and their physicians will be advised to substitute ticagrelor with 
prasugrel at 10 mg daily (5 mg in patients weighing less than 60 kg or age >75 years)(17) or clopidogrel 
150 mg daily. 
 
In Caucasians, the *2 allele frequency is 15-20% and *3 allele frequency is less than 1%, but up to 29% 
and 9%, respectively, in Asians. Although we are genotyping for *3, because of its low frequency in our 
predominant Caucasian population, we expect to detect very few such patients in Rochester (more may be 
expected from the Canadian, Arizona, and Florida sites). We expect (assuming Hardy-Weinberg 
equilibrium) approximately 4% of patients to be homozygous for the *2 allele (*2/*2), 32% to be 
heterozygous for the *2 allele, and 64% to be WT. Thus, we will expect around 36% of patients that go  
on to PCI will be carriers of one or two *2 alleles. However, to be conservative we will estimate 30% of 
the 4,255 enrolled Caucasian patients and 50% of the 1,015 Asian patients, or ~ 1,784 patients to be 
carriers of the CYP2C19 reduced function allele. After randomization, we anticipate there will be 
approximately 892 patients in each group, i.e. the conventional therapy group receiving clopidogrel who 
are retrospectively identified to have CYP2C19 reduced function allele and the prospectively genotyped 
group whose therapy was guided by the Spartan device results and are retrospectively identified to have 
CYP2C19 reduced function. 
 
The CYP2C19*17 allele frequency in Caucasians is approximately 21-23% and 3% in Asians, and it 
occurs at a frequency of ~26% of Caucasian patients with the *2 allele. The *17 allele is considered a 
gain-of-function allele and has been shown in some studies to lead to enhanced response to clopidogrel 
(via platelet function testing) and a higher rate of bleeding events(7,18,19,20). However, other studies have not 
demonstrated increased platelet inhibition or altered clinical outcomes with the *17 allele (2,3,21,22). Taken 
together, it is unclear how patients with the *17 allele would respond to clopidogrel, and the combined 
effect of *2 and *17 on CYP2C19 function and response to clopidogrel is additionally uncertain. 
Therefore, for the purposes of this study, *17 will not be taken into consideration for prospective 
treatment decisions. However, we will utilize the *17 information to perform retrospective secondary 
analyses to determine its effect (alone and in the presence of *2 or *3) on bleeding risk and MACE. 
 
DNA will be collected and stored for retrospective analysis for both the prospective genotyping group and 
the conventional treatment group. DNA will be analyzed by the ABI TaqMan platform sometime after  
the one year time point from the PCI and completion of duration of anti-platelet therapy to identify those 
patients with one or two copies of CYP2C19 reduced function allele. In cases where the initial sample 
collected to analyze the DNA at the one year time point is found to be an unviable sample, the subject  
will be contacted and asked to provide another DNA sample via a blood sample or saliva sample. In the 
prospective genotyping group, DNA will be analyzed prospectively using the Spartan Bioscience  
platform after PCI. Patients with CYP2C19*2 or *3 reduced function allele will be assigned to receive 
ticagrelor 90 mg. twice daily. Subjects without the reduced function allele will be assigned to receive 
clopidogrel 75 mg once daily. The goal of the study is to determine the difference in MACE in the 
CYP2C19 reduced function allele prospectively genotyped group receiving ticagrelor compared with the 
retrospectively genotyped and identified group receiving clopidogrel. It is hypothesized that there will be 


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Ticagrelor 180 mg 
Clopidogrel 300-600 mg 
PCI loading dose 
lower events in the ticagrelor arm compared with clopidogrel. The design of the study is outlined in the 
figures below. 
 
Loading dose pre-PCI: 
All patients will receive a standard loading dose of antiplatelet therapy per the individual institution’s 
routine clinical guidelines (prior to PCI, during PCI, or first dose after PCI), i.e. clopidogrel 300-600 mg 
or ticagrelor 180 mg. If patients receive ticagrelor 180 mg as a loading dose, and are then assigned to 
receiving clopidogrel as maintenance therapy, a loading dose of clopidogrel 300-600 mg as per 
institutional preference will be recommended post-randomization as the next scheduled dose and 75 mg 
once daily as subsequent maintenance dosing. Similarly, when a transition is made from clopidogrel to 
ticagrelor, those loaded with 300-600 mg clopidogrel and assigned to receiving ticagrelor will get as a 
next scheduled dose, ticagrelor 180 mg as a loading dose post-randomization and will then receive 90 mg 
twice daily as maintenance therapy(23). 
          
Figure 1 
↓ 
 
↓ 
or 
↓ 
↓ 
↓ 
↓ 
↓ 
* 
↓ 
↓ 
* 
↓ 
 
↓ 
↓ 
↓ 
↓ 
 
 
* Dependent upon randomization to conventional arm or prospective genotyping arm, 
subjects may receive clopidogrel or ticagrelor as subsequent anti-platelet therapy, see 
below 
 
 
 
 
 
 
 
 
 
 
 
Ticagrelor 180 mg 
Clopidogrel 75 mg 
Ticagrelor 90 mg 
Clopidogrel 300-600 mg 
Ticagrelor 90 mg bid 
Clopidogrel 75 mg qd 
Ticagrelor 90 mg bid 
Clopidogrel 75 mg qd 
Onset 
Next scheduled dose 
Maintenance dose 




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6. STUDY POPULATION AND ELIGIBILITY CRITERIA 
 
6.1 Study Population and Source of Participants 
The study population will be all patients who present with ACS, or stable CAD at the selected U.S.A. 
sites, and those who present with ACS at the selected international sites, and undergo PCI, require 
anti-platelet therapy for at least 12 months, and have consented to the study. The source of 
participants will be patients who are referred to the cardiac catheterization laboratory and may be 
eligible for PCI. Patients are referred to the cardiac catheterization laboratory from the outpatient 
clinic, emergency room, or the hospital setting. 
 
6.2 Inclusion/Exclusion Criterion 
 
6.2.1 Inclusion 
 
Patient >18 years of age 
 
Patient presents with ACS or stable CAD 
 
Patient is eligible for PCI 
 
Patient is willing and able to provide informed written consent 
 
Patient is willing to provide a DNA sample (via blood draw or saliva) for genotyping 
 
6.2.2 Exclusion 
 
Patient not able to receive 12 months of dual anti-platelet therapy 
 
Failure of index PCI 
 
Patient or physician refusal to enroll in the study 
 
Patient with known CYP2C19 genotype prior to randomization 
 
Planned revascularization of any vessel within 30 days post-index procedure and/or 
of the target vessel(s) within 12 months post-procedure 
 
Anticipated discontinuation of clopidogrel or ticagrelor within the 12 months follow 
up period (e.g. for elective surgery) 
 
Serum creatinine >2.5 mg/dL within 30 days of index procedure 
 
Platelet count <80,000 or >700,000 cells/mm3, or white blood cell count <3,000 
cells/mm3 if persistent (at least 2 abnormal values) within 30 days prior to index 
procedure. 
 
History of intracranial hemorrhage 
 
Known hypersensitivity to clopidogrel or ticagrelor or any of its components 
 
Inability to take aspirin at a dosage of 100 mg or less 
 
Patient is participating in an investigational drug or device clinical trial that has not 
reached its primary endpoint 
 
Patient previously enrolled in this study 
 
Patient is pregnant, lactating, or planning to become pregnant within 12 months 
 
Patient has received an organ transplant or is on a waiting list for an organ transplant 
 
Patient is receiving or scheduled to receive chemotherapy within 30 days before or 
after the procedure 


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 
Patient is receiving immunosuppressive therapy or has known immunosuppressive or 
autoimmune disease (e.g. human immunodeficiency virus, systemic lupus 
erythematous, etc.) 
 
Patient is receiving chronic anticoagulation therapy (i.e. vitamin K antagonist, direct 
thrombin inhibitor, Factor Xa inhibitor) 
 
Concomitant use of simvastatin/lovastatin >40 mg qd 
 
Concomitant use of potent CYP3A4 inhibitors (atazanavir, clarithromycin, indinavir, 
itraconazole, 
ketoconazole, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin and voriconazole) or inducers (carbamazepine, dexamethasone, 
phenobarbital, phenytoin, rifampin, and rifapentine) 
 
Non-cardiac condition limiting life expectancy to less than one year, per physician 
judgment (e.g. cancer) 
 
Known history of severe hepatic impairment 
 
Patient has a history of bleeding diathesis or coagulopathy or will refuse blood 
transfusions 
 
Patient has an active pathological bleeding, such as active gastrointestinal (GI) 
bleeding 
 
Current (within 6 months) substance abuse (e.g. alcohol, cocaine, heroin, etc.) 
 
7. STUDY INTERVENTIONS 
 
7.1 Intervention 
The study interventions include a blood draw, three buccal swabs (in the prospective genotype arm), a 
genotyping survey (first 1,000 subjects), randomization, and genotype analysis. Genotyping for 
CYP2C19 will be retrospective in the conventional therapy arm and both prospective and 
retrospective in the CYP2C19 prospective genotyping arm. A survey regarding patients’ perceptions 
of genotyping and the results of genotyping will also be performed on the first 1,000 subjects. 
 
7.2 Randomization 
Patients will be randomized to one of two groups. The two arms are: the conventional therapy arm in 
which the patients will receive clopidogrel with retrospective genotype analysis performed at the end 
of one year of treatment, and the prospective genotyping arm, in which patients will have prospective 
genotyping performed to guide anti-platelet therapy. Patients in this group who are identified to have 
reduced function CYP2C19 allele will receive ticagrelor and patients with WT CYP2C19 allele will 
receive clopidogrel. Drug therapy with ticagrelor and clopidogrel will be given as per clinical 
guidelines. Both of these drugs are FDA approved and will be given for FDA approved indications 
for at least 12 months after index PCI. Ticagrelor will be administered at 90 mg twice daily, and 
clopidogrel will be administered at 75 mg daily. All patients will receive a standard loading dose of 
antiplatelet therapy per the individual institution’s routine clinical guidelines (prior to PCI, during 
PCI, or first dose after PCI), i.e. clopidogrel 300-600 mg or ticagrelor 180 mg. If patients receive 
ticagrelor 180 mg as a loading dose, and are then assigned to receiving clopidogrel as maintenance 
therapy, a loading dose of clopidogrel 300-600 mg as per institutional preference will be 
recommended as the next scheduled dose and 75 mg once daily as subsequent maintenance dosing. 
Similarly, when a transition is made from clopidogrel to ticagrelor, those loaded with 300-600 mg 
clopidogrel and assigned to receiving ticagrelor will get as a next scheduled dose, ticagrelor 180 mg 
as a loading dose and will then receive 90 mg twice daily as maintenance therapy(23). Specific 
randomization-guided treatment (i.e. clopidogrel or genotype-guided ticagrelor) will commence 
within 72 hours after index PCI as soon as clinically possible. If ticagrelor is discontinued 


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prematurely in the reduced function CYP2C19 allele patient due to intolerance and there is no 
contraindication for continued dual anti-platelet therapy, the patients and their physicians will be 
advised to substitute ticagrelor with prasugrel at 10 mg daily (5 mg in patients weighing less than 60 
kg and age ≥75 years)(17) or clopidogrel 150 mg daily. 
 
7.3 Concomitant Therapies 
Current ACC/AHA guidelines for the management of acute coronary syndromes including unstable 
angina, NSTEMI, and STEMI will be followed uniformly for all patients(24,25). The drug prescribing 
information for ticagrelor recommends the use of aspirin at a maintenance dose of 75-100 mg daily. 
Concomitant administration of lovastatin or simvastatin and ticagrelor will increase lovastatin or 
simvastatin plasma concentrations. Hence, lovastatin or simvastatin doses greater than 40 mg when 
administered concomitantly with ticagrelor will be avoided as per prescribing information. 
Concomitant use of potent CYP3A4 inhibitors (atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) or 
inducers (carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, and rifapentine) cannot 
be used as well. Cardiovascular medications taken during the study will be recorded in the source 
documentation and in the electronic case report form (eCRF). 
 
Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. Consider using another acid- 
reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active 
metabolite. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity 
of clopidogrel than did omeprazole or esomeprazole. 
 
7.4 Dose Justification 
The dose of clopidogrel and ticagrelor will be prescribed as per clinical guidelines as described in the 
published prescribing information for both these drugs. This information is outlined in Appendix A. 
 
7.5 Side Effects 
The side effects of these FDA-approved drugs have been fully outlined in the Appendix as per the 
published prescribing information. 
 
7.6 Summary of the Risks and Benefits 
 
7.6.1 Potential Benefits: 
This study involves administration of ticagrelor with potential beneficial effects in 
patients with reduced function CYP2C19 allele. Thus, if subjects receive ticagrelor rather 
than clopidogrel, they could potentially experience greater clinical benefit. 
 
7.6.2 Potential Risks 
Buccal Swab 
There are no known risks associated with obtaining a buccal swab. 
 
Blood draw 
Blood draw will occur after venous and or arterial access has been obtained for the 
cardiac catheterization procedure and a determination has been made that PCI will be 
performed. A total of 10 mL of blood will be collected after venous and or arterial access 
for clinical reasons or a separate venipuncture for a research blood draw. Potential risks 


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of blood drawing include bleeding at the puncture site, bruising, pain, and rarely, 
infection at the site of the needle stick. These risks occur in a very small portion of the 
population. If a subject’s initial blood sample is not available or processed appropriately, 
we may obtain a replacement10 mL blood sample either by a separate research blood 
draw or by addition to a clinical blood draw. 
 
Genotyping 
The risks of learning genetic test results may include emotional upset, insurance or job 
discrimination, and/or family conflicts from learning unknown information about family 
members. Patients in the conventional therapy arm may request that their genotyping 
results be sent to their physicians at the end of the study. Patients in both groups may 
discuss with their physicians the potential risks, benefits, and costs of choosing to have 
the results verified by clinical genetic testing in a CLIA certified lab and to learn the test 
results. 
 
Anti-platelet Therapy 
Patients in this study will be undergoing PCI as part of their clinical care. Oral anti- 
platelet therapy after PCI is clinically indicated and is considered standard of care. 
Therefore, patients in the study will have the potential risks associated with their anti- 
platelet therapy. These potential risks, however, are not considered potential risks of the 
study because anti-platelet therapy is indicated for their clinical care. Clopidogrel and 
ticagrelor are both FDA approved to prevent thrombosis in the ACS population, and will 
be administered at recommended doses for maintenance therapy as per standard 
guidelines. 
 
Ticagrelor 
Common adverse events include major and minor bleeding (8.7%), headache (6.5%), 
raised serum creatinine (7.4%), cough (4.9%), dyspnea (13.8%), atrial fibrillation (4.2%), 
and syncope (1.7%). 
 
Ticagrelor may cause significant, sometimes fatal, bleeding. Hence patients with active 
pathological bleeding or history of intracranial hemorrhage, bleeding diathesis, and on 
chronic anticoagulation such as warfarin will be excluded. 
 
Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor; thus 
patients unable to take aspirin at 100 mg or less will be excluded. 
 
In a randomized, double-blind study of patients with acute coronary syndrome, major 
bleeding events (not related to CABG) were reported in 4.5% of patients who received 
ticagrelor (n=9235) compared with 3.8% of patients who received clopidogrel (n=9186). 
Both were co-administered with aspirin and other standard therapy for 6 to 12 months. 
The bleeding episodes were fatal or life-threatening in 2.1% of ticagrelor-treated patients 
compared with 1.9% of clopidogrel-treated patients. Fatal events were reported in 0.2% 
of patients in each group. Fatal or life-threatening intracranial bleeding was reported in 
0.3% and 0.2% of ticagrelor- and clopidogrel-treated patients, respectively(7). In a 
randomized, double-blind study of patients with acute coronary syndrome who  
underwent CABG surgery, major bleeding events were reported in 85.8% of patients who 
received ticagrelor (n=770) compared with 86.9% of patients who received clopidogrel 
(n=814). Both were co-administered with aspirin and other standard therapy for 6 to 12 
months. The bleeding episodes were fatal/life-threatening in 48.1% of ticagrelor-treated 


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patients compared with 47.9% of clopidogrel-treated patients. Fatal bleeding events were 
reported in 0.9% and 1.1%, respectively, of patients(7). 
 
If possible, minor bleeding should be managed without discontinuing ticagrelor therapy 
since therapy discontinuation increases the risk of myocardial infarction, stent 
thrombosis, and death. Although discontinuation increases the risk of subsequent adverse 
cardiovascular events, ticagrelor should be stopped 5 days prior to surgery, when 
possible. Hence if a surgical procedure is planned including CABG, surgery patients will 
be excluded since they will be unable to complete the 12-month duration of anti-platelet 
therapy. 
 
In a randomized, double-blind study of patients with acute coronary syndrome, headache 
was reported in 6.5% of patients who received ticagrelor (n=9235) compared with 5.8% 
of patients who received clopidogrel (n=9186). In a randomized, double-blind study of 
patients with acute coronary syndrome, a greater than 50% increase in serum creatinine 
levels were reported in 7.4% of patients who received ticagrelor (n=9235) compared with 
5.9% of patients who received clopidogrel (n=9186). Both were co-administered with 
aspirin and other standard therapy for 6 to 12 months. Creatinine levels generally did not 
progress, and often decreased with continued treatment(26). Dyspnea associated with 
ticagrelor therapy was usually mild to moderate and often resolved during continued 
treatment. Underlying disease should be ruled out in patients who develop new, 
prolonged, or worsening dyspnea during ticagrelor treatment. There is no specific 
treatment required if dyspnea is confirmed to be caused by ticagrelor. Ticagrelor should 
be continued without interruption [product information: Brilinta® oral tablets, ticagrelor 
oral tablets. AstraZeneca LP (per manufacturer), Wilmington, DE, 2011]. In a 
randomized, double-blind study of patients with acute coronary syndrome, dyspnea 
(exertional, nocturnal, paroxysmal nocturnal, and at rest) was reported in 13.8% of 
patients who received ticagrelor (n=9235) compared with 7.8% of patients who received 
clopidogrel (n=9186). The concomitant use of potent cytochrome P450 3A4 inhibitors 
(e.g. clarithromycin, ketoconazole, itraconazole, voriconazole) is associated with 
increased plasma levels of ticagrelor, hence patients would be at an increased risk for 
bleeding. Patients taking these drugs are excluded from this protocol and  patients 
enrolled in the study will be cautioned not to commence therapy with these agents. 
 
If ticagrelor is discontinued prematurely in the reduced function CYP2C19 allele patient 
due to intolerance and there is no contraindication for continued dual anti-platelet 
therapy, the patient and their physician will be advised to substitute ticagrelor with 
prasugrel at 10 mg daily (5 mg in patients weighing less than 60 kg or age≥75 years)(17) or 
clopidogrel 150 mg daily. 
 
Clopidogrel 
Triple therapy with aspirin, clopidogrel, and warfarin led to a greater risk of bleeding 
than dual therapy with aspirin and clopidogrel following coronary stent placement. A 
retrospective study to evaluate bleeding risk in 107 consecutive patients on chronic 
warfarin therapy who received triple therapy was compared with a cohort of 107 
randomly selected patients receiving dual therapy following coronary stent placement. 
Following a loading dose of clopidogrel 300 milligrams (mg) at the time of stent 
placement, all patients received clopidogrel 75 mg daily, as well as aspirin (81 mg or 325 
mg). Patients on triple therapy were started on a maintenance dose of warfarin the day 
following stent placement. Patients were followed for a mean duration of 211 +/- 114 
days and 250 +/- 137 days in the triple and dual therapy groups, respectively. Patients on 


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triple therapy were younger than the patients on dual therapy (mean age, 69 +/- 11 years 
vs 74 +/- 6 years, respectively; p=0.03). Eighty-two percent (82%) of patients in the  
triple therapy group had hypertension compared with 68% in the dual therapy group 
(p=0.01). Following stent placement, major bleeding was 6.6% in the triple  therapy 
group and 0% in the dual therapy group (p=0.014), and minor bleeding was 14.9% and 
3.8% (p=0.01) in the triple and dual therapy groups, respectively. One death  occurred 
due to intracranial hemorrhage in a patient on triple therapy with a history of major 
bleeding(27). Therefore, patients on chronic vitamin K antagonist therapy will be  
excluded from this study. 
 
In the Platelet inhibition and patient Outcomes (PLATO) trial, patients randomized to 
ticagrelor prior to surgical intervention for acute coronary syndrome had significantly 
fewer cardiovascular deaths, MI, or stroke compared with patients on clopidogrel(7). This 
analysis of PLATO, a multicenter, randomized, double-blind, double-dummy controlled 
trial of ticagrelor or clopidogrel in patients aged 53 to 69 years old presenting with acute 
coronary syndrome, compares the composite event rates in patients undergoing invasive 
management (coronary angiography, percutaneous coronary intervention (PCI), coronary 
artery bypass graft). Ticagrelor patients (n=6,732) received a 180 milligram (mg) loading 
dose then 90 mg twice daily (plus placebo clopidogrel); clopidogrel patients (n=6,676) 
received a 300 mg loading dose then 75 mg once daily (plus placebo ticagrelor) for 6 to 
12 months. PCI patients were eligible for an additional 300 mg clopidogrel loading dose 
(or placebo) at investigators' discretion (event rates did not vary significantly when 
stratified by clopidogrel loading dose). All patients received aspirin 75 to 100 mg per 
day. At 12 months post-intervention, cardiovascular death, MI or stroke (primary 
composite endpoint) occurred in 569 (9%) ticagrelor patients compared with 665 (10.7%) 
clopidogrel patients [hazard ratio, 0.84; 95% confidence interval (CI), 0.75-0.94; 
p=0.0025]. Incidences of cardiovascular death (5.3% vs 6.6%; p=0.0023) and MI (3.4% 
vs 4.3%; p=0.025) were significantly lower in the ticagrelor group compared with the 
clopidogrel group, although the incidences of stroke were not significantly different 
between the 2 groups. Total major bleeding [per Thrombolysis in Myocardial Infarction 
(TIMI) definition] occurred in 689 ticagrelor patients (11.5%) and 691 clopidogrel 
patients (11.6%) (95% CI 0.89 to 1.10; p=0.8803), and severe bleeding (per Global Use 
of Strategies to Open Occluded Coronary Arteries definition) occurred in 185 (2.9%) of 
ticagrelor patients compared with 198 (3.2%) of clopidogrel patients (95% CI 0.74 to 
1.12; p=0.3785). Dyspnea occurred more frequently in ticagrelor patients compared with 
clopidogrel patients (13.9% versus 8%, p less than 0.0001) and was cause for 
discontinuing therapy in 0.8% of the ticagrelor group(28). 
 
8. RECRUITMENT PROCEDURES 
 
8.1 Common Recruitment Procedures 
All patients undergoing PCI are treated by a cardiologist in the cardiac catheterization laboratory and 
hence recruitment efforts will be primarily based on targeting patients that are referred for coronary 
angiography to be performed in the cardiac catheterization laboratory. Some important recruitment 
strategies to be considered include: 
 
Presentations or meetings with cardiologist practices within each center to educate care providers 
regarding the genotyping assay, possible results of the assay, the lack of proven therapies in 
CYP2C19 reduced function allele patients and the TAILOR-PCI trial. Each site should have  
some method of identifying patients referred to the cardiac catheterization laboratory. Referrals  
to the cardiac catheterization laboratory for most hospitals are present in databases or scheduling 


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calendars that can be accessed. Study coordinators can use this list to screen for eligible patients. 
Screening of outpatient or hospitalization records will be undertaken for patient eligibility. 
 
Patients who are being seen for clinic visits, determined by their physician to have a need to be 
scheduled for a cardiac catheterization procedure, and are eligible for a PCI. The physician will 
discuss with the patient the need for the procedure and inform them that there is a research study 
available. The physician will then contact a member of the clinical research team to speak with 
the patient. A list of study contact names and numbers will be placed in the clinic for the 
physicians to easily access study staff. 
 
Patients who present to the hospital may need coronary angiography. The physician determines 
eligibility for a PCI. The study coordinator and/or physician may discuss with the patient the 
research study. 
 
8.2 Informed Consent 
As a general guidance, patients will typically be approached when referred for coronary angiography 
in the outpatient or the inpatient setting or within 48 hours after index PCI. When a potential subject 
is identified, the study coordinator and/or site principal investigator (PI) will review the inclusion and 
exclusion criteria. If the patient is eligible, the study coordinator and/or PI will explain the study, 
review the consent form, answer questions, and if the patient is willing to participate, the consent 
form will be signed. 
 
If the subject is consented prior to coronary angiography, the subject will then undergo coronary 
angiography as scheduled and only if PCI is performed and the patient requires at least one year of 
dual anti-platelet therapy, will the subject then be enrolled in the study, randomized, and begin anti- 
platelet drug therapy based on randomization to the conventional therapy arm or the prospective 
genotyping arm. 
 
8.3 Confidentiality and HIPAA/Privacy Requirements 
Subjects enrolled in the study will be identified with a study number. Within each participating site, 
subjects will also be identified by their site-specific registration number and their name but these 
subject identifiers will not be released outside of the respective participating sites and any 
publications will exclude any kind of subject identifiers that could be correlated with the specific 
subject. Genotype data will be collected specifically for the research protocol and clinical and 
demographic data will also be collected from the subject’s medical records for the purposes of the 
research protocol, but all data will be de-identified before being released to any of the participating 
sites. 
 
9. SCREENING PROCEDURES 
Subjects will be referred to the study or will be identified using the recruitment strategies outlined in 
section 8. The subject’s clinical records will be reviewed to determine if the subject meets the entry 
criteria. Additional information may be collected from face to face or phone interviews with the subject 
and/or the subject’s physician. If the subject meets entry criteria and is willing to participate, informed 
consent will be obtained. 
 
The subject will have blood drawn for genotyping at the time of coronary angiography only if they are to 
undergo a PCI with required dual anti-platelet therapy for at least 12 months. For those subjects who are 
consented following PCI, blood sampling will be conducted by the phlebotomy team. Subjects will then 
be randomized to the conventional therapy or prospective genotyping arm. The blood samples of all 
subjects will be stored for genotyping to be performed at the end of 12 months after index PCI. The 


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subjects who are randomized to prospective genotyping will have 3 buccal swabs taken and processed for 
rapid genotyping and, based on the genotype, will be assigned to clopidogrel or ticagrelor. 
 
10. BASELINE EVALUATIONS AND RANDOMIZATION 
 
10.1 Evaluations Performed During the Baseline Period 
Results from any standard of care tests and procedures related to angiography and PCI, which are 
performed by participants’ physicians, will be collected and used for this study. 
 
Routine standard of care tests & procedures related to coronary angiography and PCI 
procedures typically include: 
 
Phlebotomy for routine blood work including complete blood count and creatinine 
 
Electrocardiogram 
 
Clinical history 
 
Physical examination 
 
Pregnancy test (for women of child-bearing potential if not done clinically within 7 days 
prior to PCI) 
 
Research tests & procedures: 
 
Obtain permission to obtain protected health information from outside facilities for any 
events or hospitalizations related to study endpoints for up to 12 months after enrollment. 
 
Obtain 10 mL of blood. 
 
Obtain 3 buccal swabs for rapid genotyping assay. 
 
A survey will be conducted on the first 1,000 subjects regarding subjects’ perception towards 
and experience with genotyping. This survey will be collected during the baseline visit and 
repeated at 6 months following PCI. 
 
Conventional therapy arm 
Participants randomized to this group will be retrospectively genotyped 1 year after index PCI. 
After randomization, the Biospecimens Accessioning and Processing (BAP) Laboratory will be 
notified to process the blood samples for genomic DNA extraction and storage for future analysis. 
After one year, Mayo Laboratories will utilize the ABI TaqMan assay for analysis of three 
variants in the CYP2C19 gene: *2, *3, and *17. 
 
Briefly, the TaqMan assay uses PCR primers to amplify the gene segment in which the 
CYP2C19*2, *3, and *17 alleles are located, as well as three sets of 2 separate detection probes, 
each of which is specific for WT and variant alleles. Each probe is labeled with a different 
detection fluorescent dye, along with a quencher dye. During amplification, the detection probe 
anneals to its target sequence. If there is complete complementarity between the probe and the 
target sequence, then the probe is cleaved by the 5' nuclease activity of Taq DNA polymerase 
when the enzyme extends from the upstream primer into the region of the probe. When this 
cleavage occurs, the detection dye is released from the quencher dye and a fluorescent signal is 
detected. The dependence on polymerization ensures that cleavage of the probe occurs only if the 
target sequence is being amplified. The ABI PRISM 7500 Sequence Detection System is a 
flexible system designed to take full advantage of the benefits of fluorogenic probe detection.  
The 7500 system has a built-in thermal cycler and a laser directed via fiber optic cables to each of 
the 96 sample wells. The system is capable of distinguishing and quantitating multiple 
fluorophores in each sample well. The software analyzes the data by first calculating the 
contribution of each component dye to the experimental spectrum. Each reporter signal is then 


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divided by the fluorescence of an internal reference dye (ROX) in order to normalize for non- 
PCR related fluorescence fluctuations occurring well to well or over time 
 
Prospective genotyping arm 
Participants randomized to this group will be prospectively genotyped for CYP2C19 variants. 
Study coordinators at each site will utilize the rapid turnaround Spartan Bioscience in vitro 
diagnostic assay for analysis of three variants in the CYP2C19 gene: *2, *3, and *17. Briefly, a 
sample collection kit containing three Spartan swabs will be utilized to obtain three buccal swabs 
from each study participant and inserted into their respective reaction tubes. The tube will be 
tapped to mix the sample and reagents and then the swab will be inserted into the Spartan 
Analyzer. The Analyzer is a thermal cycler with optical detection capability. It is designed to 
determine an individual’s CYP2C19*2, *3, and *17 genotype. The unit utilizes optical detection 
channels to detect WT and variant alleles via a proprietary oligonucleotide capture and 
fluorescent detection method. After one year of index PCI, like the non-prospective genotyping 
arm, all subjects in the prospective genotyping arm will also have the ABI TaqMan assay for 
analysis of three variants in the CYP2C19 gene: *2, *3, and *17 and results will be correlated to 
have a uniform platform for comparison and this will also result in validation of the Spartan 
diagnostic assay platform. 
 
10.2 Randomization Procedures 
After a subject has been consented, completed coronary angiography, and has met eligibility 
requirements, the subject will be randomized. Randomization will be performed using Medidata 
Balance. Subjects will be randomized at a 1:1 ratio to either 1) conventional therapy or  2)  
prospective genotyping with genotype-guided antiplatelet therapy (either clopidogrel or ticagrelor). 
Randomization will be stratified by age, sex, site, and CAD presentation (stable CAD, unstable 
angina/NSTEMI or STEMI). 
 
10.3 Genomic Research 
A 10 mL blood sample will be collected from subjects for plasma samples, DNA extraction, ABI 
TaqMan assay for CYP2C19*2, *3, and *17 genotype, and future genomic research. In cases where 
the initial sample collected to analyze the DNA at the one year time point is found to be an unviable 
sample, the subject will be contacted and asked to provide another DNA sample via a blood sample or 
saliva sample. For subjects who provide consent to allow their DNA to be stored for future genomic 
analysis other than the CYP2C19 genotyping being performed for the purposes of this study, their 
DNA will be stored in the BAP laboratory for future studies. Subjects will be given the option to opt 
in or out of the genomic component of the study. 
 
11. FOLLOW-UP EVALUATIONS 
 
11.1 Evaluations Performed During the Follow-up Period 
Subjects will be contacted by site coordinators via telephone at 30 days (-2/+7 days), 6 months (+/- 28 
days) and 12 months (+/- 28 days) after the date of their index PCI to assess alive/dead status, 
determine if the subject has been hospitalized since their PCI or a last follow-up phone call, and to 
assess drug compliance and current drug regimen. Education levels and computer literacy data also 
will be collected during one of these calls which may help to interpret the outcomes of the study.  At 
least 3 attempts (on different days) will be made to contact subjects. Antiplatelet therapy drug 
compliance will be assessed during the phone call. If subjects were hospitalized, copies of the 
discharge summaries of those hospitalizations will be obtained. If 3 unsuccessful attempts are made to 
contact subjects by telephone, a medical record review can be conducted to obtain follow-up 


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information. 
11.2 Evaluations for Study Completion, Study Withdrawals, and Treatment 
Discontinuation 
Study Completion 
A subject will be considered to have completed the study if he or she completed all assessments and 
procedures during the index PCI and follow-up period of 1 year for primary endpoint events. All 
randomized patients will have a follow-up assessment (telephone contact at 1, 6, and 12 months) to 
determine survival status and hospitalization data. If the subject dies during this period, the study 
coordinator and/or PI should make every effort to obtain details of the subject’s death from the 
relevant hospital or subject’s physicians and/or relatives. If confirmation of death is not available 
through these mechanisms, the study coordinator and/or PI will attempt to confirm the subject’s death 
through a death index search. 
 
Study Withdrawal 
If the subject is lost to follow up, every effort will be made to contact the subject and determine the 
reason that will then be documented, including the measures taken to follow-up. If subject withdraws 
or drops out of the study, the reason for withdrawal from the study is to be documented on the case 
report form (CRF) and in the source document. The study coordinator or investigator must attempt to 
document re-hospitalization data unless the subject expressly refuses to provide this information. If 
subjects withdraw from the main part of the study, they will be given the following options regarding 
future genomic research: either the DNA extracted will be retained and used as specified in the 
original consent form; or the subject may withdraw consent for CYP2C19 genotyping and/or future 
unspecified genomic research, in which case the DNA sample will be destroyed. If the subject 
withdraws consent for future genomic research alone and would want to continue the main part of the 
study, the DNA sample will be destroyed after CYP2C19 genotyping is performed. 
 
Treatment discontinuation 
A subject may be discontinued from dual anti-platelet therapy if: 
 
The investigator or treating physician believes that for safety reasons (e.g. bleeding 
complications) it is the in the best interest of the subject to stop treatment. 
 
The subject becomes pregnant and treating physician feels the risks of treatment outweigh the 
benefits. 
 
The subject dies. 
 
Subjects who terminate dual anti-platelet therapy due to an adverse event should be followed to 
determine the outcome of the adverse event, in addition to the pre-specified follow-up assessments as 
above. Interruption of treatment will not be considered treatment discontinuation. If ticagrelor is 
discontinued prematurely in the reduced function CYP2C19 allele patient due to intolerance and there 
is no contraindication for continued dual anti-platelet therapy, the patients and their physicians will be 
advised to substitute ticagrelor with prasugrel at 10 mg daily (5 mg in patients weighing less than 60 
kg or age ≥ 75 years)(17) or clopidogrel 150 mg daily. 
 
11.3 Study Schedule of Assessments 
Enrolled subjects will be required to complete up to 5 study visits/contacts (screening, randomization, 
and telephone follow-up on months 1, 6, and 12). 


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Table 1. Schedule of Assessments to be performed during the study 
 
Screening/Randomization V1 & 2 
Treatment (Phone Interview) 
EOT/Safety 
Endpoint 
Pre- 
Procedure 
** 
Index 
Procedure 
Post- 
Procedure 
V3 
V4 
V5 
30 Days 
(-2/+7 days) 
6 months 
(+/-28 days) 
12 months 
(+/- 28 days) 
Assessment of 
Eligibility 
x 
Informed Consent 
x 
Genotyping Survey6 
x 
x 
Hospitalization 
Intake1 
x 
Medications 
x 
x 
x 
x 
x 
x 
Vitals 
x 
β-HCG Pregnancy 
test2* 
x 
Creatinine* 
x 
x 
CK/CK-MB* 
x 
x 
Troponin T/I* 
x 
x 
Angiogram/PCI 
procedure* 
x 
Genotyping 
x3 
x 
x4 
Randomization 
x 
Hospitalization 
Dismissal 
x 
Electrocardiogram* 
x 
x 
Follow-up outcomes 
x 
x 
x 
x 
x 
Study Endpoint 
Events 
x 
x 
x 
x 
x4 
Death Event Form4 
End of Treatment 
x 
x 4 5 
Education Level & 
Computer Literacy 
*** 
                                  x 
 
1 Hospitalization forms to be completed for each hospitalization during study participation 
2 Only in women of childbearing potential (local urine or serum pregnancy test) 
3 Complete only if randomized to prospective genotyping 
4 Complete only if subject dies after randomization and before 12 month treatment phase 
5 Complete only if subject terminates participation prior to 12 months 
6 Completed for first 1,000 subjects only 
*Data only will be collected from these clinically indicated tests/procedures 
**If subject is screened/randomized post-procedure, these items will be collected post-procedure 
***This information will be collected once at any of these phone interviews, unless the patient has already completed these visits.  
Because these questions were not part of the original consent, the patient will be given the chance to opt out of these questions. 
 
11.4 Digital & Extended Follow-Up Sub-Study 
 
The research objective of the digital registry sub-study is similar to the research objective of the parent NIH 
funded TAILOR-PCI trial, which is to assess major adverse cardiovascular events in patients who have 
undergone percutaneous coronary intervention (PCI) based on their CYP2C19 genotyping status, beyond the 1 
year follow up of the parent study. Our sub-study to create a registry is important for multiple reasons. The 
extended follow up allows for collection of a greater number of events and hence more power to test the primary 
hypothesis of TAILOR-PCI. The registry will inform the CV community of the real world practice of continuing 
dual anti-platelet therapy (DAPT) beyond 1 year post PCI. We will also be able to define the role of the 
CYP2C19 genotype on the clinical efficacy of clopidogrel beyond 1 year post-PCI, a variable that has not yet 




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If 3 unsuccessful attempts are made to contact subjects by telephone, a medical record review can be conducted to 
obtain follow-up information.  Medical records may be reviewed beyond the initial length of study identified in the 
signed consent form, as a retrospective chart review.  If the subject has died, the study coordinator and/or PI should 
make every effort to obtain details of the subject’s death from the relevant hospital or subject’s physicians and/or 
relatives.  If confirmation of death is not available through these mechanisms, the study coordinator and/or PI will 
attempt to confirm the subject’s death through a death index search. 
 
Table 2.  Digital Registry Schedule of Events 
Visit Windows 
Baseline Visit 
 
Weekly Activities 
 
Monthly Activities 
from digital consent 
date up to 24 mos. 
post index PCI 
Activities every 6 
months from digital 
consent date 
Informed Consent 
x 
 
 
 
Eureka Registration 
x 
 
 
 
Heart Rate 
x 
(before and after the 
6 minute walk test) 
x 
(30 sec HR) 
x 
(before and after the 
6 minute walk test) 
 
Duke Activity Score 
x 
 
 
x 
 
Dyspnea Scale 
x 
 
 
x 
 
Angina Diary 
x 
x 
 
 
Seattle Angina Score 
x 
 
x 
 
6 minute walk test 
x 
 
 
 
x 
 
Geofencing (optional)** 
x 
 
 
 
BORG Scale 
x 
(after the 6 minute 
walk test) 
 
x 
(after the 6 minute 
walk test) 
 
Medication Review ** 
x 
 
x 
 
Hospitalization Review ** 
x 
 
x 
 
Anxiety Survey 
x 
 
 
x 
 
**If additional information is required for patient entry visits, a member of the study team may reach out to the 
patient by phone to inquire about any ER visits, hospitalizations, or cardiac events. 
 
Specifically, the digital registry activities are based on patient provided questionnaires such as: Seattle Angina 
Questionnaire, Duke Activity Status Index, Modified Medical Research Council Dyspnea Scale, and Anxiety 
survey: GAD-7. Other patient reported data collected may include the angina diary, hospital-geofencing, heart 
rate and activity measurements, and a self-performed 6-minute walk test.  Hospital-geofencing refers to the 
ability of the Eureka application to identify if the subject has been within 200 meters of a hospital for 4 hours or 
longer.  If so, a notification will be sent to patients inquiring about their symptoms, reason for hospitalization, 
and what specific tests were done (Figure 6).  The 6 minute walk test is a self-performed test used in conjunction 
with the Eureka application.  As part of the test, the application will measure the patient’s heart rate at rest, after 
test completion, and during recovery.  The accelerometer function of the application measures the total distance 
walked in the allotted time, and also determines whether the patient has a change in cadence (pace), or takes time 
to rest.  After the test, the subject will complete a Borg Rating of Perceived Exertion Scale survey which will 
include rating breathing difficulty at the worst part of the test and what if anything kept the subject from walking 
farther and faster.      
 
 
 


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The following disclaimer for participants will be included on the TAILOR-PCI digital follow-up website and 
informed consent form:  The information obtained will be used solely for the purpose of research and will not be 
used to provide you with clinical care.  If you experience any new or worsening symptoms, please contact your 
health care provider, or seek medical attention.  If you think you are having a medical emergency, call 911.  
 
To compare the accuracy of hospital-geofencing in discerning MACE, these subjects may also be contacted for 
follow-up by a study team member using a telephone script to determine whether MACEs have occurred. In the 
case that a hospitalization was not registered, the patient will be able to self-report any events as part of the 
follow-up phone notifications.  If MACEs have occurred in subjects participating in the digital follow-up, Mayo 
Clinic Data Coordinating Center (MCDCC) will receive this indication in the file received from UCSF Eureka 
Data Coordinating Center (EDCC).  If needed, a Mayo Clinic Digital Follow-Up study team member may obtain 
the subject’s identifying information and Authorization to Release Protected Health Information from UCSF 
EDCC in order to request medical records from the patient’s health care facility to ascertain clinical events.  If 
MACEs are noted for subjects participating in the extended follow-up phone calls done by site study 
coordinators, medical records devoid of all patient identifiers will be sent to a designated study team member at 
the MCDCC to ascertain clinical events, as is being done in the parent TAILOR-PCI trial. 
 
The consented subject in the digital follow-up may provide access to phone accelerometer-based step-counts and 
any self-report or connected device measures (such as weight or blood pressure) through HealthKit in iOS and 
GoogleFit in Android; may allow geolocation for determination when they are hospitalized; and may turn on 
notifications to allow the University of California San Francisco Eureka Data Coordinating Center to send push 
notifications for activities and surveys for hospitalization detection. Specifically, in addition to the consent, the 
participant will have to actively allow each of these as separate items (eg. share each HealthKit or GoogleFit 
item, turn on “share my location”, and turn on “allow notifications”). In other words, they could opt out of any 
or all of these activities if they choose to do so. 
 
Patient Confidentiality: 
Patient-provided digital data will reside encrypted on the subject’s phone until an internet connection is 
established, at which time the data is transmitted encrypted to the UCSF-Eureka data servers automatically. 
Once transfer is automatically confirmed via the endpoint (this happens as part of the built in API transferring 
data privately between the app and server), the data is deleted from the phone.  The data servers are on a 
HIPAA-compliant stack in Amazon Web Services (BAA in place) and data is stored encrypted. The data being 
obtained is primarily patient-reported data. The transmitted data will be hosted on a HIPAA compliant cloud 
based platform provided by Amazon Web Services that is accessible to and managed by the University of 
California San Francisco Eureka Data Coordinating Center. This platform will generate a unique participant 
code tied to the TAILOR-PCI Subject ID that will also tie to the unique Eureka User ID created during 
registration.  A Mayo Clinic Digital Follow-Up study team member may also access the subject’s identifying 
information to request medical records from the patient’s health care facility to ascertain clinical events.  Follow-
up study data from phone calls collected on TAILOR-PCI subjects is stored in the Medidata Rave system which 
is compliant with Code of Federal Regulations Title 21 (21 CFR) Part 11 and the Federal Information Security 
Management Act (FISMA). Both the physical and network security of the Medidata system is ensured through 
multiple measures. Physical security of the Medidata centers is managed through building guards, smart-ID 
badges with electronic access, video surveillance, and biometric scanners. Network security starts with border 
protection that includes routers and load balancers to provide high availability even during Distributed Denial of 
Service (DDOS) attacks. Data is protected from workstation to destination through the use of Secure Socket 
Layer (SSL) encryption with a minimum key length of 256 bits. The hosting site has dedicated disaster recovery 
facilities and automatically creates back-up files of the database on a regular basis according to standard research 
procedures.  Each study site has access to only the data of subjects enrolled at their site.  The site study 
coordinators will have edit access to the data and are responsible for entry and editing of all information 
obtained through follow-up phone calls.  A Mayo Clinic Digital Follow-Up study team member will be 
responsible for entering digital enrollment in Medidata Rave, in addition to hospitalization and study endpoints 
obtained from medical records, if not already recorded by the site study coordinator.  The Medidata web 




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Figure 6 
 
            
 
 
12. OUTCOME DETERMINATIONS 
 
12.1 Primary Outcome 
The primary outcome will be the time to occurrence of the composite endpoint of a major 
adverse cardiac event (MACE), i.e. non-fatal myocardial infarction, non-fatal stroke, CV 
mortality, severe recurrent ischemia, and stent thrombosis if not captured in other events, from 
the time of randomization through one-year of follow-up. 
 
12.2 Secondary and Exploratory Pre-specified Outcomes 
Secondary outcomes will include: The incidence of major or minor bleeding in subjects with 
reduced function CYP2C19 allele(s) receiving ticagrelor versus clopidogrel. 
Exploratory pre-specified outcomes include: 
 
The effect of CYP2C19*17 genotype on bleeding risk, MACE, stroke, and CV survival. 
 
The effect of CYP2C19*2 or *3 genotype on multiple recurrent events (MACE, stroke, and 
CV survival) in the individual subject. 
 
Performing a pharmacoeconomic analysis of the conventional therapy approach as 
compared with the genotype-based approach in subjects who undergo PCI. 
 
Comparing the occurrence of MACE in subjects with reduced function CYP2C19 allele(s) 
to those with WT genotype receiving clopidogrel. 
 
Comparing the occurrence of MACE in subjects with reduced function CYP2C19 allele(s) 
receiving ticagrelor to those with WT genotype receiving clopidogrel. 
 
Assessing the effect of CAD presentation: a) Stable coronary artery disease; b) Unstable 
angina or NSTEMI; and c) STEMI on the effect of ticagrelor in subjects with reduced 
function CYP2C19 allele(s) and on the association of CYP2C19 genotype and occurrence 
of MACE. 
 
To assess the mechanism of coronary stent thrombosis in subjects with reduced function 
CYP2C19 allele(s) receiving ticagrelor versus clopidogrel. 
 
To assess implementation of a CLIA-approved CYP2C19 pharmacogenetic testing on the 


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Spartan platform (accuracy of genetic testing by sequence analysis, and genotype failure 
rates). 
 
Exploratory outcomes will also include the individual components of the primary outcome. 
 
To assess compliance with dual anti-platelet therapy by phone survey. 
 
To assess patients’ attitudes towards genotyping and the results of genotyping. 
 
12.3 Clinical Event Definition and Adjudication 
All clinical endpoints will be adjudicated by an independent Adjudication Committee that will 
be blinded to study treatment. The following clinical event definitions will be used by the 
Adjudication Committee: 
 
Cardiovascular death 
Death from cardiovascular causes or cerebrovascular causes and any death without another 
known cause. 
 
Myocardial infarction 
The diagnosis of myocardial infarction is dependent on whether it is spontaneous- or 
procedure- related: 
 
Spontaneous: Cardiac biomarkers (creatinine kinase-myocardial band, Troponin T or I) 
exceed the upper limit of normal according to the individual hospital's laboratory 
parameters or clinical presentation which is consistent or suggestive of ischemia. 
 
Procedure-related excluding index PCI: 
o In subjects with normal pre-procedural cardiac biomarkers, myocardial infarction 
within 24 hours post-PCI is indicated by cardiac biomarkers elevated above 3 
times the upper limit of normal. 
o In subjects with elevated pre-procedural biomarkers, myocardial infarction within 
24 hours post-PCI is indicated by cardiac biomarkers elevated above 3 times the 
upper limit of normal after biomarkers have exhibited a rise and fall indicative of 
completion of the presenting infarct. 
o MI greater than 24 hours post-PCI but prior to discharge is evidenced by any of the 
following: 
a. A rise and fall in cardiac biomarkers (preferably troponin) with at least one 
of the values in the abnormal range for that laboratory, together with at least 
one of the developments listed below, is a manifestation of myocardial 
infarction. The 
abnormal range for your laboratory means levels above the 99th percentile 
of the upper reference limit (URL) for normal subjects. 
i. 
Ischemic symptoms; 
ii. 
ECG changes indicative of new ischemia (new ST-T changes, new 
left bundle branch block, or loss of R wave voltage); 
iii. 
Development of pathological Q waves in 2 or more contiguous 
leads in the ECG (or equivalent findings for true posterior MI); 
iv. 
Imaging evidence of new loss of viable myocardium or new 
regional wall motion abnormality; 
v. 
Documentation in the medical record of the diagnosis of acute 
myocardial infarction based on the cardiac biomarker pattern in the 
absence of any items enumerated in 1-4 due to conditions that may 
mask their appearance (e.g. peri-operative infarct when the subject 
cannot report ischemic symptoms, baseline left bundle branch 
block, or ventricular pacing). 
b. Imaging evidence of a region with new loss of viable myocardium at rest in 


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the absence of a non-ischemic cause. This can be manifested as: 
i. 
Echocardiographic, CT, MR, ventriculographic or nuclear imaging 
evidence of left ventricular thinning, or scarring and failure to 
contract appropriately (i.e. hypokinesis, akinesis, or dyskinesis); 
ii. 
Fixed (non-reversible) perfusion defects on nuclear radioisotope 
imaging (e.g. MIBI, thallium). 
o Peri-CABG (within the first 72 hours following CABG) is defined as an increase 
of biomarkers greater than 5 times the upper limit of normal for your laboratory 
(i.e. above  5 times the 99th percentile upper reference limit for a 'normal' 
population) compared with the pre-CABG biomarker value closest to the time of 
surgery plus one of the following: 
 
New pathological Q waves or new LBBB; 
 
Angiographically documented new occlusion or thrombosis of a graft or 
native coronary artery since the preoperative angiogram; 
 
Imaging evidence of new loss of viable myocardium at rest in the absence 
of a non-ischemic cause. 
 
Severe recurrent cardiac ischemia 
Recurrent cardiac ischemia and at least one of the following, but not fulfilling the criteria for MI: 
 
New or presumed new ischemic ECG changes (ST elevation ≥1 mm (0.1 mV) or ST depression 
≥0.5 mm (0.05 mV), or T wave inversion ≥1 mm (0.1 mV) in at least 2 adjacent leads) 
 
Leading to urgent revascularization (PCI or CABG) unless not advised on reasoned 
grounds. Urgent revascularization (PCI or CABG) must occur during the same 
hospitalization as an in- patient episode of recurrent ischemia or be performed during the 
re-hospitalization resulting from an out-patient episode of recurrent myocardial ischemia. 
In countries where waiting lists for revascularization procedures exist, revascularization 
within 30 days of an episode of recurrent ischemia will qualify as urgent. For patients with 
a previous PCI, it will be recorded if revascularization is necessary for previously treated 
vessels (i.e. urgent target vessel revascularization) and any occurrences of stent thrombosis 
will be documented. PCI is defined as any attempt at revascularization even if not 
successful (e.g. angioplasty, atherectomy, or  stenting). 
 
Other definitions: 
o Recurrent cardiac ischemia: Cardiac ischemic symptoms >10 minutes at rest 
(started  with exercise or spontaneously and did not resolve with rest), resulting in 
hospitalization if an outpatient, or prolongation of hospitalization if an inpatient 
but not fulfilling criteria for MI. 
o Cardiac ischemic symptoms: chest pain or discomfort or equivalent (e.g. neck or 
jaw symptoms, dyspnea believed to represent an angina pectoris equivalent) 
believed due to impaired coronary flow secondary to atherosclerotic disease. 
 
Stent thrombosis 
Definite (presence of acute coronary syndrome with angiographic or autopsy evidence of 
thrombus or occlusion) or probable (unexplained deaths within 30 days after the procedure or 
acute myocardial infarction involving the target-vessel territory without angiographic 
confirmation)(29). 
 
Cerebrovascular accident (CVA) 
Loss of neurological function caused by an ischemic or hemorrhagic event with residual 
symptoms lasting at least 24 hours after onset or leading to death. 
 
Transient ischemic attack (TIA) 


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Loss of neurological function that was abrupt in onset but with complete return of function 
within 24 hours, presumed to be due to vascular etiology. 
 
Bleeding 
All bleed events that require some form of intervention (e.g. doctor’s visit, ER visit, 
hospitalization) will be captured, recorded, and classified as major, minor, or minimal. 
 
Major bleeding 
Symptomatic intracranial hemorrhage or clinically overt bleeding (including imaging) 
with a hemoglobin drop of ≥5 g/dL (adjusted for transfusion by 1 g/dL per unit of 
transfused blood). 
 
 
Minor bleeding 
Clinically overt bleeding (including imaging) with a hemoglobin drop of 3 to <5 g/dL 
(adjusted for transfusion by 1 g/dL per unit of transfused blood). 
 
 
Minimal bleeding 
Clinically overt bleeding (including imaging) with a hemoglobin drop of <3 g/dL 
(adjusted for transfusion by 1 g/dL per unit of transfused blood)(30). 
 
Coronary Artery Bypass Grafting (CABG) 
A type of surgery that improves blood flow to the heart. During CABG, a healthy artery or vein 
from the body is connected, or grafted, to the blocked coronary artery. The grafted artery or 
vein bypasses (that is, goes around) the blocked portion of the coronary artery. This creates a 
new path for oxygen- rich blood to flow to the heart muscle. Surgeons can bypass multiple 
coronary arteries during one surgery. 
 
Percutaneous Coronary Intervention (PCI) 
Also called coronary angioplasty, this is a procedure used to open clogged heart arteries. 
Angioplasty involves temporarily inserting and inflating a tiny balloon where the artery is 
clogged to help widen the artery. 
 
Ventricular Fibrillation 
A condition in which there is uncoordinated contraction of the cardiac muscle of the 
ventricles in the heart, making them quiver rather than contract properly. 
 
Ventricular Tachycardia 
A type of tachycardia, or a rapid heartbeat, that starts in the bottom chambers of the heart, 
called the ventricles. 
 
Other cardiac surgeries 
Any other surgery on the heart (excluding CABG). Examples include ventricular assist device, 
pacemaker, valve repair, and heart transplant. 
 
13. QUALITY CONTROL ACTIVITIES 
 
13.1 Training Sessions and Certification Procedures 
An Operations Manual details overall study processes and procedures. It will contain instructions 
describing how the study is conducted, what procedures are performed, in what order, by whom, 
and under what circumstances. Investigator and study coordinator training sessions will be held to 
provide appropriate instruction regarding the study. 


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13.1.1 Genotyping via SPARTAN® Bioscience 
Spartan Bioscience will provide installation and training of personnel to use the equipment 
and run the buccal swabs. Each study site will receive a Spartan Analyzer. Spartan will 
perform instrument installation. Following equipment installation, Spartan will provide 
training to study personnel at each site. Each trainee will have the opportunity to run a 
minimum of two independent runs with the Spartan CYP2C19 assay, and Spartan will 
additionally guide the trainees through more runs as needed to ensure independent trainee 
competency in performing the assay from start to finish. 
 
Each site will perform analytical validation of the Spartan platform’s performance 
characteristics prior to analyzing study samples. Buccal swabs obtained from volunteers 
will be analyzed on the Spartan instruments and compared to oral fluid DNA results 
obtained from a currently existing validated CYP2C19 automated fluorescent Sanger 
sequencing assay. All non-Rochester sites will obtain buccal swabs for analysis on their 
own Spartan instruments and ship one oral fluid sample to Mayo Rochester for CYP2C19 
sequence analysis. 
 
13.1.2 Genotyping via ABI TaqMan 
The laboratory performing this assay has extensive experience with this platform. Probes 
and primers will be designed utilizing ABI’s design services. Development and analytical 
validation will occur as per the laboratory’s established guidelines. The laboratory will 
utilize a currently existing validated CYP2C19 automated fluorescent Sanger sequencing 
assay to verify accuracy of the TaqMan assay as well as troubleshoot any potential samples 
with unclear genotypes via the TaqMan assay. Each operator of the assay will be trained as 
per the laboratory guidelines. 
 
13.1.3 Database Training 
AHRC, DCIS, and the Project Coordinator will arrange for each individual site coordinator 
to be trained with the variable definitions and data sources to ensure uniform data 
collection across study sites. 
14. PARTICIPANT SAFETY, ADVERSE EVENTS, CLINICAL ENDPOINTS, AND 
OTHER REPORTING 
 
14.1 Institutional Review Boards 
Before initiating this study, the protocol, informed consent forms, recruitment materials, and 
other relevant information will be reviewed and approved by Mayo Clinic and respective 
institutional review boards (IRB) or research ethics boards (REB). Any amendments to the 
protocol must be approved by each institution’s IRB or REB before they are implemented. Any 
amendments to the protocol and consent form(s) will be communicated to the sites upon Mayo 
IRB approval. 
 
14.2 Adverse Events 
All subjects randomized to conventional therapy will receive clopidogrel; subjects randomized 
to the prospective genotyping group will receive clopidogrel or ticagrelor based on their 
genotype. Known adverse events associated with both medications will not be considered study 
related and will not be recorded as such in the trial because they have already been identified 
with the specific antithrombotic therapy, which is clinically indicated for the subjects’ clinical 


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care. However, participating sites must follow the policy of the IRB/REB they are utilizing, 
which may include reporting of these events to their respective ethics board. 
 
Adverse event reporting and monitoring is applicable to the study-specific procedures of this 
study, including a blood draw, three buccal swabs (in the prospective genotype arm), a 
genotyping survey (first 1,000 subjects) randomization, and genotype analysis (which will be 
used in the prospective genotype arm to determine which of two FDA-approved antithrombotic 
treatments will be used as prophylactic therapy for PCI). Any adverse event related to study-
specific procedures must be reported to the Project Coordinator. 
 
In addition, any problem or event which, in the opinion of the local investigator, was 
unanticipated, places subjects or others at a greater risk of harm than was previously known or 
recognized, and was possibly related to the research procedures will be reported to the Project 
Coordinator within 48 hours of notification. The site coordinator will record the information in 
the source documentation and will forward all relevant medical information to the Project 
Coordinator who will prepare the documents for Adjudication Committee review. 
 
14.3 Clinical Endpoints 
Information on all clinical endpoints will be recorded in the source documentation and in the 
eCRF. This information will be adjudicated by an independent Adjudication Committee that 
will be blinded to study treatment. 
 
When a MACE is suspected, the site coordinator and/or PI will notify the Project Coordinator. 
The site coordinator will record the information in the source documentation and in the eCRF 
and will forward all relevant medical information to the Project Coordinator who will prepare 
the documents for Adjudication Committee review. 
 
When any bleed requiring diagnostic study or intervention (e.g. doctor’s visit, change in 
medication, ER visit, hospitalization) is suspected, the site coordinator will record the 
information in the source documentation and in the eCRF and will forward all relevant medical 
information to the Project Coordinator who will prepare the documents for Adjudication 
Committee review. 
14.4 Other 
Known adverse events associated with both medications will not be considered study related 
and will not be recorded as such in the trial because they have already been identified with the 
specific antithrombotic therapy, which is clinically indicated for the subjects’ clinical care. 
However, when any death occurs, the site coordinator will record the information in the source 
documentation and in the eCRF and will forward all relevant medical information to the 
Project Coordinator who will prepare the documents for Adjudication Committee review. 
 
15. STATISTICAL CONSIDERATIONS 
 
15.1 Study Design 
This is a multicenter, prospective, two-arm, unblinded trial with 1:1 randomization between the 
conventional therapy arm treated with clopidogrel at standard dose and a prospective genotype 
tailored approach using clopidogrel in WT and ticagrelor in reduced function CYP2C19 
genotype subjects. Subjects in the conventional therapy group will undergo retrospective 
genotyping one year after PCI to identify those with reduced function CYP2C19 alleles. The 
study goal is to assess the effectiveness of ticagrelor in reducing the risk of 1-year MACE in 


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subjects who carry the reduced function CYP2C19 allele. Subjects will be followed by 
telephone contact for 1 year after index PCI. Endpoint analysis will occur after all subjects 
have reached the study endpoint. Predefined major protocol violations/deviations are missing 
data for the primary efficacy end point, violation of inclusion criteria, and additional protocol 
violations that will be possibly defined during the blind data review. Missing patients will be 
censored at the last follow-up visit. Alive or dead status will be specifically searched for all 
missing patients. 
 
15.2 Sample Size and Power Considerations 
 
15.2.1 Primary Endpoint 
Sample size and power calculations for the study are based on the following assumptions: 
 
2-sided log-rank test 
 
α = .05 
 
Randomization ratio of 1:1 
 
Data from the Mayo Rochester PCI registry demonstrate a 1 year rate of death, MI, 
or stroke of about 7.5% in PCIs from 2008-2009. Furthermore, the PLATO trial 
suggests  we can expect stent thrombosis or severe, recurrent ischemia in about an 
additional 3%, resulting in a baseline rate of 10.5%. The rate is expected to be 
higher in *2 or *3 allele carriers who are discharged on clopidogrel, thus we 
assume a baseline rate of 12% for primary endpoint in the control arm. 
 
Two studies suggest that the expected rate of 12% in Korean patients treated with 
clopidogrel after PCI for ACS. Kim et al.(31) observed a 10.1% event rate for death, 
myocardial infarction ,or stroke at 12 months in 306 patients with at least one 
CYP2C19*2 or *3 allele treated with PCI for acute myocardial infarction. As noted 
above, the PLATO trial suggests that stent thrombosis and severe recurrent 
ischemia may add 3% to this rate, which would result in a baseline rate over 12%. 
Oh et al.(39) observed a 10.7% event rate for cardiac death, myocardial infarction 
and repeat revascularization  at 12 months in 1011 patients treated with a drug-
eluting stent (22% AMI, 78% stable) and carrying at least one CYP2C19*2 
allele. Assuming the event rate is higher in the 
AMI subgroup and that the addition of stent thrombosis to the endpoint would 
increase the event rate, this study also suggests that a 12% event rate in the control 
group of Koreans may be expected. 
 
Given that the vast majority of patients at the Mayo sites are of European heritage, 
we expect a reduced function allele prevalence of about 30% in those  patients.  
The Canadian hospitals have a more diverse ethnic mix of patients, and we expect 
their prevalence to be anywhere from 30-50%. Thus, our sample size calculations 
assume an overall prevalence of reduced function allele carriers of 30% among 
patients recruited at those sites. We also assume the prevalence to be 50% in 
patients enrolled from South Korea and expect to enroll 1,015 subjects from there. 
Furthermore, we assume no more than 5% of patients will be lost to follow-up or 
drop out. 
 
Based on data from Mega(1) and Schuldiner(2), a hazard ratio as low as 0.60 for 
ticagrelor versus clopidogrel in reduced function allele carriers may be expected. 
We intend to power the study to detect a hazard ratio of 0.65 or smaller. This will 


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require a total of 1,694 patients with reduction function alleles to be randomized, 
and thus 5,270 patients will be enrolled. 
 
Table 3. Required sample size for 80% power 
 
Minimum detectable effect, hazard ratio 
0.60 
0.65 
0.70 
Number with reduction function allele 
required 
1,241 
1,694 
2,401 
Number with reduced function to 
enroll assuming 5% drop out 
1,307 
1,784 
2,528 
Number with reduced function allele 
enrolled at South Korean sites 
508 
508 
508 
Number with reduced function allele to 
enroll at non-Korean sites 
799 
1,276 
2,020 
Total number enrolled at Korean sites, 
assuming 50% prevalence 
1,015 
1,015 
1,015 
Total number to enroll at non-Korean 
sites, assuming 30% prevalence 
2,665 
4,255 
6,734 
Total number enrolled 
3,680 
5,270 
7,749 
 
15.2.2 Revised Sample Size Calculations 
At the time of this protocol revision (Version 8), the estimated event rate for the 
primary endpoint across all LOF subjects is 4.8%, substantially lower than the 
assumptions made in Section 15.2.1. We propose performing updated power 
calculations using a revised minimum detectable effect of a hazard ratio of 0.50. 
This effect size is justified by several arguments. First, ticagrelor has already been 
shown to reduce MACE events by about 16% in all ACS patients, regardless of 
genotype, in the PLATO trial. However, because our study treatment represents a 
precision medicine, pharmacogenomic approach, we expect a much greater 
treatment effect in the targeted LOF population. Second, such effect sizes have 
been seen in other studies involving CYP2C19 *2 and *3 alleles(2,40). Third, a 
meta-regression analysis of studies comparing event rates in (primarily) 
clopidogrel-treated patients who were LOF vs. WT suggested an inverse 
relationship between the overall event rate and the WT vs. LOF advantage, such 
that the predicted HR 
in very low event rates was consistent with 0.50. Finally, at low event rates, a large 
effect must exist within the LOF population in order to achieve reasonable 
number-needed-to- treat (NNT) values, since the genotype-guided dual antiplatelet 
treatment is expected to have no effect in the WT population. For example, if the 
event rate is 4% in LOF subjects on clopidogrel, and 2% in LOF subjects on 
ticagrelor, that 50% reduction would equate to a NNT of 50 subjects within the 
LOF sub-population. If the prevalence of LOF alleles is 30% in the overall 
population, that would equate to an NNT of 167. Under initial assumptions, the 
NNT in the LOF sub-population would have been 25 subjects, equating to an 
overall NNT of 75. Thus, from the perspective of NNT, we are powered to detect a 
smaller effect than under initial assumptions. 
 
Additional assumptions play a role in the power calculations. First, we assume that 
around the total enrollment mark of 3900 subjects, 20% of subjects enrolled from 


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that point forward will be from Korea. This is lower than observed so far (30%), 
due to the impending activation of additional sites in North America. Increasing 
this percentage would result in a smaller required sample size, as it would increase 
the prevalence of LOF subjects in the study. We also assume that the current 
prevalence of LOF carriers will continue in Korean (59%) and North American 
(28%) subjects. Increasing either of these prevalences would reduce the number of 
subjects required. The power calculations are based on a two-sided log-rank test at 
a Type I error rate of 0.05 with an expected randomization ratio of 1:1. Table 3 
demonstrates the calculations for total subjects enrolled assuming an event rate of 
4.5%. Table 4 gives required sample sizes for varying event rates and power levels. 
These tables show that the previous planned sample size of 5270 subjects provides 
at least 80% power if the event rate is at least 4.0%. 
 
Table 4. Revised Sample Sizes for a Minimum Detectable Hazard Ratio 
of 0.50 with an overall event rate of 4.5% 
 
80% 
Power 
85% 
Power 
90% 
Power 
N of LOF subjects required 
1560 
1784 
2086 
N of LOF subjects accounting for 5% dropout 
1643 
1878 
2196 
N of LOF patients expected from Korea 
747 
828 
937 
N of LOF patients expected from North America 
896 
1050 
1259 
Total patients expected from Korea 
1275 
1413 
1599 
Total patients expected from North America 
3192 
3742 
4486 
Total number of patients to enroll 
4467 
5155 
6085 
 
Table 5. Required Sample Sizes for a Minimum Detectable Hazard Ratio 
of 0.50 at varying event rates and power assumptions 
 
Baseline 
event rate 
Power at 
n=5270 
Sample size needed for given power 
80% 
85% 
90% 
5.0% 
89.3% 
3955 
4570 
5409 
4.5% 
85.8% 
4467 
5155 
6085 
4.0% 
81.6% 
5052 
5827 
6875 
15.2.3 Secondary Endpoint 
To assess the incidence of major or minor bleeding not related to CABG. The 
PLATO trial observed a 1-year rate of major or minor bleeding of 14.6% in 
subjects receiving clopidogrel, and the genetic sub-study observed no significant 
decrease in major bleeding in those with loss-of-function alleles. Thus, assuming a 
14.6% rate of major or minor bleeding at 12 months in reduced function subjects 
receiving clopidogrel, 1,694 subjects will provide 80% power if the bleeding rate 
in the ticagrelor group is at least 19.7%. 
 
15.3 Randomization 
Subjects will be randomized on a 1:1 ratio stratified by age, sex, site, and CAD 
presentation, i.e. unstable angina/NSTEMI, STEMI, or stable CAD. 
 


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15.4 Statistical Comparisons of Baseline Factors 
For continuous variables such as age, means, and standard deviations overall and within 
treatment group will be calculated. If the variable is moderately to severely skewed, 
medians and 25th and 75th percentiles will be computed. For discrete variables, frequencies 
and percentages will be calculated both overall and within treatment group. Standardized 
differences will be used as a measure of imbalance between the groups. 
 
15.5 Specification of the Primary Analyses 
Hypothesis 1A. The effect of genotype-guided antiplatelet therapy versus conventional care 
in patients with a reduced function CYP2C19 allele will be estimated using a Cox 
proportional hazards regression model, with covariates including variables used for 
stratified randomization and other subject factors associated with MACE. The analysis will 
be conducted under the intention-to-treat principle, with follow-up beginning at 
randomization, but with genotype defined by the Taqman genotyping assay. Those whose 
prospectively defined genotype disagrees with their TaqMan-based genotype will 
nevertheless be analyzed based on the TaqMan result, which is the only result that is 
available in both arms. A sensitivity analysis will be done, taking into account the Spartan 
result. In the retrospective genotyping group, reduced function status will be determined by 
the TaqMan assay results at least one year after PCI. Subjects who withdraw or  are lost 
during follow-up will be treated as censored at the date of last contact. Patients who 
complete follow-up at 12 months will be considered censored from that point onward. The 
proportional hazards assumption will be assessed visually using plots of scaled Schoenfeld 
residuals. A two-sided likelihood ratio test will be used to assess the significance of the 
partial effect of treatment; a p-value less than 0.05 will be considered statistically 
significant. Kaplan- Meier curves will be used to display survival free of MACE estimates 
over the first year of follow-up. 
 
Hypothesis 1B. It is also important to determine the effect of genotype-guided  antiplatelet 
therapy versus conventional care in patients with the wild type CYP2C19 allele. In this 
case,  both groups will be given clopidogrel, but the genotype-guided group patients and 
their physicians will know prospectively that they have the wild-type allele, at least based 
on the Spartan platform. The analysis will be done as outlined above in the LOF group, 
again defined  by the TaqMan-based assessment of wild-type status. It is expected that the 
null hypothesis will prevail, but it is important to confirm that knowledge of genotype in 
and of itself does not have an effect on the rate of MACE events. 
Finally, note that the entire allocation of type 1 error is placed on Hypothesis 1A, and the 
analysis of Hypothesis 1B is seen as confirmatory of the null hypothesis. If the null 
hypothesis in 1A is rejected, i.e. a treatment benefit is seen with ticagrelor versus 
clopidogrel in LOF patients (or the converse), then (and only then) a formal test of 
Hypothesis 1B will be conducted at the 0.05 level. The purpose of this second test is to 
inform the overall assessment of treatment effect in the entire randomized study 
population. In any case, an assessment of treatment effect in the overall randomized study 
population will be done for estimation and descriptive purposes only, since it will have 
insufficient power to detect a treatment effect. If the null hypothesis in 1B is rejected, then 
that result will be factored into any overall assessment of benefit of the prospective 
genotyping treatment strategy. 
 
 
 
 


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15.6 Specification of the Secondary Analyses 
For secondary analyses involving 1-year endpoints (e.g. MACE, bleeding), Cox 
proportional hazards models with appropriate covariates will be used to compare the 1-year 
rate of secondary endpoints according to intention-to-treat classification. A p-value less 
than 0.05 will be considered statistically significant. Additionally, unadjusted treatment 
effects will also be estimated and tested as a secondary analysis. Confidence intervals for 
binomial measures will be computed using the Wilson CI method for 95% coverage 
probability. Mechanisms of stent  failure for subjects with coronary stent thrombosis and 
with reduced function CYP2C19 allele will be compared between ticagrelor and 
clopidogrel using Pearson’s chi-squared test. 
 
15.7 Subgroup Analyses 
 
15.7.1 Interaction Between CAD Presentation and Genotype-guided Therapy 
We will analyze the primary endpoint of MACE between reduced function allele 
carriers on clopidogrel versus those on ticagrelor within ACS presentation class, 
stable CAD, unstable angina/NSTEMI, and STEMI. We will test for the 
significance of the  interaction between CAD presentation and genotype-guided 
antiplatelet therapy with a Cox proportional hazards model. 
 
15.7.2 Interaction Between *17 Carriers and *2/*3 and Antiplatelet Therapy 
We will analyze MACE and bleeding endpoints with Cox proportional hazards 
models with main effects for *17 allele carrier, *2/*3 carrier and clopidogrel vs. 
ticagrelor therapy. We will test for interactions between antiplatelet therapy and 
*17 allele, plus interaction between *17 and *2/*3 alleles. 
 
15.7.3 Additional Subgroup Analyses 
We will analyze the effect of genotype-guided therapy on the primary endpoint of 
MACE in reduced function carriers within the subgroups of current smokers,  
elderly patients (age ≥75 years), women, diabetics, white/Caucasians, Asians, 
patients with creatinine clearance <30 mL/min, and on proton pump inhibitors. 
Interaction tests will be used to test whether the effect of genotype-guided 
antiplatelet therapy is different between these subgroups and the remaining 
reduced function allele carriers. 
It should be noted that these subgroup analyses will have less power than the 
primary analysis, while being subject to greater type 1 error because of multiple 
comparisons. While not proposing formal multiple comparisons procedures, we 
propose to invoke usual calculations for controlling the risk of type I errors, and to 
regard these subgroup analyses as exploratory. 
 
15.8 Monitoring for Futility and Efficacy 
Both efficacy and futility monitoring require three estimates: 1) a best current estimate of 
the treatment effect, as well as 2) uncertainty of the estimate (standard error and/or 
confidence interval), and 3) an estimate of what proportion of the study’s final 
information is currently in hand, that is, the current value of “information time”. 
Information time is critical both in assessing conditional power (futility) as well as in 
doing interim testing using group sequential approaches. Appendix C details how to 


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construct a combined likelihood combining the information from the complete and the 
incomplete subject data, which produces the first two required estimates, using likelihood 
calculations, and specifically, using the profile likelihood method to get down to the one-
dimensional likelihood for the treatment effect parameter. 
Appendix C also details how to estimate information time (the third required measure). 
Once we have a current z-score (effect divided by standard error) for the treatment effect, 
as well as our current estimate of information time, we can then do standard calculations 
for conditional power (futility) and efficacy 
Futility Monitoring: We propose that this assessment be based on our calculation of 
conditional power, as described in Appendix C. In addition to the conditional power 
calculation, we will provide the modified unconditional power calculation based on 
current estimates of event rates and the estimate and 95% CI of the average event rate in 
LOF subjects. We specifically propose that at the time of DSMB reviews, that 
consideration be given to stopping the trial if the ratio of conditional power to initial 
power falls below the proportion of remaining information time. For example, if the 
initial power is 85%, and the proportion of remaining information time is 40%, then the 
conditional power should exceed 34% (0.85*0.4). The basis for the moving target of 
conditional power is the “sunk cost” argument. The initial study design is assumed to 
equate the expected utility of a positive result with the cost of the entire study. By 
equating the ratio between conditional power and initial power, the cost-benefit ratio is 
maintained. This means that the bar for conditional power for continuing gets 
progressively lower, as more of the total study costs become a “sunk cost.” 
Efficacy Monitoring: Although we neither recommend, nor anticipate,stopping early for 
efficacy, we recognize the need to provide for an exit strategy that permits a statistically 
valid conclusion to be drawn when it is desired to stop the trial and claim efficacy. We 
therefore propose using the efficacy stopping boundary proposed by Peto and 
Haybittle41,42, namely we use a 2-sided nominal p-value of 0.001 for all interim looks 
(critical value 3.291), where the looks are at 40%, 60%, and 80% of information time, 
and we are thereby entitled to conduct the final test at the 0.0495 level (critical value = 
1.965 rather than 1.960). This procedure accommodates the fact that our knowledge of 
information time is limited by the vagaries of incomplete (and changing) endpoint 
ascertainment and incomplete genetic ascertainment.  The use of a fixed critical value 
independent of information time is very helpful in this unique context of uncertainty 
around the precise value of information time. This means a critical value of 3.291 would 
obtain at any interim look, independent of at what interim time the look occurred. At the 
final look, the critical value of 1.965 rather than 1.96 will be applied, which has an 
infinitesimal impact on power. We propose up to 3 interim looks, and that these occur at 
information times of approximately 40%, 60%, and 80%. 
 
15.9 Assumptions Monitoring 
 
15.9.1 Event Rate in the Stable CAD Patients 
To increase generalizability of the study, we have included PCI for stable CAD as 
part of the inclusion criteria.  Recognizing, however, that the event rate in this 


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population may  be substantially lower than in the ACS population, we intend to 
plan for the possibility that the inclusion of the stable CAD patients might 
jeopardize the power of the trial. Thus, once the first batch of TaqMan results is 
available for the conventional arm subjects, we will monitor event rates monthly 
within the reduced function subjects of this arm and quit enrollment of stable CAD 
patients if the event rate for the primary endpoint is significantly lower than that 
for ACS subjects and we are nearly certain that continued enrollment will reduce 
the study power below 75%. Significance of the difference between stable CAD 
and ACS subjects in the conventional treatment arm will be  assessed by a one-
sided log rank test conducted at a 0.005 Type I error rate. The assessment of study 
power will be conducted using Bayesian estimation methods. The 1- year event 
rate will be estimated from the reduced function subjects in the conventional 
treatment arm. Using Bayes Theorem we will calculate the posterior distribution of 
study power, given the current event rate and a prior distribution for the event rate 
(beta distribution with a mean of 0.12 and 99% of the probability density between 
0.04 and 0.20), while maintaining the initial study design assumptions of hazard 
ratio and sample size. In particular, we will calculate the probability that the power 
of the study will exceed 75%. We will be nearly certain that continued enrollment 
will reduce the study power below 75% if the aforementioned probability is less 
than 1%. Additionally, we  will assess whether the generalizability of findings is 
jeopardized. While generalizability does not mean that we must have adequate 
power for the stable CAD subgroup (since the entire study would then be 
overpowered), it is reasonable to expect that the hazard ratio for prospective 
genotyping ought to at least trend in the correct direction (<1.0) within  the 
subgroup. Thus, we will calculate the probability that the stable CAD subgroup 
hazard ratio could be ≥1.0 under the assumption of a true hazard ratio of 0.50 and 
expected enrollment of 1,694 reduced function subjects. The probability 
calculation will depend on the expected final number of stable CAD reduced 
function subjects and the event rate within that group. To be conservative, we will 
use the upper limit of a 99% confidence limit for the event rate when calculating 
the probability of discordant hazard ratio. 
 
15.9.2 Event Rate in Subjects Enrolled at Korean Sites 
Similarly, there is some concern that the event rate for the primary endpoint may 
be substantially lower in patients enrolled at Korean sites. We will follow a similar 
procedure as above to safeguard the power of the trial. Once the first batch of 
TaqMan results is available for the conventional arm subjects, we will monitor 
event rates monthly within the reduced function subjects of this arm and quit 
enrollment of subjects at Korean sites if the event rate for primary endpoint is 
significantly lower than that of subjects enrolled at non-Korean sites and we are 
nearly certain that continued enrollment in Korea will reduce the study power 
below 75%. Significance of the difference between Korean-enrolled and non-
Korean enrolled subjects in the conventional treatment arm will be assessed by a 
one-sided log rank test conducted at a 0.005 Type I error rate. The assessment of 
study power will be conducted using Bayesian estimation methods. The 1- year 
event rate will be estimated from the reduced function subjects in the conventional 
treatment arm. Using Bayes Theorem we will calculate the posterior distribution 
of study power, given the current event rate and a prior distribution for the event 
rate (beta distribution with a mean of 0.12 and 99% of the probability density 
between 0.04 and 0.20), while maintaining the initial study design assumptions of 
hazard ratio and sample size. In particular, we will calculate the probability that 
the power of the study will exceed 75%. We will be nearly certain that continued 


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enrollment will reduce the study power below 75% if the aforementioned 
probability is less than 1%. 
 
15.9.3 Cross-over Monitoring 
Cross-over may potentially affect the power of the study. Patients in the 
conventional therapy arm who switch to ticagrelor prior to experiencing the 
primary endpoint may lower the event rate of the conventional therapy arm, 
resulting in a smaller treatment effect and lower power. Similarly, patients in the 
prospective genotyping arm who are assigned ticagrelor and who switch to 
clopidogrel may increase the event rate of the prospective genotyping arm, also 
resulting in a loss of statistical power. Here we define the cross-over rate as the 
proportion of enrolled subjects who switch from their protocol- assigned dual 
antiplatelet therapy to the other treatment. This does not include patients who 
switched to another treatment (such as prasugrel) or who stop treatment altogether, 
as we expect these occurrences to be rare and their effects on power difficult to 
predict. Each month, the cross-over rate in each arm will be calculated and the 
effect on statistical power according to a priori study assumptions calculated. If the 
revised power is less  than 60%, the DSMB will be notified and asked to approve 
continuation of the trial. Study enrollment and activities will continue while the 
DSMB deliberates. The study statistician will provide power calculations for the 
trial based on the current cross-over rate in each arm using both a priori study 
assumptions as well as observed enrollment and event rates at that time. Based on 
the current study assumptions, a cross-over rate of 10% will, on average, result in a 
reduction in statistical power to around 60%. 
 
15.9.4 Spartan Performance Monitoring 
Disagreement between the Spartan and TaqMan results may also affect the power 
of the trial. For example, if the Spartan device incorrectly identifies a reduced 
function carrier as a wild-type carrier, that subject would be prescribed clopidogrel, 
potentially increasing the event rate in the prospective genotyping arm. As 
TaqMan genotyping results become available, we will monitor the agreement 
between Spartan and TaqMan results among subjects with conclusive test results, 
both overall and at each study site. If the disagreement exceeds 5% at any site with 
20 or more subjects analyzed, or exceeds 10% at any site with less than 20 subjects 
analyzed, enrollment at that site will be suspended until the Spartan device is re-
validated as per the pre-enrollment validation process. 
 
16. TRIAL MANAGEMENT 
 
16.1 Data Management Oversight 
Data management oversight will be the responsibility of contracted data coordinating centers, 
AHRC (North American sites) and DCIS (Korean sites), and Mayo Clinic Rochester. The 
responsibilities of AHRC, DCIS, and Mayo Clinic are outlined below: 




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queries generated by identification of incomplete or inconsistent data will be raised directly within the 
electronic eCRF and should be resolved by the study coordinator or PI in a timely manner. 
Corrections or changes in the data management system are tracked with the retention of the original 
data and the corrected data with the date of data entry and submitting personnel. Sites with persistent 
delays or difficulties in data capture will be provided additional study-based training. 
 
16.3 Quality Control Procedures 
Two levels of database quality control will be performed. The first level consists of programmatic 
consistency checks and/or range checks. The second level of database quality is a record or panel 
level of control. Programs will be written to identify suspected duplicate and blank or missing  
records and records not double-entered within and across database tables. AHRC at the U.S.A. and 
non-Korean international sites and DCIS at the Korean sites will be responsible for communication 
and action on reports generated directly from Medidata Rave®. The Mayo statistician will be 
responsible for all other reports. These internal data quality and process compliance audits are 
routinely conducted on internal ongoing studies to document the frequency of random errors and 
identify systematic deviations so that they can be corrected. Other periodic quality control checks  
will document the frequency of random entry errors and identify systematic and process errors. 
 
In general, the following issues will be addressed: 
 
Data completeness: Completion by the clinical centers of all evaluations mandated by the 
protocol is checked. 
 
Procedural errors: Errors in performing study procedures, e.g. taking the blood samples. 
 
Remedial action will be taken as appropriate; otherwise, the protocol and Operations Manual may be 
revised as appropriate. Training and recertification will be made available to redress deficiencies and 
misunderstandings. 
 
16.4 Site Monitoring 
See Appendix D. 
 
16.5 Study Completion and Closeout Procedures 
AHRC and DCIS will conduct closeout procedures for each site in accordance with the trial 
Monitoring Plan. Study closeout activities are performed to confirm that the site investigator’s study 
obligations have been met and post-study obligations are understood. Verification that study 
procedures have been completed, data have been collected, and study intervention(s) and supplies are 
returned to the responsible party or prepared for destruction will be conducted at the end of the trial. 
The following (minimally) will be verified: 
 
Comparison of the investigator’s correspondence and study files against the Coordinating 
Center's records for completeness; 
 
Assurance that all data queries have been completed; 
 
Assurance that correspondence and study files are accessible for external audits; 
 
Assurance that the investigator will notify the IRB/REB of the study’s completion and store a 
copy of the notification; 
 
Participant notification of the study completion. 


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16.6 Hardware and Software Configuration 
 
16.6.1 Hardware and Database Software 
Study data will be captured and stored using Medidata Rave (Medidata Solutions) with 
servers physically located in Houston, Texas. Study personnel will interact with the 
database via web browser. 
 
16.6.2 Statistical Software 
SAS version 9.3 or higher (Cary, NC) will be used as the principal application for the 
management of analysis data files and statistical computations. R will be used to provide 
supplementary functions as needed. 
 
16.6.3 Access Control and Confidentiality Procedures 
Access permissions to the Medidata Rave system will be set at the time of the database 
build and will be updated as necessitated by personnel changes. Each study site will only 
have access to subjects enrolled at their site. Only the site study coordinators will have 
edit access to the data and will be responsible for entry and editing. Other  study 
personnel will be granted read-only access, as appropriate. Medidata Rave will create 
copies of the data as SAS data sets on a server maintained by the Division of Biomedical 
Statistics and Informatics at Mayo Rochester on a nightly basis. These secondary files 
will be accessible by the Mayo statistician. 
 
16.6.4 Security 
Database and Web servers will be secured by a firewall and through controlled physical 
access. The Medidata Rave system has security features to ensure that study personnel 
accessing the database have the proper authority to perform the functions he or she 
requests of the system. Unix group-access control will provide access security for the 
secondary SAS data sets used by the Mayo statistician. Workstation login is secured by 
extensive user-password facilities under Unix and Windows. 
 
16.6.5 Back-up Procedures 
Medidata Rave automatically creates back-up files of the database on a regular basis 
according to standard research procedures. Additionally, the hosting site has dedicated 
disaster recovery facilities. 
 
16.6.6 Virus Protection 
All disk drives that provide network services and all user computers will be protected 
using virus-scanning software. Standard research policies will be applied to update these 
protection systems periodically throughout the study. 
 
16.6.7 Data Management Activities 
In general, the following data management procedures will be applied: 
 
Paper CRFs will be designed specifically for the needs of this study and will serve as 
a tool to assist the study coordinator with data entry into an electronic database. 
Subject identification information to be captured will include the participant’s study- 
specific ID number, initials, and date of birth as allowed by local IRB/REB. The 


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subject’s name, address, medical record number and social security number will not 
be captured in the electronic database. 
 
Information will be abstracted from the participant’s medical charts and other source 
documents. All CRFs will be completed according to the current Good Clinical 
Practice (GCP) guidelines. Training on completing the CRFs will be included in the 
training session described in the Manual of Procedures. 
 
For every record type, the data dictionary will identify key fields (e.g. the 
participant’s ID number and the type and date of evaluation); the field type (e.g. 
numeric, character, checklist, or date), and ranges for impossible and improbable 
values. 
 
There will not be double data entry for this study 
 
16.6.8 Reports and Summaries 
A variety of standard progress reports will be prepared either automatically by Medidata 
Rave or as directed by the Mayo statistician during the course of the trial and includes: 
 
Data Status/Exception Reports: lag in entering CRFs into the database, missing visits, 
missing pages, listing of outstanding queries, and summary of totals of outstanding 
queries; 
 
Quality Control Reports: duplicates, missing from table, blanks; 
 
Data Surveillance Reports: query frequencies, perfect data; 
 
Protocol Deviation Reports: numbers of ineligible participants enrolled in the study; 
 
Weekly accrual reports (overall and by trial arm and genotype); and 
 
Data and Safety Monitoring Board (DSMB) reports: Accrual reports, eligibility 
violations, demographics, CYP2C19 genotype results, endpoints rates, and other key 
information needed for assessing the quality and safety of the trial. These will be 
provided to the DSMB at least 1 week prior to their next scheduled meeting. 
 
Reports will be prepared for the periodic meetings of the Adjudication Committee 
containing information required for clinical event assessment. Some reports, such as the 
data exception report, may be generated more frequently as required. 
 
16.7 
Biological Sample Management 
For the prospective genotype-guided arm, three buccal swabs will be obtained to be immediately 
processed and analyzed by the Spartan RX. All subjects will have one 10 mL tube of EDTA 
anticoagulated blood collected and will be sent to the Mayo Clinic Rochester BAP laboratory for 
DNA extraction for 12 month CYP2C19 genotyping, as outlined. FedEx will be  used  for 
shipping so that shipments may be tracked. For subjects who provide consent to allow their DNA 
to be stored for future genetic analysis other than the CYP2C19 genotyping being performed for 
the purposes of this study, their DNA will be stored in the BAP laboratory for future studies. 
Subjects who enroll at Mayo Clinic Rochester or the University of Ottawa Heart Institute and 
who provide consent to allow their sample to be stored for future research will have plasma 
extracted from their whole blood sample to be stored in the BAP laboratory for future use. 
Sample kits, shipping containers, and FedEx air bills will be provided to the other sites by Mayo 
Rochester. 


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17. STUDY ADMINISTRATION 
 
17.1 Cooperative Agreement Mechanism 
The funding mechanism used to undertake this project is a “Subcontract Agreement” between Mayo 
Clinic Rochester and participating study sites. Under the subcontract agreement, the Steering 
Committee, supports, and/or stimulates the study and is substantially involved with investigators in 
conducting the study by facilitating performance of the effort in a “partner” role. The site PI serves  
on the Steering Committee, and he/she or another scientist at that site may serve on other project 
committees, when appropriate. At the same time, however, the Steering Committee does not assume  
a dominant role, direction, or prime responsibility for this research project. 
 
Site PIs have lead responsibilities in all aspects of the project at their site, including implementing any 
modifications to the trial design, conduct of the trial, quality control, and collaboration with other 
investigators, unless otherwise provided for by the Steering Committee. 
 
Mayo Clinic retains custody of and has primary rights to the center-specific and collaborative data, 
subject to government rights-of-access consistent with current Health & Human Services (HHS), 
Public Health Service (PHS), and National Institutes of Health (NIH) policies. The protocol and 
governance policies call for the continual submission of data centrally to the MCR Biostatistics Core 
for the collaborative database. At a minimum, the database will contain the key variables selected by 
the Steering Committee for: standardization across all clinical centers; the submittal of copies of the 
collaborative datasets to each site PI upon completion of the project; procedures for data analysis; 
reporting and publication; and procedures to protect and ensure the privacy of medical and genetic 
data and records of individuals. 
 
During or within 3 years beyond the end date of the project period, unpublished data, unpublished 
results, data sets not previously released, or other study materials or products are to be made available 
to any third party only with the approval of the Steering Committee. 
 
Upon completion of the project, the overall PI is expected to put the intervention materials and 
procedure manuals into the public domain and/or make them available to other investigators 
according to the approved plan for making data and materials available to the scientific community 
for the conduct of research at no charge other than the costs of reproduction and distribution. 
 
The Steering Committee reserves the right to terminate or curtail the project (or an individual award) 
in the event of: a) failure to develop or implement mutually agreeable collaborative measurement, 
participant eligibility, and data management sections of the protocols; b) substantial shortfall in 
subject recruitment, follow-up, data reporting, quality control, or other major breech of protocol; c) 
substantive changes in the agreed-upon protocols with which the Steering Committee cannot concur; 
d) reaching a major project outcome substantially before schedule with persuasive statistical 
significance; or e) human subject ethical issues that may dictate a premature termination. 
 
Any disagreement that may arise in scientific/programmatic matters (within the scope of the award) 
between award recipients and the Steering Committee may be brought to arbitration. An arbitration 
panel will be composed of 3 members: one selected by the Steering Committee or by the individual 
site PI in the event of an individual disagreement; a second member selected by the Principal 
Investigator, and the third member selected by the other 2 members. This special arbitration 
procedure in no way affects the site PI’s right to appeal an adverse action that is otherwise appealable 
in accordance with the PHS regulations at 42 CFR part 50, Subpart D, and HHS regulation at 45 CFR 
part 16 under applicable statutes, regulations, and terms of the award. 


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17.2 Steering Committee 
The Steering Committee is the main governing body of the project. The composition of the Steering 
Committee may be found in appendix E. Each member of the Steering Committee will have an 
individual vote. All decisions are determined by majority vote. The Chair of the Steering committee 
will be the deciding vote in case of a tie. 
 
All major scientific decisions are determined by the Steering Committee. It assumes overall 
responsibility for the design and conduct of the trial. It appoints (and disbands) committees and 
subcommittees as the need arises; designs, approves, and implements the study protocols; oversees 
the development of the Operations Manual; monitors subject recruitment and treatment delivery; 
evaluates data collection and management; oversees quality assurance procedures; and implements 
changes and enhancements to the study as required. It also has primary responsibility for facilitating 
the conduct of the trial and reporting the project’s results. The Steering Committee will meet at least 
twice annually, preferably at one of the national or international cardiology meetings or via 
teleconference if necessary. 
 
17.3 Executive Committee 
The Steering Committee will set the overall guidance of the conduct of the TAILOR-PCI trial. There 
will be the need, however, for ongoing management decisions and input from trial leadership outside 
of the regularly scheduled Steering Committee meetings. The Executive Committee will serve to 
provide day-to-day guidance of the trial, will serve to provider overall coordination of issues outside 
of the Steering Committee, and will serve to enhance communications among all of the sites and sub- 
committees of TAILOR-PCI. It will be comprised of a small number of the Steering Committee 
membership including the PI, the Steering Committee Chair, the Co-PI, and other members who are 
recognized as senior clinicians or trialists. The Executive Committee will liaison with the Steering 
Committee when appropriate and will serve as the major communications channel for all of the site 
coordination. 
 
17.4 Publications Committee 
See Appendix F. 
 
17.5 Data and Safety Monitoring Board 
See Appendix G. 
 
17.6 Adjudication Committee 
All reported adverse events and clinical endpoints, including any bleeds requiring intervention, will 
be adjudicated by an independent Adjudication Committee that will be blinded to study treatment. 
 
17.6.1 Adverse Event and Clinical Endpoint Reporting 
When any problem or event which, in the opinion of the local investigator, was 
unanticipated, places subjects or others at a greater risk of harm than was previously 
known or recognized, and was possibly related to the research procedures occurs, the site 
coordinator and/or PI will notify the Project Coordinator within 48 hours of becoming 
aware of the event. The site coordinator will record the information in the source 
documentation and will forward all relevant medical information to the Project 
Coordinator who will prepare the documents for Adjudication Committee review. 


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When a MACE is suspected, the site coordinator and/or PI will notify the Project 
Coordinator within 48 hours of becoming aware of the event. The site coordinator will 
record the information in the source documentation and in the eCRF and will forward all 
relevant medical information to the Project Coordinator who will prepare the documents 
for Adjudication Committee review. 
 
When any bleed requiring diagnostic study or intervention (e.g. doctor’s visit, change in 
medication, ER visit, hospitalization) is suspected, the site coordinator will record the 
information in the source documentation and in the eCRF and will forward all relevant 
medical information to the Project Coordinator who will prepare the documents for 
Adjudication Committee review. 
 
When any death occurs, the site coordinator will record the information in the source 
documentation and in the eCRF and will forward all relevant medical information to the 
Project Coordinator who will prepare the documents for Adjudication Committee review. 
 
17.7 Monitoring 
See Appendix H. 
 
17.8 Informed Consent Procedures 
All eligible patients will provide written informed consent using procedures reviewed and approved 
by the Mayo Clinic IRB and respective institutional IRBs/REBs at other U.S.A. and international 
sites. Informed consent will be undertaken by study personnel in person with the patient. The patient 
has the option of declining participation. No study procedures will be conducted until the signed 
documents have been provided. Any modifications to the protocol that warrants revision to the 
informed consent document will be reviewed and approved by each site’s respective IRB/REB. The 
revised consent form will be shared with previously enrolled subjects and a new signature obtained as 
directed by each site’s respective IRB/REB. 
 
17.9 Confidentiality 
Subjects enrolled in the study will be identified with a study number. Within each participating site, 
subjects will also be identified by their site-specific registration number and their name but these 
subject identifiers will not be released outside of the participating site. Genotype data will be 
collected specifically for the research protocol. Clinical and demographic data will also be collected 
from the subject’s medical records for the purposes of the research protocol but all data will be de- 
identified before being released outside of that participating site. Any publications will exclude any 
kind of subject identifiers that could be correlated with the specific subject. 
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coronary syndromes. NEJM. 2007 Nov 15;357(20):2001-15. 
 
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outcomes among subjects treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 
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11. Hulot, JS, Collet JP, Silvain J., et al. Cardiovascular Risk in Clopidogrel-Treated Patients According 
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12. Paré G, Mehta SR, Yusuf S, Anand SS, et. al. Effects of CYP2C19 genotype on outcomes of 
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13. Bhatt, DL, et al. The relationship between CYP2C19 polymorphisms and ischemic and bleeding 
outcomes in stable outpatients: the CHARISMA genetics study. European Heart Journal; March 26, 
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14. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, 
Shah SH, Becker RC; PLATO investigators., Effect of CYP2C19 and ABCB1 single nucleotide 
polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary 
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platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011 Dec 
28;306(24):2704-14. 
 
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Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement. Circ 2010; 121: 
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Clopidogrel After Percutaneous Coronary Intervention: The GIFT (Genotype Information and 
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the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction 
(Updating the 2007 Guideline) A Report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011 
 
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37. Puymirat E, Aissaoui N, Coste P, et al. Comparison of efficacy and safety of a standard versus a 
loading dose of clopidogrel for acute myocardial infarction in patients >75 years of age (from the 
FAST-MI registry). Am J Cardiol 2011;108(6):755-9. 
 
38. Oh IY, Park KW, Kang SH, et al. Association of cytochrome P450 2C19*2 polymorphism with 
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Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic 
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APPENDICES 
 
A. Ticagrelor and Clopidogrel Dose Justification and Side-effects 
Ticagrelor Dose Justification (normal dosage, oral route) 
Acute coronary syndrome - Thrombosis; Prophylaxis 
For patients with ACS, unstable angina, NSTEMI, or STEMI, the recommended 
ticagrelor loading dose is 180 mg orally once plus aspirin (usually 325 mg), followed by 
a maintenance dose of ticagrelor 90 mg twice daily with aspirin 75 to 100 mg once daily. 
Maintenance doses of aspirin greater than 100 mg daily are not recommended(28). 
 
Percutaneous coronary intervention - Thrombosis; Prophylaxis 
a. For patients with ACS, unstable angina, NSTEMI, or STEMI undergoing PCI, 
the recommended maintenance dose of ticagrelor is 90 mg twice daily with 
aspirin 75 to 100 mg once daily. Maintenance doses of aspirin greater than 100 
mg daily is not recommended(28). 
b. Subjects who have received a loading dose of clopidogrel may be started on 
ticagrelor maintenance dosing(28). Ticagrelor should be discontinued at least 5 
days prior to surgery, when possible(28). Ticagrelor is contraindicated in patients 
with severe hepatic impairment. 
 
Clopidogrel Hydrogen Sulfate Dose Justification (normal adult dosage, oral 
route) 
Clopidogrel should be discontinued 5 days prior to elective surgery, if an antiplatelet 
effect is not desired(21). 
1. Acute ST segment elevation myocardial infarction - Percutaneous coronary 
intervention - Thrombosis; Prophylaxis 
a. Initial loading dose, 300 mg or 600 mg ORALLY plus aspirin once prior to 
or at the time of PCI(34) 
b. Maintenance, 75 mg ORALLY plus aspirin once daily(34) 
c. Bare metal stents: duration of therapy for at least 12 months(34) 
d. Drug-eluting stents: duration of therapy for at least 12 months; continuation 
of therapy beyond 15 months may be considered(34) 
2. Acute ST segment elevation myocardial infarction - Thrombosis; Prophylaxis 
a. Optional loading dose of 300 mg ORALLY, followed by 75 mg ORALLY 
once daily in combination with aspirin 75 to 325 mg, with or without 
thrombolytics(28) 
3. Cerebrovascular accident, Recent - Thrombosis; Prophylaxis 
a. 75 mg ORALLY once daily(28) 
4. Myocardial infarction, Recent - Thrombosis; Prophylaxis 
a. 75 mg ORALLY once daily(28) 
5. Non-ST segment elevation myocardial infarction, acute - Percutaneous coronary 
intervention - Thrombosis; Prophylaxis 
a. Initial loading dose, 300 mg to 600 mg with aspirin 75 to 325 mg as soon as 
possible; maintenance, 75 mg ORALLY plus aspirin 75 to 325 mg once 


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daily(35,36) 
b. Alternate loading dose, 600 mg ORALLY, followed by 150 mg maintenance 
dose daily for 6 days, then 75 mg daily in low bleeding risk patients(36,37) 
c. Bare metal stents: duration of therapy for at least 1 month and ideally up to 
12 months(36) 
d. Drug-eluting stents: duration of therapy for at least 12 months(1) 
6. Non-ST segment elevation myocardial infarction, acute - Thrombosis; Prophylaxis 
a. Loading dose, 300 mg ORALLY once; maintenance, 75 mg ORALLY once 
daily with aspirin 75 mg to 325 mg ORALLY once daily(35,36) 
7. Percutaneous coronary intervention - Thrombosis; Prophylaxis - Unstable angina 
a. Initial loading dose, 300 mg to 600 mg with aspirin 75 to 325 mg as soon as 
possible; maintenance, 75 mg ORALLY plus aspirin 75 to 325 mg once 
daily(26,35) 
b. Alternate loading dose, 600 mg ORALLY, followed by 150 mg maintenance 
dose daily for 6 days, then 75 mg daily in patients with low bleeding risk(35,36) 
c. Bare metal stents: duration of therapy for at least 1 month and ideally up to 
12 months(36) 
d. Drug-eluting stents: duration of therapy for at least 12 months(36) 
8. Peripheral arterial occlusive disease - Thrombosis; Prophylaxis 
a. 75 mg ORALLY once daily(35) 
 
Dosage in Hepatic Insufficiency 
1. Dosage adjustments for clopidogrel are not necessary in patients with hepatic 
impairment(35). 
2. No dosage adjustment is necessary for mild to moderate cirrhosis (Child-Pugh class 
A or B) based on a 10-day multiple-dose study in subjects with cirrhosis and matched 
controls. The mean peak concentration, time to peak concentration, and area under 
the concentration-time curve (AUC) for clopidogrel's major metabolite (SR 26334) 
did not differ statistically between groups. The geometric mean for AUC in patients 
with cirrhosis failed to reach the predetermined threshold of clinical significance (1.5 
times above the geometric mean in controls). The mean percentage inhibition of 
platelet aggregation and mean bleeding time prolongation factor were statistically 
similar between cirrhotics and controls(38). 
 
Dosage in Geriatric Patients 
1. No dosage adjustments are necessary(35,39). 
2. Clopidogrel 75 milligrams/day for 10 days was associated with statistically similar 
reductions of 55% to 57% in adenosine diphosphate (ADP)-induced platelet 
aggregation among healthy young, healthy elderly, and elderly patients with 
intermittent claudication. All three groups also experienced statistically equivalent 
prolongation of bleeding time (by a factor of 1.47 to 1.59). For clopidogrel's 
metabolite, SR 26334, the average peak concentration and the extent of absorption 
were significantly higher in the two elderly groups compared with the young 
volunteers, which did not translate into an age-related pharmacodynamic 
difference(39). 
3. Loading Dose: In the FAST-MI Registry analysis of patients 75 years of age and 
older with acute myocardial infarction (n=791; mean age 81 +/- 4 years old), a 
clopidogrel loading dose (greater than or equal to 300 mg) was not associated with an 
increased risk of major bleeding or transfusion but did not significantly decrease 12 
month mortality when compared with standard clopidogrel therapy (less than 300 


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mg). There were 466 patients who received a clopidogrel loading dose of at least 300 
mg (300 mg in 384 patients, 375 mg in 5 patients, 450 mg in 16 patients, 600 mg in 
60 patients, ad 900 mg in 1 patient) and 325 patients who received standard 
clopidogrel therapy (75 mg in 287 patients, 150 mg in 27 patients, and 225 in 11 
patients). One year survival (80.7% compared with 73.5%; p=0.02) and one year 
event free survival (77.3% compared with 68.6%; p=0.009) were higher in patients 
treated with a clopidogrel loading dose (40)  
 
18.1.1 Ticagrelor Side Effects 
 
Cardiovascular effects may include atrial fibrillation (4.2%), bradyarrhythmia (Holter- 
detected), chest pain (3.1%), hypertension (3.8%), hypotension (3.2%), loss of 
consciousness, and syncope. 
 
Endocrine/Metabolic effects may include gynecomastia (0.23%). 
 
Gastrointestinal effects may include diarrhea (3.7%), and nausea (4.3%). 
 
Hematologic effects may include bleeding, major (4.5%), and bleeding major and minor 
(8.7%). 
 
Musculoskeletal effects may include backache (3.6%), and chest pain, non-cardiac 
(3.7%). 
 
Neurologic effects may include dizziness (4.5%) and headache (6.5%). 
 
Renal effects may include increased uric acid level and raised serum creatinine level 
(7.4%). 
 
Respiratory effects may include cough (4.9%) and dyspnea (13.8%). 
 
Other side effects may include fatigue (3.2%). 
 
18.1.2 Clopidogrel Side Effects (<2% unless otherwise stated) 
 
Cardiovascular effects may include coronary artery stent thrombosis, hypotension, and 
vasculitis. 
 
Dermatologic effects may include acute generalized exanthematous pustulosis, bullous 
dermatosis, contusion, erythema multiforme, erythematous rash, fixed drug eruption, 
lichen planus, pruritus, Stevens-Johnson syndrome, and urticaria. 
 
Gastrointestinal effects may include colitis, gastrointestinal hemorrhage (2%-2.7% with 
aspirin), and pancreatitis. 
 
Hematologic effects may include agranulocytosis, aplastic anemia, major bleeding (0.8% 
to 3.7%), non-major bleeding (3.6% to 5.1%), granulocytopenic disorder, hemolytic 
uremic 
syndrome, 
leukemia, 
leucopenia, 
neutropenia, 
pancytopenia 
(severe), 
postoperative hemorrhage, thrombocytopenia, and thrombotic thrombocytopenic purpura. 
 
Hepatic effects may include hepatitis, hepatotoxicity, liver failure, and liver function tests 
abnormal (up to 3% of patients). 
 
Immunologic effects may include anaphylactoid reaction, immune hypersensitivity 
reaction, and serum sickness due to drug. 
 
Musculoskeletal effects may include arthralgia, acute arthritis, myalgia, and tendinitis. 
 
Neurologic effects may include disorder of taste, epidural hematoma, intracranial 
hemorrhage, and loss of taste. 
 
Ophthalmic effects may include intraocular hemorrhage (0.05%). 
 
Psychiatric effects may include confusion. 
 
Renal effects may include abnormal renal function, hematuria, kidney disease, and serum 
creatinine raised. 
 
Respiratory effects may include bronchospasm, interstitial pneumonia, non-cardiogenic 
pulmonary edema, and respiratory tract hemorrhage. 


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 
Other effects may include angioedema, drug withdrawal, rebound effect, and 
postoperative infection. 
B. Clinical Trial Management Systems (CTMS) 
CTMS is the Mayo Clinic Research Committee-endorsed institutional resource for clinical data 
management. CTMS is a robust institutional effort initiated in 2009 to address emerging changes 
within the data and statistical coordinating centers affiliated with National Cancer Institute (NCI)- 
funded cooperative groups. In 2009, NCI selected Medidata Rave (http://www.mdsol.com/) as  
the required data collection tool for all cooperative studies. To capitalize on Mayo Clinic and the 
NCI’s investment in Medidata Rave, Mayo Clinic formalized a three-tier data management 
infrastructure with the Medidata Rave product as the premier system. 
 
Medidata Rave is a product for multi-center clinical trials conducted under 21 CFR Part 11 
requirements. This web-based system provides ease of use coupled with an integrated 
randomization module (Medidata Balance), custom reporting, robust data validation routines, and 
straightforward integration with SAS. 
 
Electronic Data Capture 
Medidata Rave allows for data collection in multisite studies. During the course of the data 
entry into Medidata Rave, the system provides real-time within-CRF and inter-CRF data 
consistency verification. Medidata Rave is flexible in nature so that all data can be entered 
even if “required” fields and or other consistency checks requirements are not satisfied. The 
system uses an internal “flagging” or “query” system to distinguish the valid from the invalid 
data thereby ensuring compliance with the FDA guidance document “Computerized Systems 
Used in Clinical Trials.” All data discrepancy issues are tracked and audited by the system to 
ensure the highest quality data is available for analysis and study reporting. 
 
Contained within the CTMS initiative at Mayo Clinic is a diverse set of administrative and 
technical personnel to support the development and implementation of clinical trials in 
Medidata Rave. While the time necessary to program Medidata Rave’s eCRFs has been 
directly budgeted, the CTMS initiative supports protocol independent activities such as 
software/server maintenance, data standards, institutional system integrations, SAS data, and 
training of study personnel through institutional resources. 
 
The dedicated virtual private network (VPN) connection between Mayo Clinic and Medidata 
Rave provides the conduit for data connectivity. Clinical trial data hosted in Medidata Rave 
is accessible when needed for SAS using the SAS OnDemand Connection, in combination 
with Mayo Clinic’s SAS Pipeline program, which creates a common and direct combination 
of the metadata (labels, formats, etc.) and data (raw values) into SAS datasets on a scheduled 
(nightly) basis. This process removes the need to separately label and format the entire 
clinical trial database separately in SAS. 
 
 
Medidata Balance 
Randomization encounters challenges in complex multisite clinical studies in which random 
assignment to study drug must be completed prior to the baseline visit and a subject can fail 
to attend the baseline visit or be deemed ineligible for the study based on the final 
inclusion/exclusion criteria assessed at the baseline visit. It is possible that some individuals 
will not receive active treatment after treatment assignment has been established. Medidata 
Balance uses a novel multidimensional dynamic allocation algorithm minimizing imbalances 


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across multiple dimensions including overall study, sites, factors, and cross-factor strata. It  
is also highly flexible with extensive weighting and can be applied to most randomization 
scenarios including unbalanced designs. The algorithm in Medidata Balance represents a 
novel multidimensional dynamic allocation algorithm for treatment assignments. 
 
 
C. Statistical Calculations 
 
Likelihood Method for Real Time Estimation of Treatment Effect and Event Rates: At any point in 
time during the TAILOR-PCI trial, there are two sources of data on the treatment effect: 1) data from 
subjects with 1 complete year of follow-up and TaqMan processing completed (“complete” data), and 
2) the data on those with less than 1 year of follow-up or without TaqMan processing, half of whom 
have been genotyped using SPARTAN (“incomplete”). The complete subjects have complete 
endpoint and genotype data, while the incomplete subjects have incomplete endpoint and incomplete 
genotype data. Nevertheless, both sets of data have information on the treatment effect, and this 
information can be quantified. The analysis of the subjects who have undergone TaqMan is 
straightforward; a good approximation is a binomial comparison between the two LOF groups, in 
terms of their one year event rate. To recover the information in the prospectively randomized 
subjects who have not had TaqMan analysis complete, we propose the following simplified yet highly 
accurate approach. 
There are 3 groups: 1) prospectively genotyped, loss of function carriers (PG-LOF) who are given 
ticagrelor, 2) prospectively genotyped, wild type subjects (PG-WT) who are given clopidogrel and 3) 
conventional therapy (CT) who are given clopidogrel. Let us simplify the primary endpoint to a 
binary outcome X (yes or no) with a probability that depends on: genotype(G), treatment(Rx), and 
follow-up time. Specifically, we assume that, for a subject with genotype G, treatment Rx, and 
observed for t years, the probability of an event is: 
 
𝐏𝐫{𝑿 = 𝟏|𝑮, 𝑹𝒙, 𝒕} = 𝝀 
 
 
𝑮,𝑹𝒙 ∗  [𝟏 − 𝑺(𝒕)] 
[𝟏 − 𝑺(𝟏)] 
 
= 𝒘(𝒕) ∗ 𝝀𝑮,𝑹𝒙 
 
where S(.) is the overall underlying survival curve for freedom from events, t is time in years. Note 
that if the subject experiences the primary endpoint, the value of t is not tied to the event time itself, 
but rather reflects the visit date (roughly 1 month, 6 months, or one year) representing the effective 
amount of follow-up for that patient (time from randomization to last follow-up date). To calculate 
S(.), we simply use the Kaplan-Meier curve for the entire study population. This fraction therefore 
represents the fraction of a “risk year” to which that subject was exposed, i.e. it is an estimate of the 
proportion of events occurring within a year that have occurred at the follow-up time for the specific 
individual. Note that we consider w(t) to be a fixed quantity, rather than a parameter, though 
technically it is estimated from the entire data set. 


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𝝀
We further assume that the event rates (1-year probabilities) are: 
 
𝝀𝑾𝑻,𝑪𝑳 = 𝝀𝟏 
𝝀𝑳𝑶𝑭,𝑻𝑰𝑪 = 𝝀𝟐 
𝝀𝑳𝑶𝑭,𝑪𝑳 = 𝝀𝟑 
We also assume that the rate of wild type subjects exposed to clopidogrel (1) is the same whether 
they are in the conventional therapy or the prospective genotyping group. This is a fundamental 
assumption, but one which will also be ultimately tested. 
The treatment effect of interest can be expressed as 𝝀𝟐⁄ , that is, the relative risk associated with 
𝟑 
 
ticagrelor in LOF subjects. The trial’s primary hypothesis is that this number is substantially less than 
1.0. (Relative risk reduction is 1 minus this quantity). Finally, let α be the population prevalence of 
the LOF genotype in the population being randomized. We can now define the likelihood 
contributions of members of each of the three groups of “incomplete” subjects. 
For those in the PG-WT and PG-LOF groups, the likelihood contributions, respectively, are: 
 
𝑳(𝝀𝟏|𝑿, 𝒕) = [𝝀𝟏 ∗ 𝒘(𝒕)]𝑿  ∗ [𝟏 − 𝝀𝟏 ∗ 𝒘(𝒕)](𝟏−𝑿) 
𝑳(𝝀𝟐|𝑿, 𝒕) = [𝝀𝟐 ∗ 𝒘(𝒕)]𝑿  ∗ [𝟏 − 𝝀𝟐 ∗ 𝒘(𝒕)](𝟏−𝑿) 
For those in the CT group, the likelihood contribution is a weighted average of the likelihood 
contributions that would be obtained under (WT, CLOP) and (LOF, CLOP) conditions, weighted by 
the probability of each genotype, namely: 
𝑳(𝝀𝟏, 𝝀𝟑, 𝜶|𝑿, 𝒕) = (𝟏 − 𝜶) ∗ 𝑳𝟏(𝑿, 𝒕) + 𝜶 ∗ 𝑳𝟑(𝑿, 𝒕) 
where L1 and L3 have the obvious definitions parallel to the ‘known-genotype' likelihoods spelled out 
above. If this were the only data available, then the 4 parameters (λ1, 2, 3, ) would not be 
identifiable, i.e.  and 3 would be completely confounded. However, we have one further piece of 
data: the numbers of LOF and WT subjects in the PG group. These numbers can be put into a 
binomial likelihood with  as the only parameter. The random variable corresponding to this 
proportion is statistically independent (at least uncorrelated), with all the other likelihood pieces. 
Therefore, the overall likelihood is the product of all the conditional likelihood pieces for the 
members of the 3 groups, along with this binomial likelihood for the prevalence of LOF. This serves 
to identify both  and therefore 3 as parameters. Thus in this complete likelihood, all 4 parameters 
are identified. Thus, the incomplete data provides a likelihood that is informative about the treatment 
effect (subject to the null hypothesis assumption regarding the effect of knowledge of genotype on the 
WT/CLOP response). The likelihood from these data can be combined with the simple TaqMan 
binomial data to derive a combined likelihood which incorporates both pieces of information. 
Estimation of Information Time: We can also estimate the proportion of total study information 
contained in the current data. First, we estimate the expected information at the end of the trial as the 


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inverse of the expected square of the standard error of the hazard ratio of interest. Our expected 
power of 85.8% implies that our expected z-score at the end of the trial is 3.031. Given a minimum 
detectable effect size of 0.50, the expected standard error at study end is 0.2287 (log(0.5)/3.031). 
Thus the expected final information is 19.1. Second, the available information in the current data is 
calculated using a profile likelihood approach to estimate the standard error of the current estimate of 
the treatment effect. The ratio of the current information to the expected final information is the 
estimated information time. 
Calculation of conditional power: Conditional power is a function of the current effect estimate z- 
score and information time. Its formula is: 
𝐶𝑃(𝑡, 𝑍𝑡) = 1 −(
𝜱−𝟏(𝟎.𝟗𝟕𝟓)−𝑍𝑡∗√𝑡
√(1−𝑡)
) −(𝜱−𝟏(𝟎. 𝟗𝟕𝟓) + 𝜱−𝟏(𝑷𝟎)) ∗√(1 −𝑡) 
 
where t is information time, Zt is the current z-score, Φ is the cumulative Gaussian distribution 
function, Φ-1 is its inverse and P0 is the unconditional study power under initial study assumptions. Zt 
will be calculated from the log of the estimated effect and its estimated standard error. 
 
 
D. Site Monitoring 
 
AHRC (U.S.A. and Canadian sites) and DCIS (Korean sites) will conduct periodic on-site monitoring 
visits during the course of the study. At a minimum, AHRC and DCIS will ensure that the monitor 
reviews eligibility, safety, and outcome data for the first 3-5 subjects. Additional monitoring visits 
will be scheduled in accordance with the Trial Monitoring Plan. Over the entire study, it is anticipated 
that 10% of all randomized subjects will be monitored.  
 
The purposes of monitoring visits are to: 
 
Ensure the rights and safety of participants; 
 
Confirm that the study is conducted in accordance with Good Clinical Practice (GCP) guidelines; 
 
Ensure maintenance of required documents; 
 
Verify adherence to the protocol; 
 
Monitor the quality of data collected; 
 
Ensure accurate reporting and documentation of study endpoints and unanticipated, serious, and 
related problems; and 
 
Ensure that IRB/REB submissions/approvals are up-to-date. 
 
During monitoring visits, the data recorded on CRFs are reviewed and verified against source 
documents to ensure: 
 
Informed consent has been obtained and documented in accordance with IRB/REB/FDA 
regulations; 
 
The information recorded on the forms is complete and accurate; 
 
There are no omissions in the reports of specific data elements; 
 
Missing examinations are indicated on the forms; and 
 
Participant disposition when exiting the study is accurately recorded. 


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E. Steering Committee membership 
 
Dr. Chet Rihal Chair 
Dr. Ahmed Hasan 
Dr. Derek So 
Dr. Dawn Abbott 
Dr. David Holmes 
Dr. Liewei Wang 
Dr. Jang-Ho Bae 
Dr. Myung Ho Jeong 
Dr. Richard Weinshilboum 
Dr. Linnea Baudhuin 
Dr. Amir Lerman 
Dr. Michael Farkouh 
Dr. Verghese Mathew 
Dr. Bernard Gersh 
Dr. Naveen Pereira 
Dr. Shaun Goodman 
Dr. Yves Rosenberg 
Dr. Paul Gordon 
Dr. Jorge Saucedo 
 
 
F. Publications Committee 
 
The Executive Committee will serve as an ad hoc Publications Committee and will take ultimate 
responsibility for final data analysis and submission of the TAILOR-PCI trial for publication and 
presentation. It will also review all requests for publication and sub-studies and adjudicate any 
controversies regarding publications. It will make decisions by a majority vote but will strive for 
consensus if at all possible in its work to prioritize publication requests. It is the intent of the Steering 
Committee to include all site PI’s as authors for the first publication. Order of authorship (outside of 
the PI and Steering Committee Chair) will be based upon enrollment success, adherence, data 
completion and other trial effort at the individual sites. The processes and tasks of the Publications 
Committee for establishing authorship has been described in detail by Whellan et al.(25) 
 
 
G. Data and Safety Monitoring Board 
 
A data and safety monitoring board (DSMB) will be assembled twice per year to ensure data quality 
and participant safety and to provide independent advice to the Steering Committee regarding 
progress and the appropriateness of study continuation. Minutes will be taken during each meeting 
and shared with each site. The Mayo statistician will generate statistical reports for the DSMB. If the 
assumptions upon which the power and sample size calculations were based appear not to hold in the 
enrolled patients (e.g. the primary endpoint rate is lower than expected), the DSMB may advise the 
Steering Committee to modify the protocol to allow a larger sample size.  At least one additional 
member will be added to the DSMB to review the digital follow-up sub-study with relevant 
technology experience. 
 
H. Monitoring 
 
On-site monitoring activities will be performed at all sites by AHRC at the U.S.A. and non-Korean 
international sites and DCIS at the Korean sites. The monitor will review the Regulatory Binder, the 
first 3-5 subjects, and then some percentage thereafter at each site in accordance with standard 
operating procedures set forth in the Trial Monitoring Plan. Information regarding the types of visits 
is outlined in the Operations Manual.