Clinical trial NCT03672097
Conditions: Acute Coronary Syndrome (ACS)
Keywords: Percutaneous Coronary Intervention (PCI) ST elevation myocardial infarction (STEMI) Non-ST elevation myocardial infarction [NSTEMI] Unstable angina (UA) Prasugrel ACS-PCI
Sponsor: Daiichi Sankyo Taiwan Ltd., a Daiichi Sankyo Company
Start date: 2018-10-16; Completion date: 2020-08-19
Enrollment: 204 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase IV, multicenter trial is designed to assess the efficacy of prasugrel in preventing the formation of blood clots in Taiwanese patients with ACS who have been treated with PCI.

Detailed description:

Arms: arm 1: Participants with ACS who underwent PCI, and were previously taking clopidogrel, receive a maintenance dose (MD) of prasugrel for a total of 28 weeks (optionally up to a maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI)
Interventions: intervention 1: Prasugrel
Intervention descriptions: intervention 1: Prasugrel, oral tablets, containing 3.75 mg per tablet

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 3 / 77 
 
 
Confidential 
INVESTIGATOR AGREEMENT  
 
I confirm that I have read and that I understand this protocol, the package insert, and other product 
information provided by the sponsor. I agree to conduct this study in accordance with the requirements 
of this protocol and also protect the rights, safety, privacy, and well-being of study subjects in 
accordance with the following: 
 
 
The ethical principles that have their origin in the Declaration of Helsinki. 
 
International Conference on Harmonization Harmonized Tripartite Guideline for Good 
Clinical Practice E6. 
 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
Regulatory requirements for reporting serious adverse events defined in this protocol. 
 
Terms outlined in the Clinical Study Site Agreement.  
 
 
 
 
 
Signature of Investigator 
Date 
 
 
Investigator Name (print or type) 
 
 
 
Investigator’s Title 
 
 
 
Name of Facility 
 
 
 
Location of Facility (City) 
 
 
 
 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 4 / 77 
 
 
Confidential 
REASON FOR SUBSTANTIAL AMENDMENT 01 
 
This amended study protocol is prepared with the following changes: 
 To include the optional follow-up to a maximum 12 months of P2Y12 inhibitor treatment based 
on the approved reimbursement of prasugrel for 12 months by the National Health Insurance 
Administration (NHIA). The study was initially planned for a final Visit 5 at Week 28, and 
there is now an optional Visit 6 at the maximum of 12 months P2Y12 inhibitor treatment after 
ACS underwent PCI(at investigators' discretion). 
 To add, based on communicated usual clinical practice, the possibility of a previous new loading 
dose of clopidogrel before the maintenance dose clopidogrel which will be flexibly considered  
between 2 and 8 weeks based on investigator's previous usual practice, which in any case will 
be always before any study procedure and therefore before the switch to prasugrel. 
 To precise the lower limits for exclusion based on hemoglobin < 10.5 g/dL or hematocrit < 30% 
is referred at screening, and any severe left ventricular systolic dysfunction, EF < 35% will 
exclude patients if within 3 months before screening or baseline. 
 To reduce, based again on communicated usual clinical practice on marketed products, the need 
of contraception for women to one single method instead of current two to collect data as 
similar to real world clinical setting. 
 To precise the definition of non-compliance with study drug separately by study period 
 To precise ticagrelor maintenance will be dosed as bid, clopidogrel maintenance as once daily, 
aspirin maintenance as per day, and prasugrel as once daily. 
 To precise the compliance formula to discount lost tablets but not returned. 
 
Detailed changes are summarized in the following table: 
 
Section 
Page 
Old text 
New text 
Heading 
All 
Final Version 1.0 
Amendment 01, Final Version 1.0 
 
All 
14/May/2018 
10/Jan/2019 
Cover 
1 
<<blank>> 
<<New row with amendment 
history>> 
Reason for 
substantial 
amendment 01 
4 
<<blank>> 
<<New section with details of the 
substantial amendment 01>> 
Summary Study 
design 
15 
28-week switching study 
28 weeks (optionally up to a 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI) switching study 
 
15 
28-WEEK SWITCHING STUDY: 
28-WEEK (OPTIONALLY UP TO 
A MAXIMUM 12 MONTHS OF 
P2Y12 INHIBITOR TREATMENT 
AFTER ACS UNDERWENT PCI) 
SWITCHING STUDY: 
 
15 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
 
15 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 5 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
 
15 
[…] to the end of the 28-week MD 
treatment period […] 
[…] to the end of the 28-week 
prasugrel MD treatment, or the 
maximum 12-month of P2Y12 
inhibitor treatment after ACS 
underwent PCI. […] 
Summary Number of 
Subjects 
15 
200 enrolled 
200 under prasugrel treatment 
Summary Dose 
Levels 
15 
Prasugrel 3.75 mg 
Prasugrel 3.75 mg once daily. 
Summary Duration 
of Treatment 
16 
Maximum 12 months per subject 
Maximum 12 months of P2Y12 
inhibitor treatment per subject 
Summary Period of 
Evaluation 
16 
<<blank>> 
Optional MD treatment of up to a 
maximum overall 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI (Period 1 of 4 
weeks + Period 2 of up to a 
maximum overall 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI) 
Summary Inclusion 
criteria 
16 
• clopidogrel maintenance dose 
(MD) of 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
clopidogrel loading dose (LD) of 
300 mg or 600 mg at the time of 
PCI 
• or ticagrelor MD of 90 mg bid 
and aspirin 81-100 mg for 2-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
and aspirin 81-100 mg for 2-4 
weeks following ticagrelor LD of 
180 mg at the time of PCI 
• or clopidogrel maintenance dose 
(MD) 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
ticagrelor LD of 180 mg at the time 
of PCI 
• clopidogrel maintenance dose 
(MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel 
loading dose (LD) of 300 mg or 600 
mg at the time of PCI 
• or ticagrelor MD of 90 mg bid and 
aspirin 81-100 mg per day for 1-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
once daily and aspirin 81-100 mg 
per day for 2-4 weeks (either 
directly or via clopidogrel loading 
dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg 
at the time of PCI 
• or clopidogrel maintenance dose 
(MD) 75 mg once daily and aspirin 
81-100 mg per day for 2-8 weeks 
following ticagrelor LD of 180 mg 
at the time of PCI 
• or based on investigator’s 
judgement with at least 2 weeks 
continues use of clopidogrel MD 
and aspirin 81-100 mg per day 
before switching to prasugrel and 
maximum 8 weeks P2Y12 inhibitors 
MD treatment (prasugrel is not 
allowed) 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 6 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
Summary Exclusion 
criteria 
16 
(5) Subject with hemoglobin <10.5 
g/dL, or hematocrit < 30% 
(5) Subject with hemoglobin <10.5 
g/dL, or hematocrit < 30% at 
screening 
 
16 
(6) Subject with severe left 
ventricular systolic dysfunction, EF 
< 35% 
(6) Subject with severe left 
ventricular systolic dysfunction, EF 
< 35% within 3 months before 
baseline (visit 2) 
 
16 
(10) Female pregnant or of child 
bearing potential, unless she has a 
negative serum pregnancy test at 
screening and agrees to use two 
methods of contraception during 
the study 
(10) Female pregnant or of child 
bearing potential, unless she has a 
negative serum pregnancy test at 
screening and agrees to use at least 
one method of contraception during 
the study 
Summary Endpoints 
17 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
 
17 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 
Primary endpoint 
17 
[…] after 28-week MD treatment 
weeks. 
[…] after 28 MD treatment weeks 
(optional maximum 12-month 
P2Y12 inhibitor treatment after ACS 
underwent PCI […] 
Secondary variables 
18 
• Minor and clinically relevant 
bleeding events after 28 MD 
treatment weeks 
• Major adverse cardiovascular 
events (MACE) including 
cardiovascular death, non-fatal 
myocardial infarction (MI), 
non-fatal stroke, stent 
thrombosis and 
revascularization after 28 MD 
treatment weeks 
• All cause deaths after 28 MD 
treatment weeks 
• Adverse events after 28 MD 
treatment weeks  
• Minor and clinically relevant 
bleeding events after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• Major adverse cardiovascular 
events (MACE) including 
cardiovascular death, non-fatal 
myocardial infarction (MI), non-
fatal stroke, stent thrombosis and 
revascularization after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• All cause deaths after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• Adverse events after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 7 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
treatment after ACS underwent 
PCI) 
Summary Main 
criteria for 
evaluation and 
analysis 
18 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
 
18 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 
 
19 
Primary variable: 
Incidence of major bleeding events 
(non-coronary artery bypass 
grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) 
major) after 28 MD treatment will 
be summarized with their 
corresponding 95% confidence 
interval, including median times to 
events as per Kaplan-Meier 
estimates. 
Primary variable: 
Incidence of major bleeding events 
(non-coronary artery bypass 
grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) 
major) after 28 MD treatment 
period (optionally maximum 12-
month P2Y12 inhibitor treatment 
period after ACS underwent PCI) 
will be summarized with their 
corresponding 95% confidence 
interval, including median times to 
events as per Kaplan-Meier 
estimates. 
 
 
19 
Secondary variables: 
Incidence of events after 28 MD 
treatment (minor or clinically 
relevant bleeding events, major 
adverse cardiovascular events) will 
be summarized with their 
corresponding 95% confidence 
interval, including median times to 
events as per Kaplan-Meier 
estimates. 
Percentage of all cause deaths and 
adverse events after 28 MD 
treatment will be summarized with 
their corresponding 95% 
confidence interval. 
Incidence of events (minor or 
clinically relevant bleeding events, 
major adverse cardiovascular 
events) after 28 MD treatment 
weeks up to maximum 12-month 
P2Y12 inhibitor treatment after 
ACS underwent PCI, based on 
investigator's discretion, will be 
summarized with their 
corresponding 95% confidence 
interval, including median times to 
events as per Kaplan-Meier 
estimates.  
Percentage of all cause deaths and 
adverse events after 28 MD 
treatment weeks (optionally up to a 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion) will be 
summarized with their 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 8 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
corresponding 95% confidence 
interval. 
Summary Study 
schedule and 
anticipated date of 
completion 
19 
May-Jul 2018: EC/IRBD/Health 
Authorities submission 
Nov 2018 – May 2020: 
Recruitment and treatment period 
Jun-Jul 2020: Database lock 
Oct-Nov 2020: Clinical Study 
Report 
May-Jul 2018: EC/IRB/Health 
Authorities submission 
Nov 2018 - Aug 2020: Recruitment 
and treatment period 
Sep-Oct 2020: Database lock 
Jan-Feb 2021: Clinical Study 
Report 
Table of contents 
20 
 
<<updated>> 
5.2 Study rationale 
27 
<<blank>> 
Based on investigator's discretion, 
the study will offer this second 
period until maximum 12-month 
P2Y12 inhibitor treatment after ACS 
underwent PCI to assess bleeding 
events, major adverse 
cardiovascular events (MACE), and 
all cause deaths. 
6.1.1.1 Primary 
Ogjective 
29 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
6.1.2 Period 2 
29 
6.1.2 PERIOD 2 (+24 weeks) 
6.1.2 PERIOD 2 (+24 weeks 
[optionally up to a maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI, based on 
investigator's discretion]) 
6.1.2.1 Primary 
objective 
30 
[…] to the end of the 28-week MD 
treatment period 
[…] to the end of the 28-week MD 
treatment period (optional 
maximum 12-month P2Y12 inhibitor 
treatment period after ACS 
underwent PCI) 
6.1.2.2 Secondary 
objectives 
30 
[…] to the end of the 28-week MD 
treatment period 
[…] to the end of the 28-week MD 
treatment period (optional 
maximum 12-month P2Y12 inhibitor 
treatment period after ACS 
underwent PCI) 
6.2.1.1 Primary 
Endpoint 
31 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
6.2.2 Period 2 
31 
6.2.2 PERIOD 2 (+24 weeks) 
6.2.2 PERIOD 2 (+ 24 weeks 
[optionally up to a maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI, based on 
investigator's discretion]) 
6.2.2.1 Primary 
endpoint 
31 
[…] after 28-week MD treatment 
period 
[…] after 28 MD treatment weeks 
or up to maximum 12-month P2Y12 
inhibitor treatment after ACS 
underwent PCI) 
6.2.2.2 Secondary 
endpoints 
31 
[…] after 28-week MD treatment 
period 
[…] after 28 MD treatment weeks 
or up to maximum 12-month P2Y12 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 9 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
inhibitor treatment after ACS 
underwent PCI) 
7.1 Overall study 
design and plan 
33 
[…] 28-week 
[…] 28-week (optionally up to a 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion) 
 
33 
(a) clopidogrel maintenance dose 
(MD) of 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
clopidogrel loading dose (LD) of 
300 mg or 600 mg at the time of 
PCI; or (b) ticagrelor MD of 90 mg 
bid and aspirin 81-100 mg for 2-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
and aspirin 81-100 mg for 2-4 
weeks following ticagrelor LD of 
180 mg at the time of PCI; or (c) 
clopidogrel maintenance dose 
(MD) 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
ticagrelor LD of 180 mg at the time 
of PCI 
(a) clopidogrel maintenance dose 
(MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel 
loading dose (LD) of 300 mg or 600 
mg at the time of PCI; or (b) 
ticagrelor MD of 90 mg bid and 
aspirin 81-100 mg per day for 1-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
once daily and aspirin 81-100 mg 
per day for 2-4 weeks (either 
directly or via clopidogrel loading 
dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg 
at the time of PCI; or (c) 
clopidogrel maintenance dose (MD) 
of 75 mg once daily and aspirin 81-
100 mg per day for 2-8 weeks 
following ticagrelor LD of 180 mg 
at the time of PCI; or (d) based on 
investigator’s judgement with at 
least 2 weeks continues use of 
clopidogrel MD and aspirin 81-100 
mg per day before switching to 
prasugrel and maximum 8 weeks 
P2Y12 inhibitors MD treatment 
(prasugrel is not allowed) 
 
33 
Eligible subjects will receive open-
label prasugrel MD 3.75 mg and 
aspirin 81-100 mg. The 
investigator’s judgement will be 
followed […] 
Eligible subjects will receive open-
label prasugrel MD 3.75 mg once 
daily and aspirin 81-100 mg per 
day. The investigator’s discretion 
will be followed […] 
 
33 
After signing the study informed 
consent, subjects will enter a 
flexible screening period based on 
the investigator’s judgement 
After signing the study informed 
consent, subjects will enter a 
flexible screening period based on 
the investigator’s discretion 
 
33 
[…] Period 2 of +24-week 
prasugrel MD treatment 
[…] Period 2 of +24-week 
prasugrel MD treatment (optionally 
up to a maximum 12 months of 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
Page 10 / 77 
 
 
Confidential 
Section 
Page 
Old text 
New text 
P2Y12 inhibitor treatment after ACS 
underwent PCI) 
 
33 
[…] treatment week 28 visit 
[…] treatment week 28 visit 
(optionally up to a maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI, based on 
investigator's discretion) 
Figure 1 
34 
 
<<updated>> 
7.2 Discussion of 
study design, 
including the choice 
of control groups 
34 
This trial is designed as a phase 4, 
multicenter, non-comparative, open 
label, 28-week switching study 
[…] 
This trial is designed as a phase 4, 
multicenter, non-comparative, open 
label, 28 weeks (optionally up to a 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI) switching study 
[…] 
 
34 
(a) clopidogrel maintenance dose 
(MD) of 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
clopidogrel loading dose (LD) of 
300 mg or 600 mg at the time of 
PCI; or (b) ticagrelor MD of 90 mg 
bid and aspirin 81-100 mg for 2-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
and aspirin 81-100 mg for 2-4 
weeks following ticagrelor LD of 
180 mg at the time of PCI; or (c) 
clopidogrel maintenance dose 
(MD) 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
ticagrelor LD of 180 mg at the time 
of PCI 
(a) clopidogrel maintenance dose 
(MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel 
loading dose (LD) of 300 mg or 600 
mg at the time of PCI; or (b) 
ticagrelor MD of 90 mg bid and 
aspirin 81-100 mg per day for 1-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
once daily and aspirin 81-100 mg 
per day for 2-4 weeks (either 
directly or via clopidogrel loading 
dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg 
at the time of PCI; or (c) 
clopidogrel maintenance dose (MD) 
of 75 mg once daily and aspirin 81-
100 mg per day for 2-8 weeks 
following ticagrelor LD of 180 mg 
at the time of PCI; or (d) based on 
investigator’s judgement with at 
least 2 weeks continues use of 
clopidogrel MD and aspirin 81-100 
mg per day before switching to 
prasugrel and maximum 8 weeks 
P2Y12 inhibitors MD treatment 
(prasugrel is not allowed). 
 
34 
The prasugrel MD dose for this 
study (3.75 mg) 
The prasugrel MD dose for this 
study (3.75 mg once daily) 
 
34 
The investigator’s judgement 
The investigator’s discretion 
 
34 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 


 
 
 
 
Protocol No.: CS747S-B-A4003  
 
 
 
Amendment 01, Final version 1.0  
 
 
 
10/Jan/2019 
 
 
 
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Confidential 
Section 
Page 
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New text 
 
34 
<<blank>> 
Based on the investigator's 
discretion, patients will be offered 
to extend Period 2 up to maximum 
12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI 
for an additional safety assessment 
of the same objectives. 
 
34 
[…] during a longer Period 2 (+24 
weeks) 
[…] during a longer Period 2 (+24 
weeks or optionally up to a 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI based on 
investigator's discretion). 
8.0 Selection of 
study population 
36 
(a) clopidogrel maintenance dose 
(MD) of 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
clopidogrel loading dose (LD) of 
300 mg or 600 mg at the time of 
PCI; or (b) ticagrelor MD of 90 mg 
bid and aspirin 81-100 mg for 2-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
and aspirin 81-100 mg for 2-4 
weeks following ticagrelor LD of 
180 mg at the time of PCI; or (c) 
clopidogrel maintenance dose 
(MD) 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
ticagrelor LD of 180 mg at the time 
of PCI 
(a) clopidogrel maintenance dose 
(MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel 
loading dose (LD) of 300 mg or 600 
mg at the time of PCI; or (b) 
ticagrelor MD of 90 mg bid and 
aspirin 81-100 mg per day for 1-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
once daily and aspirin 81-100 mg 
per day for 2-4 weeks (either 
directly or via clopidogrel loading 
dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg 
at the time of PCI; or (c) 
clopidogrel maintenance dose (MD) 
of 75 mg once daily and aspirin 81-
100 mg per day for 2-8 weeks 
following ticagrelor LD of 180 mg 
at the time of PCI; or (d) based on 
investigator’s judgement with at 
least 2 weeks continues use of 
clopidogrel MD and aspirin 81-100 
mg per day before switching to 
prasugrel and maximum 8 weeks 
P2Y12 inhibitors MD treatment 
(prasugrel is not allowed). 
8.1 Inclusion criteria 
36 
• clopidogrel maintenance dose 
(MD) of 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
clopidogrel loading dose (LD) of 
300 mg or 600 mg at the time of 
PCI 
• clopidogrel maintenance dose 
(MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel 
loading dose (LD) of 300 mg or 600 
mg at the time of PCI 


 
 
 
 
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• or ticagrelor MD of 90 mg bid 
and aspirin 81-100 mg for 2-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
and aspirin 81-100 mg for 2-4 
weeks following ticagrelor LD of 
180 mg at the time of PCI 
• or clopidogrel maintenance dose 
(MD) 75 mg and aspirin 81-100 
mg for 4-8 weeks following 
ticagrelor LD of 180 mg at the time 
of PCI 
• or ticagrelor MD of 90 mg bid and 
aspirin 81-100 mg per day for 1-4 
weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg 
once daily and aspirin 81 100 mg 
per day for 2-4 weeks (either 
directly or via clopidogrel loading 
dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg 
at the time of PCI 
• or clopidogrel maintenance dose 
(MD) 75 mg once daily and aspirin 
81-100 mg per day for 2-8 weeks 
following ticagrelor LD of 180 mg 
at the time of PCI 
• or based on investigator’s 
judgement with at least 2 weeks 
continues use of clopidogrel MD 
and aspirin 81-100 mg per day 
before switching to prasugrel and 
maximum 8 weeks P2Y12 inhibitors 
MD treatment (prasugrel is not 
allowed) 
8.2 Exclusion 
criteria 
37 
(5) Subject with hemoglobin <10.5 
g/dL, or hematocrit < 30% 
(5) Subject with hemoglobin <10.5 
g/dL, or hematocrit < 30% at 
screening 
 
37 
(6) Subject with severe left 
ventricular systolic dysfunction, EF 
< 35% 
(6) Subject with severe left 
ventricular systolic dysfunction, EF 
< 35% within 3 months before 
baseline (visit 2) 
 
37 
(10) Female pregnant or of child 
bearing potential, unless she has a 
negative serum pregnancy test at 
screening and agrees to use two 
methods of contraception during 
the study 
(10) Female pregnant or of child 
bearing potential, unless she has a 
negative serum pregnancy test at 
screening and agrees to use at least 
one method of contraception during 
the study. 
8.4 Efficacy and 
safety assessments 
38 
[…] and treatment week 28 (V5) 
[…] , treatment week 28 (V5), and 
optionally up to a maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI (V6) 
based on investigator's discretion. 
8.4.1.3 
39 
[…] previous clopidogrel MD 75 
mg and/or ticagrelor MD 90 mg bid 
and aspirin 81-100 mg 
[…] previous clopidogrel MD 75 
mg once daily and/or ticagrelor MD 
90 mg bid and aspirin 81-100 mg 
per day 
8.4.1.6 Pregnancy 
test 
39 
[…] Blood pregnancy sampling 
will be obtained at screening and at 
visit 5 (week 28) 
[…] Blood pregnancy sampling will 
be obtained at screening, at visit 5 
(week 28), and optionally at visit 6 


 
 
 
 
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(maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI) or early 
termination. 
8.4.1.7 Procedure for 
clinical laboratory 
samples 
40 
[…] week 16 (visit 4) and week 28 
(visit 5) 
[…] week 16 (visit 4), week 28 
(visit 5), optionally based on 
investigator's discretion at 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI (visit 6) or early 
termination. 
 
40 
[…] from day 1 to week 28 
[…] from day 1 to week 28 and  
optionally up to a maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI) 
 
40 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
8.4.1.8 
Electrocardiogram, 
heart rate, blood 
pressure 
41 
[…] week 28 (V5) 
[…] week 28 (visit 5), optionally 
based on investigator's discretion at 
maximum 12 months of P2Y12 
inhibitor treatment after ACS 
underwent PCI (visit 6) or early 
termination 
8.4.1.9 Platelet 
function 
41 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
 
41 
[...] clopidogrel 75 MD after 4 
weeks screening 
[…] clopidogrel 75 MD after 
maximum 4 weeks screening  
8.4.2 Study 
procedures 
44 
<<blank>> 
Optional treatment maximum 12 
months of P2Y12 inhibitor treatment 
after ACS underwent PCI (Visit 6, 
Day 365 - 28). End of Period 2 
This visit is optional and will be 
based on investigator's discretion, 
and will be performed up to 
maximum overall 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, as the end of the 
Period 2. The following 
examinations/procedures will be 
performed: 
• Physical examination 
• Vital signs (including blood 
pressure) 
• Laboratory (hematology, 
biochemistry), serum pregnancy test 
(for women of childbearing 
potential) 
• Electrocardiogram 
• Recording of bleeding events 


 
 
 
 
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• Recording of major adverse 
cardiovascular events 
• Recording of all cause death 
• Recording of adverse events 
• Recording of concomitant 
medication 
 
45 
[…] following investigators' 
judgement 
[…] following investigators' 
discretion 
8.4.3.1.1 Primary 
Variables 
45 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
8.4.3.2 Period 2 
46 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks  [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 
 
46 
[…] after 28-week MD treatment 
weeks 
[…] after 28 MD treatment weeks 
or up to optional maximum 12-
month P2Y12 inhibitor treatment 
after ACS underwent PCI. 
8.4.3.2.2 Secondary 
variables 
46 
• Minor and clinically relevant 
bleeding events after 28 MD 
treatment weeks 
• Major adverse cardiovascular 
events (MACE) including 
cardiovascular death, non-fatal 
myocardial infarction (MI), non-
fatal stroke, stent thrombosis and 
revascularization after 28 MD 
treatment weeks 
• All cause deaths after 28 MD 
treatment weeks 
• Adverse events after 28 MD 
treatment weeks  
• Minor and clinically relevant 
bleeding events after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• Major adverse cardiovascular 
events (MACE) including 
cardiovascular death, non-fatal 
myocardial infarction (MI), non-
fatal stroke, stent thrombosis and 
revascularization after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• All cause deaths after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
• Adverse events after 28 MD 
treatment weeks (optional 
maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
8.5.2 
Discontinuation or 
47 
[…] (same as for the week 28 visit, 
together with the platelet function 
tests if Visit 3 is not done) and 
[…] (same as for the week 28 visit,) 
and determine the primary reason 
for the termination and where 


 
 
 
 
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withdrawal of 
individual subjects 
determine the primary reason for 
the termination and where possible 
the primary underlining reason, 
providing as much as detail as 
possible, and documenting the 
information on the eCRF.  
possible the primary underlining 
reason, providing as much as detail 
as possible, and documenting the 
information on the eCRF.  
For subject who terminated before 
Visit 3, Platelet function tests have 
to be conducted during the early 
termination visit. 
 
47 
(2) Noncompliance with 
investigational medicinal product 
(IMP) prasugrel MD + aspirin. 
(2) Noncompliance with 
investigational medicinal product 
(IMP) prasugrel MD + aspirin. 
Period 1 compliance is defined as 
80% compliance in the first 4 weeks 
with maximum 2 consecutive 
missed doses in the last week. 
Period 2 compliance is defined as 
80% compliance in the 24 weeks 
(or up to 12 months, alternatively) 
8.6.1 Treatment 
administered 
48 
Subjects will be treated with 
prasugrel 3.75 mg along with 
aspirin 81-100 mg during the study 
period. 
Subjects will be treated with 
prasugrel 3.75 mg once daily along 
with aspirin 81-100 mg per day oral 
dose during the study period. 
 
48 
The investigator’s judgement 
The investigator’s discretion 
8.6.2 Identify of 
Investigational 
product(s) 
48 
[…] The IMP will be identifiable 
by a unique identification number. 
 
<<deleted>> 
 
48 
Each card of investigational 
medication […] 
Each box of investigational 
medication […] 
8.6.3 Dosages and 
regimen 
49 
4 boxes of medication  at Visit 3 
(for 12 weeks of treatment ± 2 
weeks), and the last 4 boxes of 
medication at Visit 4 (for 12 weeks 
of treatment  ± 4 weeks). 
4 boxes of medication  at Visit 3 
(for 12 weeks of treatment ± 2 
weeks), 4 boxes of medication at 
Visit 4 (for 12 weeks of treatment ± 
4 weeks), and the last 4 boxes of 
medication at Visit 5 (for up to 
maximum 12 months of treatment) 
for those patients proposed 
following investigator's discretion 
to the optional extension period. 
 
49 
Subjects will be instructed to take 
the tablets orally per day at the 
same time. 
Subjects will be instructed to take 
the tablets once daily oral dose at 
the same time. 
 
49 
The investigator’s judgement 
The investigator’s discretion 
8.6.8 Treatment 
adherence 
50 
[…] At visit 3, 4, and 5 
[…] At visit 3, 4, 5 and 6 (optional) 
8.6.10 Drug 
accountability 
51 
[…] At visit 3, 4, and 5 
[…] At visit 3, 4, 5 and 6 (optional) 
 
51 
• Verifying that the log is 
completed with the drug 
• Verifying that the log is 
completed with the drug lot/patient 


 
 
 
 
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lot/medication ID/ patient number 
used to document each dose. 
number used to document each 
dose. 
8.6.10 Drug 
accountability 
51 
<<compliance formula did not 
consider lost tablets>> 
<<updated to account for lost 
tablets>> 
9.6 Adverse event 
collection period 
56 
[…] treatment period 2 of +24 
weeks 
[…] treatment period 2 of +24 
weeks (optionally up to a maximum 
12 months of P2Y12 inhibitor 
treatment after ACS underwent 
PCI) 
11.1.3 Efficacy 
analysis 
60 
P2Y12 reactive unit (PRU) 
P2Y12 reaction unit (PRU) 
 
60 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 
 
60 
[…] after 28-week MD treatment  
[…] after 28 MD treatment weeks 
(optional maximum 12-month 
P2Y12 inhibitor treatment after ACS 
underwent PCI) 
11.1.4.2.2 
61 
PERIOD 2 (+24 weeks) 
PERIOD 2 (+24 weeks [optionally 
up to a maximum 12 months of 
P2Y12 inhibitor treatment after ACS 
underwent PCI, based on 
investigator's discretion]) 
 
61 
[…] after 28-week MD treatment  
[…] after 28 MD treatment weeks 
(optional maximum 12-month 
P2Y12 inhibitor treatment after ACS 
underwent PCI) 
18.1 Schedule of 
Assessments 
75 
 
<<Updated>> 


 
 
 
 
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2.0 
Summary 
 
Name of Sponsor(s): Daiichi Sankyo Taiwan Ltd. 
 
Compound: Prasugrel 3.75 mg 
Title of Protocol: Phase IV, non-comparative, open label, multicenter, 28-
week switching study of prasugrel maintenance dose from clopidogrel in 
patients with acute coronary syndrome (ACS) who underwent a percutaneous 
coronary intervention (PCI) in Taiwan 
 
 
Study Number: CS747S-B-A4003 
Phase: 4 
 
Study design: Phase IV, non-comparative, open label, multicenter, 28 weeks (optionally up to a maximum 
12 months of P2Y12 inhibitor treatment after ACS underwent PCI) switching study. 
 
28-WEEK (OPTIONALLY UP TO A MAXIMUM 12 MONTHS OF P2Y12 INHIBITOR 
TREATMENT AFTER ACS UNDERWENT PCI) SWITCHING STUDY: 
 
PERIOD 1 (4-weeks) 
Primary objective: To assess the antiplatelet effect of prasugrel on P2Y12 reaction unit (PRU) value 
assessed with VerifyNow® from baseline to the end of the 4-week MD treatment period, after switching 
from clopidogrel MD to prasugrel MD. 
Secondary objectives: To assess the antiplatelet effect and safety of prasugrel from baseline to the end of 
the 4-week MD treatment period, after switching from clopidogrel MD to prasugrel MD. The antiplatelet 
effect assessments will include percentage of High on-Treatment Platelet Reactivity (HTPR) and percentage 
of platelet inhibition. The safety assessments will include major, minor and clinically relevant bleeding 
events, major adverse cardiovascular events (MACE), all cause deaths and adverse events. 
 
PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor treatment after 
ACS underwent PCI, based on investigator's discretion]) 
Primary objective: To assess the safety of prasugrel on major bleeding events from baseline to the end of 
the 28-week MD treatment period, after switching from clopidogrel MD to prasugrel MD. 
Secondary objectives: To assess the safety of prasugrel from baseline to the end of the 28-week prasugrel 
MD treatment, or the maximum 12-month of P2Y12 inhibitor treatment after ACS underwent PCI. The safety 
assessments will include minor and clinically relevant bleeding events, major adverse cardiovascular events 
(MACE), all cause deaths and adverse events. 
 
Exploratory objectives: Exploratory objectives will include the association CYP2C19 genotyping for 
subjects (targeted 100 subjects) who have signed the pharmacogenomic informed consent separately. 
 
Subject Population: 
 
Number of Subjects: 200 enrolled 
 
Number of sites: Appr. 10 sites in Taiwan 
Dose Levels: Prasugrel 3.75 mg once daily. 
 
Route of Administration: Oral 


 
 
 
 
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Duration of Treatment: Maximum 12 months of 
P2Y12 inhibitor treatment per subject 
Period of Evaluation: 
Screening of 4 weeks 
MD treatment of 28 weeks (Period 1 of 4 weeks + 
Period 2 of additional 24 weeks) 
Optional MD treatment of up to a maximum overall 12 
months of P2Y12 inhibitor treatment after ACS 
underwent PCI (Period 1 of 4 weeks + Period 2 of up 
to a maximum overall 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI) 
Safety follow-up (patients with AEs at the last 
treatment) 
The reference population will consist of patients with percutaneous coronary intervention (PCI) in patients 
with acute coronary syndrome (ACS). 
Main Criteria for Inclusion: 
(1) Subject who has provided signed informed consent. 
(2) Subject of either sex aged ≥ 20 years old at the informed consent date 
(3) Subject’s weight of at least 50 kg at the time of screening 
(4) Subject with previous diagnosis of ACS (unstable angina [UA], non-ST elevation myocardial 
infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) who has underwent PCI and 
was treated with either: 
 
clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel loading dose (LD) of 300 mg or 600 mg at the time of PCI 
 
or ticagrelor MD of 90 mg bid and aspirin 81-100 mg per day for 1-4 weeks and switching to 
clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 
2-4 weeks (either directly or via clopidogrel loading dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg at the time of PCI 
 
or clopidogrel maintenance dose (MD) 75 mg once daily and aspirin 81-100 mg per day for 
2-8 weeks following ticagrelor LD of 180 mg at the time of PCI 
 
or based on investigator’s judgement with at least 2 weeks continues use of clopidogrel MD 
and aspirin 81-100 mg per day before switching to prasugrel and maximum 8 weeks P2Y12 
inhibitors MD treatment (prasugrel is not allowed) 
 
Main Criteria for Exclusion: 
(1) Subject with active bleeding or significant increase of risk of hemorrhage such as severe hepatic 
insufficiency, peptic ulcer present, proliferative diabetic retinopathy, antecedents of severe systemic 
bleeding, gastrointestinal bleeding, macrohematuria, intraocular hemorrhage, hemorrhagic stroke, or 
intracranial bleeding), or other antecedents of bleeding diathesis or coagulopathy. 
(2) Subject with any transient ischemic attack [TIA] within 3 months before the informed consent date, or 
any ischemic stroke within 3 months before the informed consent date, or any previous hemorrhagic 
stroke. 
(3) Subject with known allergies or hypersensitivity to prasugrel, aspirin, or any of their excipients. 
(4) Subject with significant hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure 
> 110 mmHg) at either the time of screening or baseline assessment 
(5) Subject with hemoglobin <10.5 g/dL, or hematocrit < 30% at screening 
(6) Subject with severe left ventricular systolic dysfunction, EF < 35% within 3 months before baseline 
(visit 2) 
(7) Subject is under hemodialysis 
(8) Subject with evidence of severe hepatic disease, or any of the following: serum alanine transaminase 
(ALT) or aspartate transaminase (AST) ≥ 3 times the upper limit of normal (ULN) laboratory reference 
range; or bilirubin ≥ 2 times the ULN of laboratory reference range at screening. 
(9) Subject with any other results of clinical laboratory tests at the time of screening that are judged by the 
investigator that could be detrimental to the Subject or could compromise the study 


 
 
 
 
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(10) Female pregnant or of child bearing potential, unless she has a negative serum pregnancy test at 
screening and agrees to use at least one method of contraception during the study. 
(11) Subject currently enrolled in, or discontinued within the last 30 days prior to baseline from, a clinical 
study involving an off-label use of an investigational drug or device, or concurrently enrolled in a non-
observational clinical study or any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
(12) Subject who has previously completed or withdrawn from this study. 
(13) Subject with evidence of significant active neuropsychiatric disease, alcohol abuse or drug abuse, in 
the investigator's opinion 
(14) Subject who is unreliable and unwilling to make him/herself available for the duration of the study and 
who will not abide by the research unit policy and procedure and study restrictions. 
Endpoints 
PERIOD 1 (4 weeks) 
Primary endpoint:  
Mean change in the P2Y12 reaction unit (PRU) value assessed with VerifyNow® from baseline to the end of 
the 4-week MD treatment period, after switching from clopidogrel MD to prasugrel MD. 
 
Secondary variables:  
Efficacy (antiplatelet effect): 
 
Percentage of High on-Treatment Platelet Reactivity (HTPR) defined as PRU > 235. 
 
Percentage of platelet inhibition at the end of the 4-week MD treatment period, after 
switching from clopidogrel MD to prasugrel MD. 
Safety: 
 
Major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) major) after 4 MD treatment weeks. 
 
Minor and clinically relevant bleeding events after 4 MD treatment weeks 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 4 
MD treatment weeks 
 
All cause deaths after 4 MD treatment weeks 
 
Adverse events after 4 MD treatment weeks 
 
PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor treatment after 
ACS underwent PCI, based on investigator's discretion]) 
Primary endpoint:  
Major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis in myocardial infarction 
(TIMI) major) after 28 MD treatment weeks (optional maximum 12-month P2Y12 inhibitor  treatment after 
ACS underwent PCI.) 
Secondary variables:  
Safety: 
 
Minor and clinically relevant bleeding events after 28 MD treatment weeks (optional 
maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI) 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 28 
MD treatment weeks (optional maximum 12-month P2Y12 inhibitor treatment after ACS 
underwent PCI) 
 
All cause deaths after 28 MD treatment weeks (optional maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent PCI) 
 
Adverse events after 28 MD treatment weeks (optional maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent PCI) 
 


 
 
 
 
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EXPLORATORY  
Association CYP2C19 genotyping for subjects (targeted 100 subjects) who have signed the 
pharmacogenomic informed consent form separately. 
 
Main Criteria for Evaluation and Analysis: 
PERIOD 1 (4 weeks) 
Primary variable: 
Mean change in the P2Y12 reaction unit (PRU) value assessed with VerifyNow® from baseline to the end of 
the 4-week MD treatment period, after switching from clopidogrel MD to prasugrel MD will be analyzed 
with a paired t-test model. Mean changes will be presented with their corresponding 95% confidence 
interval. 
Secondary variables: 
Percentage of High on-Treatment Platelet Reactivity (HTPR) defined as PRU > 235 will be summarized 
with their corresponding 95% confidence interval. 
Percentage of platelet inhibition at the end of the 4-week MD treatment period, after switching from 
clopidogrel MD to prasugrel MD will be obtained together with its 95% confidence interval. 
Incidence of events after 4 MD treatment weeks (major bleeding events, minor or clinically relevant 
bleeding events, major adverse cardiovascular events) will be summarized with their corresponding 95% 
confidence interval, including median times to events as per Kaplan-Meier estimates. 
Percentage of all cause deaths and adverse events after 4 MD treatment weeks will be summarized with their 
corresponding 95% confidence interval. 
 
PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor treatment after 
ACS underwent PCI, based on investigator's discretion]) 
Primary variable: 
Incidence of major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) major) after 28 MD treatment period (optionally maximum 12-month P2Y12 
inhibitor treatment period after ACS underwent PCI) will be summarized with their corresponding 95% 
confidence interval, including median times to events as per Kaplan-Meier estimates. 
 
Secondary variables: 
Incidence of events (minor or clinically relevant bleeding events, major adverse cardiovascular events) after 
28 MD treatment weeks up to maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI, 
based on investigator's discretion, will be summarized with their corresponding 95% confidence interval, 
including median times to events as per Kaplan-Meier estimates.  
Percentage of all cause deaths and adverse events after 28 MD treatment weeks (optionally up to a maximum 
12 months of P2Y12 inhibitor treatment after ACS underwent PCI, based on investigator's discretion) will be 
summarized with their corresponding 95% confidence interval. 
 
EXPLORATORY VARIABLES 
Association of primary and secondary variables with CYP2C19 genotype will be evaluated. Similar analysis 
to the described above may be obtained per genotype subgroups when appropriate for the size of the 
subgroup. 
Sample size Justification: A total of 200 subjects will be enrolled to have 170 completed subjects in the 
study (expected drop-out rate of 15%). 
The proposed total sample size of 170 completed subjects will allow to estimate a mean PRU value with a 
precision of around 10% and a confidence level of 95%, considering a standard deviation of 70 (Han-Young 
Jin, 2014).  


 
 
 
 
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The probability that 1 or more adverse reactions (or other events) will occur in a sample of 170 subjects with 
an anticipated incidence rate of 0.01 is 0.82%. So this sample achieves a power of 82% to find adverse 
events with incidences close to 0.01. 
This sample size will also permit enough power to detect a statistically significant reduction of the P2Y12 (≠ 
0), considering an effect size around 0.40 (μ=30, SD=70) (Han-Young Jin, 2014), using a significance level 
of 0.05 and a two-sided one-sample t-test. 
Interim analysis: No interim analysis is planned; however, the Period 1 analyses (both primary and 
secondary) will be analyzed separately per protocol. 
Study schedule and 
anticipated date of 
completion 
May-Jul 2018: EC/IRB/Health Authorities submission 
Nov 2018 - Aug 2020: Recruitment and treatment period 
Sep-Oct 2020: Database lock 
Jan-Feb 2021: Clinical Study Report 
 
 


 
 
 
 
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3.0 
Table of contents 
 
 
 
Page 
1.0 
TITLE PAGE ............................................................................................................................ 1 
2.0 
SUMMARY ............................................................................................................................. 17 
3.0 
TABLE OF CONTENTS ........................................................................................................ 22 
4.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 28 
5.0 
INTRODUCTION ................................................................................................................... 30 
5.1. 
Background .................................................................................................................... 30 
5.2. 
Study Rationale .............................................................................................................. 31 
6.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................... 32 
6.1. 
Objectives ...................................................................................................................... 32 
6.1.1 
PERIOD 1 (4 weeks) ...................................................................................... 32 
6.1.1.1 
Primary Objective ................................................................................ 32 
6.1.1.2 
Secondary Objective(s) ........................................................................ 32 
6.1.2 
PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 
inhibitor treatment after ACS underwent PCI, based on investigator's 
discretion]) ..................................................................................................... 32 
6.1.2.1 
Primary Objective ................................................................................ 32 
6.1.2.2 
Secondary Objective(s) ........................................................................ 32 
6.1.3 
Exploratory .................................................................................................... 32 
6.2. 
Endpoints ....................................................................................................................... 33 
6.2.1 
PERIOD 1 (4 weeks) ...................................................................................... 33 
6.2.1.1 
Primary Endpoint ................................................................................. 33 
6.2.1.2 
Secondary Endpoint(s) ......................................................................... 33 
6.2.2 
PERIOD 2 (+ 24 weeks [optionally up to a maximum 12 months of P2Y12 
inhibitor treatment after ACS underwent PCI, based on investigator's 
discretion]) ..................................................................................................... 33 
6.2.2.1 
Primary Endpoint ................................................................................. 33 
6.2.2.2 
Secondary Endpoint(s) ......................................................................... 33 
6.2.3 
Exploratory Endpoint(s) ................................................................................. 34 


 
 
 
 
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7.0 
INVESTIGATIONAL PLAN .................................................................................................. 35 
7.1. 
Overall Study Design and Plan: Description .................................................................... 35 
7.2. 
Discussion of Study Design, including the Choice of Control Groups .............................. 36 
8.0 
SELECTION OF STUDY POPULATION ............................................................................. 38 
8.1. 
Inclusion Criteria ............................................................................................................ 38 
8.2. 
Exclusion Criteria ........................................................................................................... 39 
8.3. 
Prior and Concomitant Therapy ...................................................................................... 40 
8.4. 
Efficacy and Safety Assessments / Variables ................................................................... 40 
8.4.1 
Description of study procedures ...................................................................... 41 
8.4.1.1 
Informed Consent ................................................................................ 41 
8.4.1.2 
Demographics...................................................................................... 41 
8.4.1.3 
Medical history and previous medication.............................................. 41 
8.4.1.4 
Physical examination ........................................................................... 41 
8.4.1.5 
Vital signs ........................................................................................... 41 
8.4.1.6 
Pregnancy test ..................................................................................... 41 
8.4.1.7 
Procedure for Clinical Laboratory Samples .......................................... 42 
8.4.1.8 
Electrocardiogram, heart rate, blood pressure ....................................... 43 
8.4.1.9 
Platelet function ................................................................................... 43 
8.4.1.10 Bleeding Events ................................................................................... 43 
8.4.1.11 All cause deaths ................................................................................... 43 
8.4.2 
Study Procedures ............................................................................................ 44 
8.4.3 
Efficacy Variables .......................................................................................... 47 
8.4.3.1 
PERIOD 1 (4 weeks) ........................................................................... 47 
8.4.3.1.1 
Primary Variables ............................................................. 47 
8.4.3.1.2 
Secondary Variables ......................................................... 47 
8.4.3.2 
PERIOD 2 (+24 weeks  [optionally up to a maximum 12 months of P2Y12 
inhibitor treatment after ACS underwent PCI, based on investigator's 
discretion]) .......................................................................................... 48 
8.4.3.2.1 
Primary Variables ............................................................. 48 
8.4.3.2.2 
Secondary Variables ......................................................... 48 
8.4.4 
Exploratory Variables ..................................................................................... 48 
8.5. 
Removal of Subjects from Therapy or Assessment .......................................................... 48 
8.5.1 
Screening failures ........................................................................................... 48 
8.5.2 
Discontinuation or Withdrawal of Individual Subjects ..................................... 49 


 
 
 
 
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8.6. 
Treatments...................................................................................................................... 50 
8.6.1 
Treatments Administered ................................................................................ 50 
8.6.2 
Identity of Investigational Product(s) .............................................................. 50 
8.6.3 
Dosages and Regimen .................................................................................... 51 
8.6.4 
Packaging and Labelling ................................................................................. 51 
8.6.5 
Storage and Disposition of Study Drug ........................................................... 52 
8.6.6 
Method of Assigning Subjects to Treatment Groups ........................................ 52 
8.6.7 
Blinding ......................................................................................................... 52 
8.6.8 
Treatment Adherence ..................................................................................... 52 
8.6.9 
Overdose ........................................................................................................ 52 
8.6.10 
Drug Accountability ....................................................................................... 53 
9.0 
ADVERSE EVENTS (AES) .................................................................................................... 54 
9.1. 
Definitions...................................................................................................................... 54 
9.1.1 
Adverse Event ................................................................................................ 54 
9.1.2 
Additional Points to Consider for AEs ............................................................ 54 
9.1.3 
Serious Adverse Event .................................................................................... 56 
9.1.4 
Unexpected Adverse Event ............................................................................. 57 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................ 57 
9.2. 
Adverse Event Severity................................................................................................... 57 
9.3. 
Relationship to Study Drug ............................................................................................. 57 
9.4. 
Action Concerning Study Medication .............................................................................. 58 
9.5. 
Outcome ......................................................................................................................... 58 
9.6. 
Adverse Event Collection Period..................................................................................... 58 
9.7. 
Adverse Event Reporting ................................................................................................ 59 
9.7.1 
Serious Adverse Events .................................................................................. 59 
9.7.2 
Non Serious Adverse Events ........................................................................... 59 
10.0 
PROTOCOL DEVIATIONS ................................................................................................... 60 
10.1. Protocol Deviations ........................................................................................................ 60 
10.2. Procedure for protocol amendments ................................................................................ 60 
11.0 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ........................ 61 
11.1. Statistical and analytical plans......................................................................................... 61 
11.1.1 
Data Sets Analyzed ........................................................................................ 61 
11.1.2 
Demographic and Other Baseline Characteristics ............................................ 61 
11.1.3 
Efficacy Analyses ........................................................................................... 62 


 
 
 
 
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11.1.3.1 Primary Efficacy Analyses ................................................................... 62 
11.1.3.1.1 PERIOD 1 (4 weeks) ......................................................... 62 
11.1.3.1.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 
months of P2Y12 inhibitor treatment after ACS underwent 
PCI, based on investigator's discretion]) ............................ 62 
11.1.3.2 Secondary Efficacy Analyses ............................................................... 62 
11.1.3.2.1 PERIOD 1 (4 weeks) ......................................................... 62 
11.1.3.2.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 
months of P2Y12 inhibitor treatment after ACS underwent 
PCI, based on investigator's discretion]) ............................ 62 
11.1.4 
Safety Analyses .............................................................................................. 62 
11.1.4.1 Primary Safety Analysis ....................................................................... 62 
11.1.4.1.1 PERIOD 1 (4 weeks) ......................................................... 62 
11.1.4.1.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 
months of P2Y12 inhibitor treatment after ACS underwent 
PCI, based on investigator's discretion]) ............................ 62 
11.1.4.2 Secondary Safety Analysis ................................................................... 63 
11.1.4.2.1 PERIOD 1 (4 weeks) ......................................................... 63 
11.1.4.2.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 
months of P2Y12 inhibitor treatment after ACS underwent 
PCI, based on investigator's discretion]) ............................ 63 
11.1.5 
Exploratory Analyses ..................................................................................... 63 
11.1.6 
Other Analyses ............................................................................................... 63 


 
 
 
 
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11.2. Determination of sample size .......................................................................................... 63 
11.3. Randomization Methods ................................................................................................. 64 
11.4. Interim Analysis ............................................................................................................. 64 
11.5. Handling of dropouts or missing data .............................................................................. 64 
11.6. Multiple Comparisons/ Multiplicity ................................................................................ 64 
11.7. Examination of subgroups............................................................................................... 64 
12.0 
ETHICS ................................................................................................................................... 65 
12.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ...................... 65 
12.2. Ethical Conduct of the Study........................................................................................... 65 
12.3. Subject Information and Consent .................................................................................... 65 
12.4. Confidentiality ................................................................................................................ 67 
12.5. Insurance Policy ............................................................................................................. 67 
13.0 
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION ........................... 68 
13.1. Source Documents .......................................................................................................... 68 
13.2. Case Report Forms ......................................................................................................... 68 
13.3. Monitoring ..................................................................................................................... 69 
14.0 
DATA QUALITY ASSURANCE ............................................................................................ 70 
15.0 
PRACTICAL ISSUES ............................................................................................................. 71 
15.1. Early Termination of the Study ....................................................................................... 71 
15.2. Publication Policy ........................................................................................................... 71 
15.2.1 
Clinical Trial Registration ............................................................................... 72 
15.2.2 
Clinical Trial Results Disclosure ..................................................................... 72 
16.0 
DATA MANAGEMENT PROCEDURES .............................................................................. 73 
16.1. Review and Confirmation of Case Report Forms ............................................................. 73 
16.2. Database production and verification .............................................................................. 73 
16.2.1 
Data Management Plan ................................................................................... 73 
16.2.2 
Database ........................................................................................................ 73 
16.2.3 
Database access .............................................................................................. 73 
16.2.4 
Quality and consistency controls ..................................................................... 73 
16.2.5 
Data queries ................................................................................................... 74 
16.2.6 
Clean File ....................................................................................................... 74 
16.2.7 
Data coding .................................................................................................... 74 


 
 
 
 
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17.0 
REFERENCE LIST ................................................................................................................ 75 
18.0 
APPENDICES ......................................................................................................................... 77 
18.1. Schedule of Assessments ................................................................................................ 77 
 


 
 
 
 
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4.0 
List of abbreviations and definition of terms 
 
Abbreviation 
Description 
ACS 
Acute Coronary Syndrome 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
bid 
Bis in Die (Latin: twice a day) 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Grafting  
CM 
Concomitant Medication 
CRF/eCRF 
Case Report Form / electronic CRF 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CVD 
Cardiovascular Disease 
DHM 
Data Handling Manual 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EoS 
End of Study Visit 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GP 
GlycoProtein 
HTPR 
High on-Treatment Platelet Reactivity 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHD 
Ischemic Heart Disease 
IMP 
Investigational Medicinal Product 
INN 
International Non-proprietary Name 
IRB 
Institutional Review Board 
ISF 
Investigator’s Study File 


 
 
 
 
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Abbreviation 
Description 
ITT 
Intention-to-Treat 
KM 
Kaplan and Meier 
LD 
Loading Dose 
MACE 
Major Adverse Cardiovascular Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MD 
Maintenance Dose 
MI 
Myocardial Infarction 
NHI 
National Health Insurance  
NSTEMI 
Non-ST Elevation Myocardial Infarction 
PCI 
Percutaneous Coronary Intervention 
PI 
Package Insert 
POC 
Point Of Care 
PP 
Per-Protocol 
PRU 
P2Y12 Reaction Unit 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
STEMI 
ST Elevation Myocardial Infarction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
ULN 
Upper Limit of Normality 
WHO 
World Health Organization 


 
 
 
 
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5.0 
Introduction  
5.1. Background 
Cardiovascular diseases (CVD) are the leading cause of death in the Western world(1-3). The global 
number of deaths from CVD has increased during the past decade by 12.5%, with CVD now 
accounting for approximately one third of all deaths globally(2). Ischemic heart disease (IHD) is 
the leading component of the global CVD burden, followed by stroke and heart failure.  
Platelets are an essential component of blood coagulation and are responsible for maintaining 
primary hemostasis under conditions of blood flow. When an arterial blood vessel is injured, 
platelets adhere to and aggregate at the vessel wall to initiate primary hemostasis as well as 
promoting secondary hemostasis to stop bleeding(4). In dysfunctional blood vessels (due to plaque 
formation, inflammation, or lipid deposition), however, platelets become activated and platelet 
aggregation may cause excessive thrombus formation and vascular occlusion, resulting in 
myocardial infarction (MI) or stroke.  
Percutaneous coronary intervention (PCI), usually with stenting, has become the standard 
treatment for acute coronary syndromes (ACS). During this procedure, trauma commonly occurs 
to the arterial endothelium that, among other effects, causes the activation and aggregation of 
platelets. Because platelet aggregation may lead to coronary thrombosis in a patient already 
vulnerable to it, antiplatelet agents are essential adjunctive therapies in patients with ACS 
undergoing PCI(5-7). Even though stent thrombosis is a rare event, it is a severe or fatal 
complication and is associated with high mortality rates(8).The goal of antiplatelet therapy is to 
provide maximal protection against thrombosis without increasing the risk of bleeding. Aspirin, 
thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors are the mainstays of antiplatelet therapy 
in patients undergoing PCI. Dual antiplatelet therapy consisting of aspirin and a P2Y12 inhibitor 
(clopidogrel, prasugrel, or ticagrelor) is state-of-the-art therapy in ACS patients undergoing PCI 
for prevention of ischemic adverse events(9, 10). However, a significant proportion of patients do 
not respond adequately to uniform antiplatelet treatment. These ‘non-responders’ have an 
increased risk for stent thrombosis, stroke, and other ischemic complications. 
There are several methods for platelet function testing (PFT), which differ with regard to the 
underlying detection principle, agonists, and sample material used for testing(4). The VerifyNow® 
system (Accumetrics, Inc., San Diego, CA, USA) is one of the most user-friendly point-of-care 
(POC) platelet function test systems because it produces rapid results at the patient bed-site. It 
consists of an instrument and disposable single-use cartridges that contains the biochemical 
reagents, agonists and fibrinogen coated beads required to perform the specific assay(11). After the 
citrated tube is inserted into the cartridge, whole blood is mixed with the platelet agonists and the 
fibrinogen-coated beads by the movement of an electromagnetic driven steel ball. When the 
antiplatelet drug does not appropriately exhibit its inhibitory effect, the platelets become activated 
by the specific agonist. As a result, the activated platelets bind to fibrinogen-coated beads, cause 
agglutination and fall out of the solution. The VerifyNow instrument measures the light 
absorbance through the sample 16 times per second. Both the rate and extent of platelet-induced 
agglutination over a fixed period of time are measured and a proprietary algorithm is used to 
report the values in reaction units. The VerifyNow platform has currently three types of single-


 
 
 
 
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use, disposable cartridges that can be used to monitor different antiplatelet drugs: aspirin, 
clopidogrel and glycoprotein (GP) IIb/IIIa therapy. 
 
5.2. Study Rationale 
Prasugrel, a third-generation thienopyridine, has demonstrated a rapid and more predictable 
antiplatelet effect, partially overcoming the problems of poor response and delayed onset of action 
of Clopidogrel(12-14). Prasugrel represents a treatment of choice for patients undergoing 
percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS)(15, 16) (Class 1 
recommendation), especially in the context of STEMI, where early administration of potent 
antiplatelet agents, together with mechanical reperfusion therapies, have dramatically improved 
the outcome(17-19). However, in the daily activity, clinicians face the decision of switching from 
clopidogrel to prasugrel at high risk of clinical events. Recent studies(19, 20) indicate that switching 
from clopidogrel to prasugrel in patients undergoing non-emergent coronary stent implantation 
seems to be tolerated with no overt signs of increased bleeding. 
Therefore, the current study is designed to assess the efficacy of prasugrel on platelet function 4 
weeks after switching from clopidogrel MD to prasugrel MD. In order to better assess the mid-
term safety, the study will include a second period until 28-week MD to assess bleeding events, 
major adverse cardiovascular events (MACE), and all cause deaths. Based on investigator's 
discretion, the study will offer this second period until maximum 12-month P2Y12 inhibitor 
treatment after ACS underwent PCI to assess bleeding events, major adverse cardiovascular 
events (MACE), and all cause deaths. 
 
 


 
 
 
 
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6.0 
Study Objectives and Endpoints 
6.1. Objectives 
6.1.1 
PERIOD 1 (4 weeks) 
6.1.1.1 
Primary Objective 
To assess the antiplatelet effect of prasugrel on P2Y12 reaction unit (PRU) value assessed with 
VerifyNow® from baseline to the end of the 4-week MD treatment period, after switching from 
clopidogrel MD to prasugrel MD. 
 
6.1.1.2 
Secondary Objective(s) 
To assess the antiplatelet effect and safety of prasugrel from baseline to the end of the 4-week 
MD treatment period, after switching from clopidogrel MD to prasugrel MD. The antiplatelet 
effect assessments will include percentage of High on-Treatment Platelet Reactivity (HTPR) and 
percentage of platelet inhibition. The safety assessments will include major, minor and clinically 
relevant bleeding events, major adverse cardiovascular events (MACE), all cause deaths and 
adverse events. 
 
6.1.2 
PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
6.1.2.1 
Primary Objective 
To assess the safety of prasugrel on major bleeding events from baseline to the end of the 28-
week MD treatment period (optional maximum 12-month P2Y12 inhibitor treatment period after 
ACS underwent PCI), after switching from clopidogrel MD to prasugrel MD. 
 
6.1.2.2 
Secondary Objective(s) 
To assess the safety of prasugrel from baseline to the end of the 28-week MD treatment period 
(optional maximum 12-month P2Y12 inhibitor treatment period after ACS underwent PCI), after 
switching from clopidogrel MD to prasugrel MD. The safety assessments will include minor and 
clinically relevant bleeding events, major adverse cardiovascular events (MACE), all cause deaths 
and adverse events. 
 
6.1.3 
Exploratory 
Exploratory objectives will include the association CYP2C19 genotyping for subjects (targeted 
100 subjects) who have signed the pharmacogenomic informed consent form separately. 
 


 
 
 
 
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6.2. Endpoints 
6.2.1 
PERIOD 1 (4 weeks) 
6.2.1.1 
Primary Endpoint 
The primary endpoint will be the mean change in the P2Y12 reaction unit (PRU) value assessed 
with VerifyNow® from baseline to the end of the 4-week MD treatment period, after switching 
from clopidogrel MD to prasugrel MD.  
 
6.2.1.2 
Secondary Endpoint(s) 
Efficacy (antiplatelet effect): 
 
Percentage of High on-Treatment Platelet Reactivity (HTPR) defined as PRU > 235. 
 
Percentage of platelet inhibition at the end of the 4-week MD treatment period, after 
switching from clopidogrel MD to prasugrel MD. 
Safety: Incidence of: 
 
Major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) major) after 4 MD treatment weeks. 
 
Minor and clinically relevant bleeding events after 4 MD treatment weeks 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 
4 MD treatment weeks 
 
All cause deaths after 4 MD treatment weeks 
 
Adverse events after 4 MD treatment weeks 
 
6.2.2 
PERIOD 2 (+ 24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
6.2.2.1 
Primary Endpoint 
The primary endpoint will be the incidence of major bleeding events (non-coronary artery bypass 
grafting [CABG] thrombolysis in myocardial infarction (TIMI) major) after 28 MD treatment 
weeks or up to maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI.  
 
6.2.2.2 
Secondary Endpoint(s) 
Safety: Incidence of: 
 
Minor and clinically relevant bleeding events after 28 MD treatment weeks or up to 
maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 
28 MD treatment weeks, or up to maximum 12-month P2Y12 inhibitor treatment after 
ACS underwent PCI 


 
 
 
 
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 
All cause deaths after 28 MD treatment weeks or up to maximum 12-month P2Y12 
inhibitor treatment after ACS underwent PCI) 
 
Adverse events after 28 MD treatment weeks or up to maximum 12-month P2Y12 
inhibitor treatment after ACS underwent PCI) 
 
6.2.3 
Exploratory Endpoint(s) 
The association CYP2C19 genotyping for available subjects (targeted 100 subjects) who have 
signed the pharmacogenomic informed consent form separately. 
 


 
 
 
 
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7.0 
Investigational Plan 
7.1. Overall Study Design and Plan: Description 
This phase 4 study is designed as multicenter, non-comparative, open label, 28-week (optionally 
up to a maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI, based on 
investigator's discretion) switching study in subjects with a previous diagnosis of Acute Coronary 
Syndrome (ACS) who had underwent Percutaneous Coronary Intervention (PCI) and were treated 
with either (a) clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg 
per day for 2-8 weeks following clopidogrel loading dose (LD) of 300 mg or 600 mg at the time 
of PCI; or (b) ticagrelor MD of 90 mg bid and aspirin 81-100 mg per day for 1-4 weeks and 
switching to clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per 
day for 2-4 weeks (either directly or via clopidogrel loading dose [LD] of 300 mg or 600 mg) 
following ticagrelor LD of 180 mg at the time of PCI; or (c) clopidogrel maintenance dose (MD) 
of 75 mg once daily and aspirin 81-100 mg per day for 2-8 weeks following ticagrelor LD of 180 
mg at the time of PCI; or (d) based on investigator’s judgement with at least 2 weeks continues 
use of clopidogrel MD and aspirin 81-100 mg per day before switching to prasugrel and maximum 
8 weeks P2Y12 inhibitors MD treatment (prasugrel is not allowed). 
Eligible subjects will receive open-label prasugrel MD 3.75 mg once daily and aspirin 81-100 mg 
per day. The investigator’s discretion will be followed for deciding on aspirin dosing as far as 
continuing the dual antiplatelet therapy (DAPT) may increase the risk of gastrointestinal bleeding; 
therefore adverse events management related to aspirin doses will be managed as per the 
investigator’s criteria for this and any other criteria based on medical judgement. 
After signing the study informed consent, subjects will enter a flexible screening period based on 
the investigator’s discretion (lasting up to a maximum of 4 weeks). Key inclusion / exclusion 
criteria will be verified to determine subject eligibility at the screening. 
There is Period 1 of 4-week prasugrel MD treatment period, starting on Day 1, followed by a 
Period 2 of +24-week prasugrel MD treatment (optionally up to a maximum 12 months of P2Y12 
inhibitor treatment after ACS underwent PCI), and thereafter a safety follow-up for patients with 
AEs at the last treatment. For early termination, all the assessments of the treatment week 28 visit 
(optionally up to a maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI, 
based on investigator's discretion) should be performed, if possible, including the safety follow-
up for AEs at the last treatment. 
A schematic of the study design is included in Figure 1 and the schedule of assessments is listed 
in Appendix 18.1. 
 


 
 
 
 
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Figure 1. Study figure 
 
 
7.2. Discussion of Study Design, including the Choice of Control Groups 
This trial is designed as a phase 4, multicenter, non-comparative, open label, 28 weeks (optionally 
up to a maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI) switching 
study in subjects with a previous diagnosis of Acute Coronary Syndrome (ACS) who had 
underwent Percutaneous Coronary Intervention (PCI) and were treated with either (a) clopidogrel 
maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 2-8 weeks 
following clopidogrel loading dose (LD) of 300 mg or 600 mg at the time of PCI; or (b) ticagrelor 
MD of 90 mg bid and aspirin 81-100 mg per day for 1-4 weeks and switching to clopidogrel 
maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 2-4 weeks (either 
directly or via clopidogrel loading dose [LD] of 300 mg or 600 mg) following ticagrelor LD of 
180 mg at the time of PCI; or (c) clopidogrel maintenance dose (MD) of 75 mg once daily and 
aspirin 81-100 mg per day for 2-8 weeks following ticagrelor LD of 180 mg at the time of PCI; 
or (d) based on investigator’s judgement with at least 2 weeks continues use of clopidogrel MD 
and aspirin 81-100 mg per day before switching to prasugrel and maximum 8 weeks P2Y12 
inhibitors MD treatment (prasugrel is not allowed). 
The prasugrel MD dose for this study (3.75 mg once daily) has been selected based on the package 
insert DSTW 201803-03, Daiichi Sankyo Taiwan Ltd. The investigator’s discretion will be 
followed for deciding on aspirin dosing as far as continuing the dual antiplatelet therapy (DAPT) 
may increase the risk of gastrointestinal bleeding; therefore adverse events management related 
to aspirin doses will be managed as per the investigator’s criteria for this and any other criteria 
based on medical judgement. 
The P2Y12 reaction unit (PRU) assessed with VerifyNow® has been selected for the evaluation 
of the study primary endpoint because this is one of the most user-friendly point-of-care (POC) 
platelet function test systems because it produces rapid results at the patient bed-site(11), and the 
VerifyNow platform consists on a validated tool which has currently three types of single-use, 


 
 
 
 
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disposable cartridges that can be used to monitor different antiplatelet drugs: aspirin, clopidogrel 
and glycoprotein (GP) IIb/IIIa therapy. The PRU will be assessed immediately before dosing as 
that will assess the steady state which is the most appropriate approach for a maintenance dose. 
For clopidogrel assessment, Day 1 (before prasugrel switch dosing) is selected as being the last 
day of clopidogrel 75 MD after 4 weeks screening (suggested test timing for clopidogrel 75 mg ≥ 
6 days of maintenance)(21). For prasugrel assessment, Week 4 is selected as being the last day of 
prasugrel 3.75 mg MD after 4 weeks treatment Period 1 (suggested test timing for prasugrel 5 mg 
≥ 5 days on maintenance)(21). 
The study has been designed with 2 periods: the first one to assess the platelet function after 4 
weeks, and a longer period up to 28 weeks for a mid-term safety assessment of bleeding events, 
major adverse cardiovascular events (MACE), and all cause deaths. Based on the investigator's 
discretion, patients will be offered to extend Period 2 up to maximum 12 months of P2Y12 
inhibitor treatment after ACS underwent PCI for an additional safety assessment of the same 
objectives. 
The study sample size is based on the expected PRU change from baseline after 4 weeks of 
treatment based on a previously published reference(22). We consider the antiplatelet effect of 
prasugrel in PRU value assessed with VerifyNow® can be observed within 4 weeks which is a 
valid recall period, assessing other safety endpoints during a longer Period 2 (+24 weeks; or 
optionally up to a maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI 
based on investigator's discretion). The selected sample size will be also enough for an 82% 
probability that 1 or more adverse reactions (or other events) will occur with an anticipated 
incidence close to 0.01. 
 
 
 


 
 
 
 
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8.0 
Selection of study Population 
The subject population will comprise male and female subjects of any race, aged at least 20 years 
at screening, with a previous diagnosis of ACS, NSTEMI, STEMI or UA, a weight of at least 50 
Kg at the time of screening, and having underwent PCI and previously treated with either (a) 
clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 2-8 
weeks following clopidogrel loading dose (LD) of 300 mg or 600 mg at the time of PCI; or (b) 
ticagrelor MD of 90 mg bid and aspirin 81-100 mg per day for 1-4 weeks and switching to 
clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 mg per day for 2-4 
weeks (either directly or via clopidogrel loading dose [LD] of 300 mg or 600 mg) following 
ticagrelor LD of 180 mg at the time of PCI; or (c) clopidogrel maintenance dose (MD) of 75 mg 
once daily and aspirin 81-100 mg per day for 2-8 weeks following ticagrelor LD of 180 mg at the 
time of PCI; or (d) based on investigator’s judgement with at least 2 weeks continues use of 
clopidogrel MD and aspirin 81-100 mg per day before switching to prasugrel and maximum 8 
weeks P2Y12 inhibitors MD treatment (prasugrel is not allowed). Prior to any and all study-
specific examinations, subjects will be informed as to the extent and nature of their study 
participation and will be given the opportunity to provide their written informed consent. 
Approximately 10 active study sites in Taiwan will include a total of 200 subjects in order to have 
at least 170 completed subjects.  
Both inclusion and exclusion criteria will be assessed during the screening period (see Section 
8.1 and Section 8.2, respectively). Corresponding information should be provided in the eCRF. 
 
8.1. Inclusion Criteria 
Subjects will be eligible for inclusion into the study only if all of the following criteria are met: 
(1) 
Subject who has provided signed informed consent. 
(2) 
Subject of either sex aged ≥ 20 years old at the informed consent date 
(3) 
Subject’s weight of at least 50 kg at the time of screening 
(4) 
Subject with previous diagnosis of ACS (unstable angina [UA], non-ST elevation 
myocardial infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) 
who has underwent PCI and was treated with either: 
 
clopidogrel maintenance dose (MD) of 75 mg once daily and aspirin 81-100 
mg per day for 2-8 weeks following clopidogrel loading dose (LD) of 300 
mg or 600 mg at the time of PCI 
 
or ticagrelor MD of 90 mg bid and aspirin 81-100 mg per day for 1-4 weeks 
and switching to clopidogrel maintenance dose (MD) of 75 mg once daily 
and aspirin 81-100 mg per day for 2-4 weeks (either directly or via 
clopidogrel loading dose [LD] of 300 mg or 600 mg) following ticagrelor 
LD of 180 mg at the time of PCI 
 
or clopidogrel maintenance dose (MD) 75 mg once daily and aspirin 81-100 
mg per day for 2-8 weeks following ticagrelor LD of 180 mg at the time of 
PCI 


 
 
 
 
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 
or based on investigator’s judgement with at least 2 weeks continues use of 
clopidogrel MD and aspirin 81-100 mg per day before switching to prasugrel 
and maximum 8 weeks P2Y12 inhibitors MD treatment (prasugrel is not 
allowed) 
 
8.2. Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria are met: 
(1) 
Subject with active bleeding or significant increase of risk of hemorrhage such as 
severe hepatic insufficiency, peptic ulcer present, proliferative diabetic retinopathy, 
antecedents of severe systemic bleeding, gastrointestinal bleeding, macrohematuria, 
intraocular hemorrhage, hemorrhagic stroke, or intracranial bleeding), or other 
antecedents of bleeding diathesis or coagulopathy. 
(2) 
Subject with any transient ischemic attack [TIA] within 3 months before the informed 
consent date, or any ischemic stroke within 3 months before the informed consent 
date, or any previous hemorrhagic stroke. 
(3) 
Subject with known allergies or hypersensitivity to prasugrel, aspirin, or any of their 
excipients. 
(4) 
Subject with significant hypertension (systolic blood pressure > 180 mmHg or 
diastolic blood pressure > 110 mmHg) at either the time of screening or baseline 
assessment 
(5) 
Subject with hemoglobin <10.5 g/dL, or hematocrit < 30% at screening 
(6) 
Subject with severe left ventricular systolic dysfunction, EF < 35% within 3 months 
before baseline (visit 2) 
(7) 
Subject is under hemodialysis 
(8) 
Subject with evidence of severe hepatic disease, or any of the following: serum alanine 
transaminase (ALT) or aspartate transaminase (AST) ≥ 3 times the upper limit of 
normal (ULN) laboratory reference range; or bilirubin ≥ 2 times the ULN of laboratory 
reference range at screening. 
(9) 
Subject with any other results of clinical laboratory tests at the time of screening that 
are judged by the investigator that could be detrimental to the Subject or could 
compromise the study 
(10) Female pregnant or of child bearing potential, unless she has a negative serum 
pregnancy test at screening and agrees to use at least one method of contraception 
during the study. 
(11) Subject currently enrolled in, or discontinued within the last 30 days prior to baseline 
from, a clinical study involving an off-label use of an investigational drug or device, 
or concurrently enrolled in a non-observational clinical study or any other type of 
medical research judged not to be scientifically or medically compatible with this 
study. 


 
 
 
 
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(12) Subject who has previously completed or withdrawn from this study. 
(13) Subject with evidence of significant active neuropsychiatric disease, alcohol abuse or 
drug abuse, in the investigator's opinion 
(14) Subject who is unreliable and unwilling to make him/herself available for the duration 
of the study and who will not abide by the research unit policy and procedure and 
study restrictions. 
 
8.3. Prior and Concomitant Therapy 
Any medication or therapy given in addition to the study medication is defined as concomitant 
medication/therapy (CM) and is to be thoroughly documented in the eCRF together with any 
previous medication administered within 4 weeks prior to the date of the informed consent 
signature until end of study. These may be prescribed by a physician or obtained by the subject 
over the counter. Concomitant medication is not provided by Sponsor. 
At each study visit, subjects will be asked whether they have taken any medication other than the 
study medication (used from signing of informed consent through the end of the study), and all 
medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF. 
To the extent possible, the dose of any CM required for chronic diseases should be kept as constant 
as possible throughout the study. Any changes in administration of any CM must be recorded by 
the investigator in the relevant eCRF page. 
Subjects must be instructed to consult first with the investigator prior to take any other medication, 
including over-the-counter products. The investigator contact the medical monitor for questions 
regarding episodic use. 
 
8.4. Efficacy and Safety Assessments / Variables 
The schedule of assessments is described in the Appendix 18.1. 
Subject recruitment for the study is competitive through all sites. Subject data must be entered –
after written informed consent is obtained– into the eCRF system as soon as possible, including 
demographic data. Data/results from screening should be added upon availability. 
Subjects not entered in the eCRF are not considered as enrolled in the study. 
Study visits are categorized according to the following schedule: pre-treatment screening visit 
(V1), treatment Day 1 (V2), treatment week 4 (V3), treatment week 16 (V4), treatment week 28 
(V5), and optionally up to a maximum 12 months of P2Y12 inhibitor treatment after ACS 
underwent PCI (V6) based on investigator's discretion. The activities planned for all study visits 
are described in this section.  
 


 
 
 
 
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8.4.1 
Description of study procedures 
8.4.1.1 
Informed Consent 
Subject Informed Consent should be obtained prior to the subject entering into the study and 
before any study specific assessment and/or procedures are performed (see Section 12.3).  
A unique subject identification number (subject number) will be assigned to each subject at the 
time of screening; this subject number will be used throughout the study. 
 
8.4.1.2 
Demographics 
Demographic information will be collected at screening, including age, gender and race. 
 
8.4.1.3 
Medical history and previous medication 
Medical history, including LD treatment during the PCI (clopidogrel LD 300 mg or 600 mg; or 
ticagrelor LD 180 mg), previous clopidogrel MD 75 mg once daily and/or ticagrelor MD 90 mg 
bid and aspirin 81-100 mg per day and stent type (BMS and/or DES), will be checked and 
recorded during the screening. Medical history to be obtained will include determining whether 
the subject has any significant conditions or diseases that stopped at or prior to Screening (time 
of informed consent). Ongoing conditions are considered concurrent medical conditions. 
All relevant previous medication, including all ongoing medication and medication of the last 4 
weeks before screening, should be recorded in the eCRF too. 
 
8.4.1.4 
Physical examination 
Complete physical examination will be performed at all study visits. Physical examinations will 
consist of the following body systems: (1) general appearance; (2) extremities; (3) skin; (4) head 
and neck; (5) eyes, ears, nose and throat; (6) lungs and chest; (7) heart/ cardiovascular; (8) 
neurological; (9) abdomen / gastrointestinal; (10) liver; (11) musculoskeletal; and (12) other. Each 
system should be assessed as normal or abnormal and in this last case if that is clinically relevant 
or not. 
 
8.4.1.5 
Vital signs 
Vital signs (height [only once at screening], weight, BMI, heart rate and blood pressure) will be 
assessed at all study visits. 
 
8.4.1.6 
Pregnancy test 
Blood pregnancy sampling will be obtained at screening, at visit 5 (week 28), and optionally at 
visit 6 (maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI) or early 
termination.  
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued and returned to the study site. In addition, any 


 
 
 
 
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pregnancies in the partner of a male subject during the study or for 4 weeks after the last dose, 
should also be recorded following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study medication or within 4 weeks of the 
last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form. 
If the female subject, or female partner of a male subject, agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time the subject/female partner of the subject became 
pregnant and provide details of treatment the subject received. 
All pregnancies from subjects on active study drug will be followed up to final outcome, using 
the pregnancy form (“EXPOSURE IN UTERO REPORTING FORM”). The outcome, including 
any premature termination, must be reported to the sponsor. An evaluation after the birth of the 
child will also be conducted. If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (ie, post-partum complications, spontaneous or induced abortion, 
stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
investigator should follow the procedures for reporting SAEs outlined in Section 9.7. 
 
8.4.1.7 
Procedure for Clinical Laboratory Samples 
Blood sampling for local assessment will be obtained at screening (visit 1), Day 1 (visit 2), week 
4 (visit 3), week 16 (visit 4), week 28 (visit 5), optionally based on investigator's discretion at 
maximum 12 months of P2Y12 inhibitor treatment after ACS underwent PCI (visit 6) or early 
termination. All samples will be collected in accordance with acceptable laboratory procedures. 
Details of these procedures and required safety monitoring will be provided by the site and 
archived in the trial master file (TMF). There is no need for fasting conditions for the analyses; 
but the same fasting or fed conditions should remain the same for all the blood samples obtained 
and analyzed at the same site for all their corresponding patients. Blood samples obtained from 
day 1 to week 28 and optionally up to a maximum 12 months of P2Y12 inhibitor treatment after 
ACS underwent PCI will be taken before prasugrel MD + aspirin administration of each 
corresponding visit.  
All laboratory values outside the normal range must be evaluated and assessed by the investigator 
for clinical relevance and in this case, they should be recorded in the eCRF as adverse events.  
The clinical analyses will be performed in a local laboratory (including hematology, biochemistry 
and pregnancy testing). An extra blood sample will be obtained at visit 3 (week 4) once during 
the whole study for the pharmacogenomic central laboratory examination for patients who sign 
the pharmacogenomic informed consent form separately.  
The following parameters will be assessed: 
 
Platelet function: P2Y12 reaction unit (PRU, also to derive the platelet reactivity [HTPR]), 
platelet inhibition (%). (See Section 8.4.1.9) 
 
Hematology: White Blood Cells (WBC), neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, Red Blood Cells (RBC), Hemoglobin, Hematocrit, Platelet Count. 


 
 
 
 
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 
Biochemistry: Total protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen 
(BUN), creatinine, sodium, potassium, chloride, LDL cholesterol. The estimated 
glomerular filtration rate (eGFR) will be calculated following the CKD-EPI Creatinine 
Equation (2009)(23, 24). 
 
8.4.1.8 
Electrocardiogram, heart rate, blood pressure 
A 12-lead ECG will be performed locally at screening (visit 1), treatment week 4 (visit 3), 
treatment week 28 (visit 5), optionally based on investigator's discretion at maximum 12 months 
of P2Y12 inhibitor treatment after ACS underwent PCI (visit 6) or early termination. Additional 
ECGs may be performed at the discretion of the investigator during any follow-up. The findings 
and any abnormality will be recorded in the eCRF as either medical history (findings at screening) 
or adverse events (any further finding or change from screening). Standard ECG parameters will 
be recorded in the eCRF (heart rate, RR, QT, QTc following both Bazzett's and Fridericia's 
methods).  
 
8.4.1.9 
Platelet function 
P2Y12 reaction unit (PRU) with the VerifyNow®, High on-treatment Platelet Reactivity (HTPR), 
and percentage of platelet inhibition will be assessed at Day 1 (pre-dosing) and treatment week 4 
(visit 3). The PRU will be assessed immediately before dosing as that will assess the steady state 
which is the most appropriate approach for a maintenance dose. For clopidogrel assessment, Day 
1 (before prasugrel switch dosing) is selected as being the last day of clopidogrel 75 MD after 
maximum 4 weeks screening (suggested test timing for clopidogrel 75 mg ≥ 6 days of 
maintenance)(21). For prasugrel assessment, Week 4 is selected as being the last day of prasugrel 
3.75 mg MD after 4 weeks treatment Period 1 (suggested test timing for prasugrel 5 mg ≥ 5 days 
on maintenance)(21). 
 
8.4.1.10 
Bleeding Events 
Major, minor and clinically relevant bleeding events will be assessed at all study visits after the 
first prasugrel MD treatment.  
 
8.4.1.11 
All cause deaths 
All cause deaths will be assessed at all study visits after the first prasugrel MD treatment.  
 


 
 
 
 
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8.4.2 
Study Procedures  
Screening assessments (Visit 1, Day -28 to Day -1)  
Subjects will be screened for enrolment within 4 weeks prior to the start of prasugrel MD. Subjects 
will be screened in accordance with predefined entrance criteria as described in Sections 8.1 and 
8.2. See Section 8.5.1 for the procedure for documenting screen failures.  
Procedures to be completed at screening include: 
 
Subject information/Informed consent signed and dated.  
 
Demographics 
 
Assessment of inclusion / exclusion criteria. 
 
Medical history and previous medication 
 
Physical examination 
 
Vital signs (including blood pressure) 
 
Laboratory (hematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram 
 
Determination of subject eligibility 
 
Recording of adverse events 
 
Treatment Day 1 (Visit 2) 
This visit will be performed on the 1st prasugrel MD administration (Day 1). The following 
examinations/procedures will be performed: 
 
Confirmation of inclusion / exclusion criteria. 
 
Confirmation of subject eligibility 
 
Physical examination 
 
Vital signs (including blood pressure) 
 
Laboratory (platelet function) to be done immediately before first dose of prasugrel MD 
+ aspirin administration of Day 1 
 
Laboratory (hematology, biochemistry) 
 
Recording of bleeding events 
 
Recording of major adverse cardiovascular events 
 
Recording of all cause death 
 
Study drug dispensing (prasugrel 3.75 mg) 
 
Recording of adverse events 
 
Recording of concomitant medication 
 


 
 
 
 
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Treatment week 4 (Visit 3, Day 28 ± 14). End of Period 1 
This visit will be performed 4 weeks after the 1st prasugrel MD administration, as the end of the 
Period 1. The following examinations/procedures will be performed: 
 
Physical examination 
 
Vital signs (including blood pressure) 
 
Laboratory (hematology, biochemistry)  
 
Laboratory (platelet function) to be done immediately before the daily dose of prasugrel 
MD + aspirin administration of Visit 3 
 
Blood sample for CYP2C19 genotyping (before prasugrel MD + aspirin administration 
of Visit 3) 
 
Electrocardiogram 
 
Recording of bleeding events 
 
Recording of major adverse cardiovascular events 
 
Recording of all cause death 
 
Study drug dispensing (prasugrel 3.75 mg) 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Treatment week 16 (Visit 4, Day 112 ± 14) 
This visit will be performed 16 weeks after the 1st prasugrel MD administration. The following 
examinations/procedures will be performed: 
 
Physical examination 
 
Vital signs (including blood pressure) 
 
Laboratory (hematology, biochemistry) 
 
Recording of bleeding events 
 
Recording of major adverse cardiovascular events 
 
Recording of all cause death 
 
Study drug dispensing (prasugrel 3.75 mg) 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Treatment week 28 (Visit 5, Day 196 ± 28). End of Period 2 
This visit will be performed 28 weeks after the 1st prasugrel MD administration, as the end of the 
Period 2. The following examinations/procedures will be performed: 
 
Physical examination 


 
 
 
 
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 
Vital signs (including blood pressure) 
 
Laboratory (hematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram 
 
Recording of bleeding events 
 
Recording of major adverse cardiovascular events 
 
Recording of all cause death 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Optional treatment maximum 12 months of P2Y12 inhibitor treatment after ACS underwent 
PCI (Visit 6, Day 365 - 28). End of Period 2 
This visit is optional and will be based on investigator's discretion, and will be performed up to 
maximum overall 12 months of P2Y12 inhibitor treatment after ACS underwent PCI, as the end 
of the Period 2. The following examinations/procedures will be performed: 
 
Physical examination 
 
Vital signs (including blood pressure) 
 
Laboratory (hematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram 
 
Recording of bleeding events 
 
Recording of major adverse cardiovascular events 
 
Recording of all cause death 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Early Termination 
In case of an early termination after 1st prasugrel MD administration and before treatment at visit 
5 (week 28), the same procedures planned for the treatment at visit 5 (week 28) should be 
performed. 
 
 
 


 
 
 
 
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Unscheduled Visit 
Unscheduled visits may be arranged following investigators' discretion for adverse event findings 
identified either at the end of study or during the follow-up period. The examinations/procedures 
may include: 
 
Physical examination 
 
Vital signs 
 
Laboratory (hematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram, heart rate, blood pressure 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Telephone Contacts 
Sites will maintain telephone contacts with subjects during the study as reminders for the study 
logistics, including the safety assessment during follow-up.  
 
8.4.3 
Efficacy Variables 
8.4.3.1 
PERIOD 1 (4 weeks) 
8.4.3.1.1 
Primary Variables 
The primary variable will be the mean change in the P2Y12 reaction unit (PRU) value assessed 
with VerifyNow® from baseline to the end of the 4-week MD treatment period, after switching 
from clopidogrel MD to prasugrel MD. 
 
8.4.3.1.2 
Secondary Variables 
Secondary variables of the period 1 will assess both efficacy and safety: 
Efficacy (antiplatelet effect): 
 
Percentage of High on-Treatment Platelet Reactivity (HTPR) defined as PRU > 235. 
 
Percentage of platelet inhibition at the end of the 4-week MD treatment period, after 
switching from clopidogrel MD to prasugrel MD. 
Safety: 
 
Major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis in 
myocardial infarction (TIMI) major) after 4 MD treatment weeks. 
 
Minor and clinically relevant bleeding events after 4 MD treatment weeks. 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 
4 MD treatment weeks. 


 
 
 
 
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 
All cause deaths after 4 MD treatment weeks. 
 
Adverse events after 4 MD treatment weeks. 
 
8.4.3.2 
PERIOD 2 (+24 weeks  [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
8.4.3.2.1 
Primary Variables 
The primary variable will be the incidence of major bleeding events (non-coronary artery bypass 
grafting [CABG] thrombolysis in myocardial infarction (TIMI) major) after 28 MD treatment 
weeks or up to maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI. 
 
8.4.3.2.2 
Secondary Variables 
Secondary variables of the period 2 will assess just safety in terms of the incidence of: 
 
Minor and clinically relevant bleeding events after 28 MD treatment weeks (optional 
maximum 12-month P2Y12 inhibitor treatment after ACS underwent PCI). 
 
Major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal 
myocardial infarction (MI), non-fatal stroke, stent thrombosis and revascularization after 
28 MD treatment weeks (optional maximum 12-month P2Y12 inhibitor treatment after 
ACS underwent PCI). 
 
All cause deaths after 28 MD treatment weeks (optional maximum 12-month P2Y12 
inhibitor treatment after ACS underwent PCI). 
 
Adverse events after 28 MD treatment weeks (optional maximum 12-month P2Y12 
inhibitor treatment after ACS underwent PCI). 
 
8.4.4 
Exploratory Variables 
The association CYP2C19 genotyping for available subjects (targeted 100 subjects) who have 
signed the pharmacogenomic informed consent form separately will be assessed as exploratory 
analysis. 
 
8.5. Removal of Subjects from Therapy or Assessment 
8.5.1 
Screening failures 
Subjects who signed the informed consent form and performed screening activities (either 
completely or partially) but not having started the 1st prasugrel MD treatment are considered 
screening failures. 
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF 
for screening visit only.  
The primary reason for screen failure should be recorded in the eCRF using the following 
categories: 


 
 
 
 
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 
AE. 
 
Did not meet inclusion criteria or did meet exclusion criteria.  
 
Significant protocol deviation. 
 
Lost to follow-up. 
 
Voluntary withdrawal, <specify reason>. 
 
Study termination. 
 
Other, <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 
 
8.5.2 
Discontinuation or Withdrawal of Individual Subjects 
If a subject having received the 1st prasugrel MD treatment terminates the study prematurely for 
any reason, all attempts should be made by the investigator to perform the procedures for the early 
termination visit (same as for the week 28 visit) and determine the primary reason for the 
termination and where possible the primary underlining reason, providing as much as detail as 
possible, and documenting the information on the eCRF. .  
For subject who terminated before Visit 3, Platelet function tests have to be conducted during the 
early termination visit. 
The primary reason for discontinuation or withdrawal of the subject from the study should be 
noted using the following categories: 
(1) Adverse Event (AE). The subject has experienced an adverse event that requires early 
termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the adverse event or 
pre-treatment adverse event.  
(2) Noncompliance with investigational medicinal product (IMP) prasugrel MD + aspirin. 
Period 1 compliance is defined as 80% compliance in the first 4 weeks with maximum 
2 consecutive missed doses in the last week. 
Period 2 compliance is defined as 80% compliance in the 24 weeks (up to 12 months, 
alternatively) 
(3) Major protocol deviation. The subject failed to meet protocol entry criteria or did not 
adhere to protocol requirements, and continued participation poses an unacceptable risk 
to the subject’s health, or a major protocol deviation occurred at the site.  
(4) Withdrawal of consent. The subject (or subject’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the case report form (eCRF). Subjects may withdraw from the study at any 
time at their own request without giving reasons and without any disadvantageous 
consequences for their subsequent medical care. 
(5) Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 


 
 
 
 
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(6) Other. 
 
In the case of study termination by the sponsor, institutional review board (IRB), independent 
ethics committee (IEC), or regulatory agency, reason for withdrawal should be captured as Other, 
Study Termination. 
If the subject is found to be pregnant during the study, the subject must be withdrawn 
immediately. The reason for withdrawal should be “major protocol deviation” unless there was a 
complication of the pregnancy which led to withdrawal, in which case the reason for withdrawal 
should be “adverse event(s)”. The procedure is described in Section 9.7. 
 
8.6. Treatments  
8.6.1 
Treatments Administered 
Subjects will be treated with prasugrel 3.75 mg once daily along with aspirin 81-100 mg per day 
oral dose during the study period. 
The investigator’s discretion will be followed for deciding on aspirin dosing as far as continuing 
the dual antiplatelet therapy (DAPT) may increase the risk of gastrointestinal bleeding; therefore 
adverse events management related to aspirin doses will be managed as per the investigator’s 
criteria for this and any other criteria based on medical judgement. 
Daiichi Sankyo Taiwan Ltd. will supply the IMP consisting of: 
 
Prasugrel 3.75 mg tablets 
 
8.6.2 
Identity of Investigational Product(s) 
Experimental treatment: 
Product Name: 
 
Prasugrel 
Drug substance:  
Prasugrel hydrochloride 
Pharmaceutical Form: 
Tablets containing prasugrel hydrochloride 3.75 mg 
Administration route: 
Oral use 
Dosage: 
Once daily administration 
Manufacturer: 
Daiichi Sankyo Propharma Co., Ltd. 
 
The IMP will be supplied as two blisters included in one medication box. The supplies will contain 
a surplus of tablets to cover the treatment period and visit windows. The IMP should be stored at 
room temperature (≤ 25ºC). 
Each box of investigational medication will be labelled with pertinent study information and 
country-specific regulatory caution statements in the country-specific language (Chinese). 
 


 
 
 
 
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8.6.3 
Dosages and Regimen 
Each subject who qualifies for the study will receive aspirin 81-100 mg per day and tablets of 
study medication: prasugrel MD 3.75 mg once daily during the study period. Subjects will receive 
2 boxes of medication at Visit 2 (for 4 weeks treatment period ± 2 weeks), 4 boxes of medication  
at Visit 3 (for 12 weeks of treatment ± 2 weeks), 4 boxes of medication at Visit 4 (for 12 weeks 
of treatment ± 4 weeks), and the last 4 boxes of medication at Visit 5 (for up to maximum 12 
months of treatment) for those patients proposed following investigator's discretion to the optional 
extension period.  
Subjects will be instructed to take the tablets once daily oral dose at the same time. The first dose 
is to be taken the day 1 when study medication has been dispensed to the subject. Based the PRU 
assessment should be done immediately before the prasugrel MD + aspirin administration, the 
investigator will give instructions to the subject for the most appropriate timing for the daily 
tablets to be taken on the dates of the visits where the PRU is assessed. 
The investigator’s discretion will be followed for deciding on aspirin dosing as far as continuing 
the dual antiplatelet therapy (DAPT) may increase the risk of gastrointestinal bleeding; therefore 
adverse events management related to aspirin doses will be managed as per the investigator’s 
criteria. 
The investigator or designee must instruct the subject to bring each of their study medication 
containers (boxes) to each clinic visit, regardless of whether the study medication boxes are 
empty. 
 
8.6.4 
Packaging and Labelling 
IMP manufacture will be performed according to Good Manufacturing Practice (GMP) standards 
and according to the currently valid version of the respective national laws applicable at Taipei, 
Taiwan. Identity and stability of the substance for the duration of the study are ensured and 
documented through Certificates of Analyses. 
Products’ labelling will show at least the following information: 
 
Name and address and contact phone of Sponsor and CRO. 
 
Trial reference code. 
 
Pharmaceutical dosage form, route of administration and quantity of dosage units. 
 
The number of the IMP, batch number and expiry date. 
 
The statement “for clinical trial use only”. 
 
The statement “keep out of the reach of children”. 
 
The medication number and the Patient Number. 
 
Storage conditions. 
 
Name, principal investigator. 
If applicable, local or country specific requirements regarding labelling of the medication boxes 
are also to be considered. 


 
 
 
 
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8.6.5 
Storage and Disposition of Study Drug 
At each study site, the investigator is responsible for the correct storage and handling of the IMP. 
The IMP must be stored in a place with access limited to the investigator and/or especially 
authorized personnel of the local study team only, i.e. study nurse or study coordinator. 
The temperature of the storage area must be monitored and documented. The investigator is 
required to inform the responsible monitor immediately in cases of deviation of the storage 
temperature from the required range (room temperature ≤ 25ºC). Furthermore adherence to the 
storage conditions will be checked routinely by the monitor during the on-site visits. 
 
8.6.6 
Method of Assigning Subjects to Treatment Groups 
Not applicable as being a non-randomized study. 
 
8.6.7 
Blinding 
Not applicable as being an open-label study. 
 
8.6.8 
Treatment Adherence 
The IMP will be self-administered by the subjects as once daily oral tablets in the morning. At 
visit 3, 4, 5 and 6 (optional), subjects will return any empty and non-used treatments providing 
information to study personnel regarding their compliance with study medication. Compliance 
will be monitored by study personnel at the site by using the source documents and will be 
recorded in the eCRF. 
Every visit after baseline will be used for dispensing new medication and collecting used 
medication in order to closely promote the treatment adherence.  
 
8.6.9 
Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to the individual subject according 
to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s).  
SAEs associated with overdose should be reported according to the procedure outlined in Section 
9.7.1. 
In the event of drug overdose, the subject should be treated symptomatically. 
 


 
 
 
 
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8.6.10 Drug Accountability 
The investigator or designee must document the receipt, dispensing, and return of IMP supplies 
and materials provided for this study in specific accountability forms included in the investigator’s 
study file (ISF). The scanned copy of drug accountability forms will be retrieved from the study 
site by the responsible monitor, and the investigator will retain the original ones. Documentation 
of drug accountability for individual subjects will be captured in the eCRF. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. Upon receipt of sponsor-
supplied drug, the investigator or designee must verify the contents of the shipments against the 
packing list. The verifier should ensure that the quantity is correct, and the medication is in good 
condition. If quantity and conditions are acceptable, they should acknowledge the receipt of the 
shipment (by signing the packing list and faxing or emailing per instructions provided on the 
form). If there are any discrepancies between the packing list and the actual product received, 
Linical must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed. Proper drug accountability includes, but is not limited to: 
 
Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 
 
Frequently verifying that actual inventory matches documented inventory. 
 
Verifying that the log is completed with the drug lot/patient number used to document 
each dose. 
 
Verifying that all containers used/assigned are documented accurately on the log. 
 
Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
Residual medication (complete blisters and boxes) must be returned to the sponsor, who will be 
responsible for accountability and destruction. If the site is responsible for destruction, the process 
must be done once the accountability is verified by the study monitor. The investigator is not 
permitted to dispense any study medication to persons not taking part in the study. Non-used drug 
will be returned to the center at visits 3, 4, 5, and 6 (optional), and compliance for prasugrel will 
be assessed as: 
 
Compliance (%) =
(Tablets dispensed) −(Tablets lost) − (Tablets returned)
Total number of days between visits
× 100 


 
 
 
 
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9.0 
Adverse Events (AEs) 
9.1. Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is defined as any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom or disease, temporally associated with the use 
of a medicinal product, regardless of its nature, intensity, seriousness, or presumed relationship 
(causality) to the product or experimental procedure used. 
Adverse Events will be collected since the informed consent signature, and all adverse events 
which occur after the first study medication intake and within 14 days after the treatment stop 
date will be considered as treatment emergent adverse events (TEAEs).  
Each TEAE will be evaluated for duration, intensity, and relationship to (or association with) the 
study treatment (or other causes). Additionally, the actions taken (e.g., administration of 
treatment) and the resulting outcome of the adverse event will be indicated on the eCRF. All 
adverse events will be followed up until resolved or as clinically required.  
Only subjects with an ongoing AE at the last study visit will be followed-up for safety reasons 
until the event is resolved or stabilized. 
Any AE, which remains unresolved after completion of the trial, requires detailed 
evaluation and follow-up until the AE has been resolved or a reasonable explanation for its 
persistence is found. 
If a worsening of any pathological condition that the subject had before the start of the study or 
medical problems that are present prior to the start of treatment but worsen during treatment occur, 
these must be considered as a new adverse event and will require a complete evaluation and the 
relevant explanation in the case report form.  
 
9.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions or underlying disease should not be 
considered AEs.) 
 
Necessitate therapeutic intervention. 
 
Require an invasive diagnostic procedure. 
 
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
 
Be considered unfavorable by the investigator for any reason. 
 
AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded as 
an AE. 


 
 
 
 
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Diagnoses vs signs and symptoms: 
 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s). 
Laboratory values and ECG findings: 
 
Changes in laboratory values or ECG parameters are only considered to be AEs if they 
are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory re-test and/or continued monitoring of an abnormal value are 
not considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention. 
 
If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as an AE. 
Pre-existing conditions: 
 
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs 
unless related to study procedures. However, if the subject experiences a worsening or 
complication of such a concurrent condition, the worsening or complication should be 
recorded appropriately as an AE. Investigators should ensure that the event term recorded 
captures the change in the condition (e.g., “worsening of…”). 
 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a AE if the episodes become more frequent, 
serious or severe in nature, that is, investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (e.g., “worsening of…”). 
 
If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of AEs: 
 
If the subject experiences a worsening or complication of an AE after starting 
administration of the study medication, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded captures 
the change in the condition (e.g., “worsening of…”). 
 
If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 


 
 
 
 
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Changes in severity of AEs: 
 
If the subject experiences changes in severity of an AE, the event should be captured once 
with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be captured appropriately as an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 
Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as AEs, but should be documented in the subject’s 
source documents. Complications resulting from an elective surgery should be reported 
as AEs. 
Insufficient clinical response (lack of efficacy): 
 
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of pre-
existing illness and lack of therapeutic efficacy. 
Overdose: 
 
Cases of overdose with any medication without manifested side effects are NOT 
considered AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered AEs and will be recorded on the AE page of 
the eCRF. 
 
9.1.3 
Serious Adverse Event 
Serious adverse events are defined as any untoward medical occurrence that at any dose:  
 
result in subject’s death. 
 
are life-threatening.  
 
result in permanent or significant disability/incapacity.  
 
cause hospital admission or prolong hospital stay.  
 
result in congenital anomalies or birth defects.  
 
medically important condition that may jeopardize the subject or may require intervention 
to prevent any of the outcomes listed above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias, 
or convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse. 
NOTE: The term “life-threatening” in the definition of “serious” refers to any adverse event that 
places the subject, in the view of the investigator, at immediate risk of death from the event as it 


 
 
 
 
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occurred, i.e., it does not include an event that, had it occurred in a more severe form, might have 
caused death.  
An overnight stay in the hospital that is only due to transportation, organization or accommodation 
problems and without medical background does not need to be handled/documented as a SAE. 
Hospitalizations due to surgical procedures for pre-existing conditions that have been planned 
before enrolment of the subject are not considered SAEs. 
 
9.1.4 
Unexpected Adverse Event 
Any adverse event, which is not described in the Reference Safety Information (RSI) of the 
package insert (PI) in nature, severity or frequency is unexpected. Expectedness will be assessed 
in relation to the RSI of the PI. For details, please check the corresponding prasugrel / aspirin 
package inserts. 
 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse reaction 
related to the treatment that is both unexpected and serious. 
 
9.2. Adverse Event Severity 
Severity of adverse events will be classified according to the following criteria:  
 
Mild  
 
Discomfort noted, but no disruption of normal daily activity.  
Moderate  
Discomfort sufficient to reduce or affect normal daily activity.  
Severe 
Inability to work or perform normal daily activity 
 
9.3. Relationship to Study Drug 
The causal relationship of an adverse event with the study medication will be established based 
on the following definitions:  
 
Related 
The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (e.g., disease under study, concurrent 
diseases, concomitant medications).  
The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
Not related 
The AE does not follow a reasonable temporal sequence from study 
drug administration, or can be reasonably explained by the subject’s 
clinical state or other factors (e.g., disease under study, concurrent 
diseases, concomitant medications). 


 
 
 
 
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Any subject who is withdrawn from the study because of an AE will be followed until the outcome 
of the event is determined, and the investigator will prepare a written summary of the event and 
document the available follow-up information on the eCRF.  
 
9.4. Action Concerning Study Medication 
 
Drug withdrawn – a study medication is stopped due to the particular AE. 
 
Dose not changed – the particular AE did not require stopping a study medication. 
 
Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
 
Not Applicable – a study medication was stopped for a reason other than the particular 
AE e.g., the study has been terminated, the subject died, dosing with study medication 
was already stopped before the onset of the AE. 
 
Dose Interrupted – the dose was interrupted due to the particular AE. 
 
9.5. Outcome 
 
Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
 
Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but 
has not returned to the normal range or to baseline; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving”. 
 
Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved”. 
 
Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but 
with some persisting paresis). 
 
Fatal – the AEs which are considered as the cause of death.  
 
Unknown – the course of the AE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
 
9.6. Adverse Event Collection Period 
Adverse events will be collected throughout the whole study period (screening of 4 weeks, 
treatment period 1 of 4 weeks, treatment period 2 of +24 weeks (optionally up to a maximum 12 
months of P2Y12 inhibitor treatment after ACS underwent PCI), and safety follow-up if needed). 
 


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10.0 Protocol Deviations 
10.1. Protocol Deviations 
Generally, a protocol deviation is not imperative for subject withdrawal. Before the statistical 
analysis begins, the protocol deviations must be taken into account for the population analysis. 
The mandatory withdrawal reasons will be considered as major protocol deviations. Other 
protocol deviations will be classified as minor protocol deviations. Additionally, the following 
major protocol deviations will be considered: 
1) Violation of one of the inclusion/exclusion criteria after enrolment into the study. 
2) Treatment incorrectly administered, or overdose. 
Any protocol deviation must be recorded in the eCRF.  
 
10.2. Procedure for protocol amendments 
Any amendment to this protocol involving a substantial change may be made as an amendment 
or addendum in writing. In order to be formalized, it is necessary to obtain the agreement of all 
the responsible people who signed the original protocol. 
Amendments that can result in substantial changes in the original protocol must be submitted and 
approved by the IRB/IEC. 
 


 
 
 
 
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11.0 Statistical Methods and Determination of Sample Size 
11.1. Statistical and analytical plans 
The statistical analysis will be performed by the Department of Biostatistics of Linical, using 
SAS®(25) version 9.4 or later. 
Statistical significance will be assessed for two-sided probability values < 0.05. 
All descriptive variables will be tabulated. Quantitative variables will be described showing their 
number of available and missing observations, mean, median, standard deviation (SD), the range 
(minimum and maximum) and the first and third quartiles. Frequency and percentage will 
describe qualitative variables. Missing values will be tabulated with their frequency but will not 
be included in the calculation of percentages. 
The main population for both the efficacy (antiplatelet effect) and the safety analysis will be the 
safety population (SAF), defined as all the subjects who have received at least one dose of study 
treatment. A Per Protocol (PP) population, defined as all the subjects of the safety population who 
do not perform any major protocol deviation 
Full details of the statistical analysis will be given in a Statistical Analysis Plan (SAP) which will 
be prepared, approved and signed before the database closure, and so before the subjects’ 
evaluability assessment. 
Any deviation from the original SAP will be included and reported in the clinical study report 
(CSR). 
 
11.1.1 Data Sets Analyzed 
The safety population (SAF) will be defined as all subjects who have received at least one dose 
of the study treatment. 
The per protocol population (PP) will be defined as all subjects in the SAF who do not experience 
a major protocol deviation. 
 
11.1.2 Demographic and Other Baseline Characteristics 
Baseline characteristics (gender, age, race, weight, height, body mass index, blood pressure, heart 
rate) for the safety population will be summarized descriptively. 
Categorical data will be summarized with absolute and relative frequencies (percentage), and 
numerical data will be summarized with the number, mean, median, standard deviation (SD), the 
range (minimum and maximum), and the first and third quartiles (if applicable). 
 


 
 
 
 
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11.1.3 Efficacy Analyses 
11.1.3.1 
Primary Efficacy Analyses 
11.1.3.1.1 PERIOD 1 (4 weeks) 
Mean change in the P2Y12 reaction unit (PRU) value assessed with VerifyNow® from baseline 
to the end of the 4-week MD treatment period, after switching from clopidogrel MD to prasugrel 
MD will be analyzed with a paired t-test model. Mean changes will be presented with their 
corresponding 95% confidence interval. 
 
11.1.3.1.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
Period 2 will include just safety analyses. 
 
11.1.3.2 
Secondary Efficacy Analyses 
11.1.3.2.1 PERIOD 1 (4 weeks) 
Percentage of High on-Treatment Platelet Reactivity (HTPR) defined as PRU > 235 will be 
summarized with their corresponding 95% confidence interval. 
Percentage of platelet inhibition at the end of the 4-week MD treatment period, after switching 
from clopidogrel MD to prasugrel MD will be obtained together with its 95% confidence interval. 
  
11.1.3.2.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
Period 2 will include just safety analyses. 
 
11.1.4 Safety Analyses 
11.1.4.1 
Primary Safety Analysis 
11.1.4.1.1 PERIOD 1 (4 weeks) 
Period 1 will include just efficacy analyses (antiplatelet effect) as primary endpoint. 
 
11.1.4.1.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
Incidence of major bleeding events (non-coronary artery bypass grafting [CABG] thrombolysis 
in myocardial infarction (TIMI) major) after 28 MD treatment weeks (optional maximum 12-
month P2Y12 inhibitor treatment after ACS underwent PCI) will be summarized with their 
corresponding 95% confidence interval, including median times to events as per Kaplan-Meier 
estimates. 
 


 
 
 
 
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11.1.4.2 
Secondary Safety Analysis 
11.1.4.2.1 PERIOD 1 (4 weeks) 
Incidence of events after 4 MD treatment weeks (major bleeding events, minor or clinically 
relevant bleeding events, major adverse cardiovascular events) will be summarized with their 
corresponding 95% confidence interval, including median times to events as per Kaplan-Meier 
estimates. 
Percentage of all cause deaths and adverse events after 4 MD treatment weeks will be summarized 
with their corresponding 95% confidence interval. 
 
11.1.4.2.2 PERIOD 2 (+24 weeks [optionally up to a maximum 12 months of P2Y12 inhibitor 
treatment after ACS underwent PCI, based on investigator's discretion]) 
Incidence of events after 28 MD treatment (optional maximum 12-month P2Y12 inhibitor 
treatment period after ACS underwent PCI) (minor or clinically relevant bleeding events, major 
adverse cardiovascular events, stent thrombosis and revascularization) will be summarized with 
their corresponding 95% confidence interval, including median times to events as per Kaplan-
Meier estimates. 
Percentage of all cause deaths and adverse events after 28 MD treatment (optional maximum 12-
month P2Y12 inhibitor treatment period after ACS underwent PCI) will be summarized with their 
corresponding 95% confidence interval. 
 
11.1.5 Exploratory Analyses 
Association of primary and secondary variables with CYP2C19 genotype will be evaluated. 
Similar analysis to the described above may be obtained per genotype subgroups when 
appropriate for the size of the subgroup. 
 
11.1.6 Other Analyses 
No other analyses are planned. 
 
11.2. Determination of sample size 
A total of 200 patients will be enrolled to have 170 completed patients in the study (expected 
drop-out rate of 15%). 
The proposed total sample size of 170 completed patients will allow to estimate a mean PRU 
value with a precision of around 10% and a confidence level of 95%, considering a standard 
deviation of 70 (Han-Young Jin, 2014).  
The probability that 1 or more adverse reactions (or other events) will occur in a sample of 170 
patients with an anticipated incidence rate of 0.01 is 0.82%. So this sample achieves a power of 
82% to find adverse events with incidences close to 0.01. 


 
 
 
 
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This sample size will also permit enough power to detect a statistically significant reduction of 
the P2Y12 (≠ 0), considering an effect size around 0.40 (μ=30, SD=70)(22), using a significance 
level of 0.05 and a two-sided one-sample t-test. 
 
11.3. Randomization Methods 
Not applicable as being a non-randomized study. 
 
11.4. Interim Analysis 
No interim analysis is planned; however, the Period 1 analyses (both primary and secondary) will 
be analyzed once the last patient has completed the 4-week treatment period. 
 
11.5. Handling of dropouts or missing data 
As a general approach, no missing data imputation is planned for the study; however, it will be 
further concreted in the Statistical Analysis Plan (SAP). 
 
11.6. Multiple Comparisons/ Multiplicity 
No adjustments for multiplicity of assessments will be considered. 
 
11.7. Examination of subgroups 
No specific subgroup of patients analysis is planned; however, it will be further concrerted in the 
Statistical Analysis Plan (SAP). 
 


 
 
 
 
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12.0 Ethics 
12.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
The participating centers have their IRB/IEC (or an IRB/IEC tutoring them) established and 
authorized by the respective authorities, whose composition is available to them and is not shown 
here. 
The Principal Investigator at each site is responsible for obtaining IRB/IEC approval for the final 
protocol, informed consent form and patient information sheet, any advertisements to recruit 
subjects, and documents to be handed out to the subjects at the next available meeting. 
Written approval of these documents must be obtained from the committee before any subject is 
enrolled at a site. 
When in accordance with local regulations IRB/IEC submission and interaction can be also 
covered by the assigned CRO. 
Each investigator will also be responsible for complying with ethical standards for clinical trials 
as per local and European laws and regulations, during the study. 
 
12.2. Ethical Conduct of the Study 
This study will be conducted with the highest respect for the individual participants (i.e., subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki (18th World Medical Assembly, 1964) and its last revision (Fortaleza, October 2013)(26), 
the ICH Harmonized Tripartite Guideline for GCP and local laws and regulations of the country 
where the study is performed (Taiwan). 
 
12.3. Subject Information and Consent 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes 
of conducting the study. The informed consent form and the subject information sheet (if 
applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 


 
 
 
 
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It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to 
the subject. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of 
rendering adequate written informed consent, then the subject’s legally acceptable representative 
may provide such consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, 
scope and possible consequences of the clinical study have been explained in a form 
understandable to them. 
The investigator will provide the subject with an information form on the product and the study 
characteristics that should be read to and/or discussed with the subject in an understandable way. 
In this document, the subjects willing to consent to participate in this study will be informed of 
the nature, extent, design and conduct of the study and their consent will be obtained in writing 
prior to inclusion to the study schedule. Subjects will be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study at any time, for any reason. 
After reading the informed consent document, the subject must give consent in writing. The 
consent must be confirmed at the time of consent by the personally dated signature of the subject 
and the personally dated signature of the person conducting the informed consent discussions. A 
copy of the subject information sheet and the signed consent forms must be given to the subjects. 
The original signed consent will be retained in the investigator’s site file. 
The principal investigator will not undertake any measures specifically required only for the 
clinical study until valid consent has been obtained. 
The investigator will not include in the study any subject without previously obtaining written 
consent from the subject. 
 


 
 
 
 
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12.4. Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
 
12.5. Insurance Policy 
Daiichi Sankyo Co. Ltd. will obtain liability insurance, in accordance with the national 
requirements established in the laws of Taiwan, which covers health impairments resulting from 
medications and/or substances/investigational products administered in the course of this study 
for which the subject has given his/her written informed consent to participate. 
 
 


 
 
 
 
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13.0 Source Documents and Case Report Form Completion 
13.1. Source Documents 
According to the guidelines on Good Clinical Practice, the Monitors Team must check the 
electronic case report form (eCRF) entries against the source documents, except for the pre-
identified source data directly recorded in the eCRF. 
During the study, the investigator will maintain adequate records for the study, including medical 
records, records detailing the progress of the study for each subject, laboratory reports, eCRFs, 
signed informed consent forms, drug disposition records, AE reports, and information regarding 
subject discontinuation and completion of the study. 
The Informed Consent Form will include a statement by which the subject allows the Sponsor’s 
duly authorized personnel, the IRB/IEC, and the regulatory authorities to have direct access to 
source data which supports the data on the eCRF (e.g., subject’s medical file, appointment books, 
original laboratory records, etc.). These personnel, bound by professional secrecy, will not 
disclose any personal identity or personal medical information. 
The process for source data verification will be documented in the monitoring plan. 
 
13.2. Case Report Forms 
The investigator must keep a written or electronic file for each subject that participates in the 
clinical trial. In that file, the subjects’ demographic and medical data, especially: name, birthday, 
gender, medical history, diseases and concomitant drug, physical examination and clinical signs, 
observed adverse events, etc. should be recorded. It must be possible, in any moment, to identify 
the subject with his/her personal file. The period that the subject participates in the clinical trial 
must be clearly specified. The data collection will be done using the Electronic Data Capture 
(EDC) market leader tool from Medidata® called RAVE®. The RAVE® platform has been 
validated according to the highest industry standards and practices. The InForm® software uses 
a secure web browser to provide access to clinical study data and management of the clinical 
study process. 
All documentation will be transcribed to an electronic CRF (eCRF). Any created documentation, 
especially the files that would be created by the technicians, must be filed. This includes the 
results of laboratory tests, ECGs, etc. These documents must be identified with the subject 
number, date of making and study code, in order to specify clearly the subject to whom this 
document belongs, and to identify the participants. 
The main objective is to get the most complete files of each candidate. 
Any result obtained during the study development will be reported in the subject’s electronic case 
report form, and if it is used, the serious adverse event form must be sent to Daiichi Sankyo 
Taiwan Ltd. 
The investigator will guarantee that all the documents sent to Daiichi Sankyo Taiwan Ltd., 
including the eCRF and other type of documents, do not contain any mention to the name of the 
subject. It is an investigator’s duty to guarantee adequate filing and storage of the study 
documentation after the end of the study as specified in the Guidelines for Good Clinical Practice. 


 
 
 
 
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All the original files must be kept as much as possible following the hospital rules, research 
institutes or local regulation, but for at least 25 years according to the legislation in force. 
 
All the eCRFs must be completed in its entirety. Any correction or amendment will be corrected 
by the investigator and the previous value recorded in the audit trail of the EDC system along 
with the reason and date of the change. 
The eCRF is considered an official document, and it must be available for the Health Authorities. 
Additional information on the data management and quality process is included in Section 13.0 
and Section 15.0. 
 
13.3. Monitoring 
Representatives of Sponsor must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. They will review study records on site and will compare them 
with source documents. They will also discuss the conduct of the study with the Investigator, and 
will verify that the facilities remain compliant with the study requirements. 
 
 


 
 
 
 
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14.0 Data Quality Assurance 
For the purpose of ensuring compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements, the sponsor’s Quality Assurance department (or authorized 
representatives) may conduct on site audits of all aspects of the clinical study either during the 
study or after the study has been completed. The investigator/institution will permit study related 
monitoring, audits, IRB/IEC review and regulatory inspection(s) by providing direct access to 
source documents. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the authorities, he will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the subjects should be respected 
during these inspections. 
The study will be conducted with an electronic case report form with a qualified single data entry 
performed by the investigators with controlled and restricted access. Additional information on 
the data management will be provided in a specific document (Data Handling Manual [DHM]). 
A full data validation plan will be performed and described in this DHM which should be 
approved before the data entry process starts. 
The database quality will be assessed before the database closure; and only when the Statistical 
Analysis Plan (SAP) is approved and the populations are determined, the database will be locked 
and moved to Statistics to perform the statistical analysis and prepare the Clinical Study Report 
(CSR). 
Additional information on the data management process is included in Section 16.0. 
 


 
 
 
 
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15.0 Practical Issues 
15.1. Early Termination of the Study 
The sponsor can prematurely terminate or suspend the study. Study sites will be closed upon study 
completion. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance. 
Reasons for discontinuation of the study may include but are not limited to the following: 
 
The risks and benefits of the study are re assessed. 
 
The incidence of AEs constitutes a potential health hazard. 
 
New scientific data on the investigational medication do not justify a continuation of the 
clinical study. 
 
Serious and/or persistent non adherence to the protocol, GCP, and/or applicable 
regulatory requirements by an investigator/institution occurs. 
 
Subject enrolment is unsatisfactory. 
 
The IRB/IEC or other regulatory authority decides to terminate or suspend approval for 
the investigation or investigator. 
Additionally, the sponsor has the right to terminate the study for any reason at any time. 
If the study is prematurely terminated or suspended for any reason, the investigator has to inform 
the subjects and assure appropriate follow up for the subjects. The sponsor should promptly 
inform the investigators or institutions and the regulatory authorities of the termination or 
suspension and the reasons for the termination or suspension within the timeframes referred to in 
applicable regulations. The IRB/IEC should also be informed promptly and provided the reasons 
for the termination or suspension by the sponsor or by the investigator or institution as specified 
by the applicable regulatory requirements. 
The last visit of the last patient (LPLV) indicates the end of the study and that end of study will 
be communicated to the IRBs/IECs and the regulatory authorities of each participating country. 
Last visit of the last subject at each site/country also indicates the end of the study for that 
site/country. 
 
15.2. Publication Policy 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 


 
 
 
 
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review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
 
15.2.1 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Daiichi Sankyo Taiwan Ltd. will, at a 
minimum register interventional clinical trials it sponsors anywhere in the world on 
ClinicalTrials.gov or other publicly accessible websites before start of study. Daiichi Sankyo 
Taiwan Ltd. contact information, along with investigator’s city, and recruiting status will be 
registered and available for public viewing.  
 
15.2.2  Clinical Trial Results Disclosure 
Daiichi Sankyo Taiwan Ltd. will post the results of clinical trials on ClinicalTrials.gov or other 
publicly accessible websites, as required by Daiichi Sankyo Taiwan Ltd. Policy/Standard, 
applicable laws and/or regulations. 


 
 
 
 
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16.0 Data Management Procedures  
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary. 
 
16.1. Review and Confirmation of Case Report Forms  
Electronic case report forms will be filled directly by the investigators.  
Prior to obtaining the clean file, checks of consistency of inclusion/non-inclusion criteria, clinical 
assessment, visit dates, compliance, concomitant treatment, adverse event, withdrawal 
information and efficacy evaluation (antiplatelet effect) will be performed.  
Data query forms will be generated to the investigator in order to clarify the data inconsistencies 
through the source data verification.  
 
16.2. Database production and verification  
16.2.1 Data Management Plan  
A validation plan is set-up according to the protocol requirements, which describes the validation 
rules to be applied, in addition to the SAE reconciliation process between the clinical database 
and the safety database (Argus). Actions that should be taken in case of data abnormalities are 
detailed. In case of missing values, out of range values, data inconsistencies or values that fail 
logical checks, correction forms (queries) are edited and transmitted to the investigator for 
clarification.  
 
16.2.2 Database  
A database will be created in order to collect all clinical and other data from the clinical trial. The 
data management will take place at the Data Management Department of Linical. 
 
16.2.3 Database access  
Access to the database will be restricted to the investigators, data managers and clinical monitors. 
Any entry in the database will be traceable through its identification and date. Audit trail of data 
changes will be assured.  
 
16.2.4 Quality and consistency controls  
The investigators will enter the clinical data in the electronic case report form.  
Prior to obtaining the clean file, checks of consistency of inclusion/exclusion criteria, clinical 
assessment, visit dates, compliance, concomitant treatment, adverse event, withdrawal 
information and efficacy evaluation (antiplatelet effect) will be performed.  
 


 
 
 
 
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16.2.5 Data queries  
Data query forms will be generated to the investigator in order to clarify the data inconsistencies 
through the source data verification.  
Only then and after all detected errors, inconsistencies or doubts cleared, will the database be 
declared a clean file and protected accordingly. 
 
16.2.6 Clean File 
A clean file will be created and registered, to which further changes will be disallowed. A 
document with the eligibility of subjects will be generated. 
 
16.2.7 Data coding  
Coding will be carried out according to standard dictionaries partly by program and then validated 
and completed by a medical doctor according to the Linical dictionaries. The latest available 
version of the following dictionaries will be used:  
 
Concomitant treatments: WHO DRUG 
 
Adverse Events: MedDRA 
All case report forms and data checking records will be retained as permanent records of the study. 


 
 
 
 
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17.0 Reference List 
 
1. 
GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life 
expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-
2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 
2016;388(10053):1459-544. Epub 2016/10/14. 
2. 
Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, Regional, 
and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. Journal of the 
American College of Cardiology. 2017;70(1):1-25. Epub 2017/05/22. 
3. 
World Health Organization. Global Health Estimates 2015: Deaths by Cause, Age, Sex, by 
Country and by Region, 2000-2015. Genevva: World Health Organization,; 2016. Available 
from: http://www.who.int/healthinfo/global burden disease/estimates/en/index1.html. 
4. 
Lenk E, Spannagl M. Platelet Function Testing-Guided Antiplatelet Therapy. Ejifcc. 
2013;24(3):90-6. Epub 2013/02/01. 
5. 
Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary 
disease. The New England journal of medicine. 1986;315(16):983-9. Epub 1986/10/16. 
6. 
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease 
and the acute coronary syndromes (2). The New England journal of medicine. 
1992;326(5):310-8. Epub 1992/01/30. 
7. 
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease 
and the acute coronary syndromes (1). The New England journal of medicine. 
1992;326(4):242-50. Epub 1992/01/23. 
8. 
Ge J, Yu H, Li J. Acute Coronary Stent Thrombosis in Modern Era: Etiology, Treatment, 
and Prognosis. Cardiology. 2017;137(4):246-55. Epub 2017/05/05. 
9. 
Damman P, van 't Hof AW, Ten Berg JM, Jukema JW, Appelman Y, Liem AH, et al. 2015 
ESC guidelines for the management of acute coronary syndromes in patients presenting 
without persistent ST-segment elevation: comments from the Dutch ACS working group. 
Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and 
the Netherlands Heart Foundation. 2017;25(3):181-5. Epub 2016/12/15. 
10. NHI - National Health Insurance Administration - Ministry of Halth and Welfare. NIH 
chapter 
2: 
Cardiovascular-renal 
drugs. 
2018 
[April 
2018]; 
Available 
from: 
https://www.nhi.gov.tw/english/. 
11. Accumetrics Inc. VerifyNow-PRU Test package insert. San Diego, CA.2007. 
12. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. 
Variability in individual responsiveness to clopidogrel: clinical implications, management, 
and future perspectives. Journal of the American College of Cardiology. 2007;49(14):1505-
16. Epub 2007/04/10. 
13. Armero S, Camoin Jau L, Omar Ait Mokhtar O, Mancini J, Burignat-Bonello C, Tahirou I, 
et al. Intra-individual variability in clopidogrel responsiveness in coronary artery disease 
patients under long term therapy. Platelets. 2010;21(7):503-7. Epub 2010/07/31. 
14. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al. Prasugrel 
achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due 
to more efficient generation of its active metabolite in aspirin-treated patients with coronary 
artery disease. European heart journal. 2008;29(1):21-30. Epub 2007/12/07. 
15. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al. 2014 ESC/EACTS 
Guidelines 
on 
myocardial 
revascularization: 
The 
Task Force 
on 
Myocardial 


 
 
 
 
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Revascularization of the European Society of Cardiology (ESC) and the European 
Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution 
of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). 
European heart journal. 2014;35(37):2541-619. Epub 2014/09/01. 
16. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al. 2014 ESC/EACTS 
guidelines on myocardial revascularization. EuroIntervention : journal of EuroPCR in 
collaboration with the Working Group on Interventional Cardiology of the European Society 
of Cardiology. 2015;10(9):1024-94. Epub 2014/09/05. 
17. De Luca G, Verdoia M, Schaffer A, Suryapranata H, Parodi G, Antoniucci D, et al. Switching 
from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center 
experience. Journal of thrombosis and thrombolysis. 2014;38(3):388-94. Epub 2014/03/25. 
18. Parodi G, De Luca G, Bellandi B, Comito V, Valenti R, Marcucci R, et al. Switching from 
clopidogrel to prasugrel in patients having coronary stent implantation. Journal of thrombosis 
and thrombolysis. 2014;38(3):395-401. Epub 2014/03/25. 
19. Verdoia M, Barbieri L, Suryapranata H, De Luca G. Switching from Clopidogrel to Prasugrel 
in patients undergoing PCI: A meta-analytic overview. Platelets. 2016;27(2):93-104. Epub 
2015/05/15. 
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