Conditions: ST Elevation Myocardial Infarction NSTEMI - Non-ST Segment Elevation MI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
Randomized clinical study evaluating superiority in platelet inhibition after administration of Ticagrelor 180 mg loading dose as an orodispersible formulation versus traditional coated tablets in patients admitted for ST elevation myocardial infarction or very high-risk non-ST elevation myocardial infarction.

Detailed description:
Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for patients with acute ST-segment elevation myocardial infarction (STEMI). Additional antithrombotic therapy prior or during intervention plays an important role in the short- and long-term outcomes after PPCI. Oral antiplatelet therapy including a platelet P2Y12 receptor inhibitors is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes. Prasugrel and Ticagrelor have been shown to be superior to Clopidogrel in patients with STEMI in reduction of ischemic complication without any increase in the bleeding risk and with a significant reduction in the stent thrombosis rate. Nevertheless, in STEMI patients, pharmacodynamic studies showed prasugrel and ticagrelor oral loading dose (LD) provided a suboptimal platelet inhibition in the first hours after LD, and at least 4 hours are required to achieve and effective platelet aggregation inhibition in the majority of patients, in part due to slowed gut motility caused by morphine use. Orodispersible tablet (ODT) is a different tablet formulation that disperses upon contact with the moist mucosal surfaces of the oral cavity and quickly release its components before swallowing; thus local drug dissolution and absorption as well as onset of clinical effect can be obtained conveniently easily and quickly by bypassing gastrointestinal tract. Recently, Ticagrelor 90 mg ODT has become available and bioequivalence studies on healthy volunteers documented its effectiveness with consequent approval by European Medicine Agency of this formulation which is currently available on the market. Thus, the aim of the present study is to evaluate the superiority in platelet inhibition with 180 mg Ticagrelor loading dose (LD) administered as ODTs as compared with standard formulation, among patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. Primary objective consists in evaluating platelet reactivity 1 hour after Ticagrelor loading dose by VerifyNow test.

Arms:
arm 1: STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as orodispersible tablets.

Intervention: administration of Ticagrelor 180 mg loading dose as orodispersible tablets. arm 2: STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as standard coated tablets.

Intervention: administration of Ticagrelor 180 mg loading dose as standard coated pills.

Interventions: intervention 1: Ticagrelor orodispersible tablets intervention 2: Ticagrelor standard tablets
Intervention descriptions: intervention 1: Ticagrelor loading dose (180 mg) given as two orodispersible tablets (each of 90 mg), to be dispersed in saliva. intervention 2: Ticagrelor loading dose (180 mg) given as two standard coated tablets (each of 90 mg) to be swallowed with water.

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
1 
 
 
 
Drug Substance 
ODT 
Study Number 
ESR-17-13174 
Version Number 
4 
Date 
January 7, 2019 
Ticagrelor Administered as Standard Tablet or orodispersiblE foRmulation 
(TASTER) Study 
Sponsor: Guido Parodi, MD, PhD 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
2 
 
 
 
 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ....................................................................................................... 1 
TABLE OF CONTENTS ..................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................... 5 
1. 
INTRODUCTION ............................................................................................... 6 
1.1 
Background .......................................................................................................... 6 
1.2 
Research hypothesis ............................................................................................. 8 
1.3 
Rationale for conducting this study ...................................................................... 8 
1.4 
Benefit/risk and ethical assessment ...................................................................... 9 
2. 
STUDY OUTCOMES ....................................................................................... 10 
2.1 
Primary endpoint ................................................................................................ 10 
2.2 
Secondary endpoints .......................................................................................... 10 
2.3 
Safety endpoint .................................................................................................. 10 
2.4 
Exploratory objectives........................................................................................ 10 
3. 
STUDY PLAN AND PROCEDURES ............................................................... 11 
3.1 
Overall study design and flow chart ................................................................... 11 
3.2 
Rationale for study design, doses and control groups .......................................... 11 
4. 
SUBJECT SELECTION CRITERIA.................................................................. 11 
4.1 
Inclusion criteria ................................................................................................ 12 
4.2 
Exclusion criteria ............................................................................................... 12 
5. 
STUDY CONDUCT .......................................................................................... 13 
5.1 
Restrictions during the study .............................................................................. 13 
5.2 
Subject enrollment <<and randomization>> <<and initiation of 
investigational product>> ................................................................................... 13 
5.2.1 
Procedures for randomization ............................................................................. 13 
5.3 
Procedures for handling subjects incorrectly enrolled<< or randomized>> 
<<or initiated on investigational product>> ....................................................... 14 
5.4 
Blinding and procedures for unblinding the study ............................................... 14 
5.4.1 
Methods for ensuring blinding............................................................................ 14 
5.5 
Treatments ......................................................................................................... 14 
5.5.1 
Identity of investigational product(s) .................................................................. 14 
5.5.2 
Doses and treatment regimens ............................................................................ 14 


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5.5.3 
Additional study drug ......................................................................................... 14 
5.5.4 
Labeling ............................................................................................................. 15 
5.5.5 
Storage ............................................................................................................... 15 
5.6 
Concomitant and post-study treatment(s)............................................................ 15 
5.7 
Treatment compliance ........................................................................................ 15 
5.8 
Discontinuation of investigational product ......................................................... 15 
5.9 
Withdrawal from study....................................................................................... 16 
6. 
COLLECTION OF STUDY VARIABLES ........................................................ 16 
6.1 
Recording of data ............................................................................................... 16 
6.2 
Data collection at enrolment and follow-up ........................................................ 17 
6.2.1 
Enrollment procedures ....................................................................................... 17 
6.2.2 
Follow-up procedures......................................................................................... 17 
6.3 
EFFICACY ........................................................................................................ 17 
6.3.1 
Efficacy variable ................................................................................................ 17 
6.4 
SAFETY ............................................................................................................ 17 
6.4.1 
Definition of adverse events ............................................................................... 18 
6.4.2 
Definitions of serious adverse event ................................................................... 18 
6.4.3 
Recording of adverse events ............................................................................... 19 
7. 
BIOLOGICAL SAMPLING PROCEDURES .................................................... 23 
7.1 
Volume of blood ................................................................................................ 23 
7.2 
Handling, storage and destruction of biological samples ..................................... 23 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples ........................................... 23 
7.3 
Labeling of biohazard samples ........................................................................... 23 
7.4 
Chain of custody of biological samples .............................................................. 24 
7.5 
Withdrawal of informed consent for donated biological samples ........................ 24 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 25 
8.1 
Ethical conduct of the study ............................................................................... 25 
8.2 
Ethics and regulatory review .............................................................................. 25 
8.3 
Informed consent ............................................................................................... 25 
8.4 
Changes to the protocol and informed consent form ........................................... 25 
8.5 
Audits and inspections ....................................................................................... 25 
9. 
STUDY MANAGEMENT ................................................................................. 26 
9.1 
Training of study site personnel .......................................................................... 26 
9.2 
Monitoring of the study ...................................................................................... 26 
9.2.1 
Source data ........................................................................................................ 27 


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Edition Number 4 
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9.3 
Study timetable and end of study ........................................................................ 27 
10. 
DATA MANAGEMENT ................................................................................... 28 
11. 
EVALUATION AND CALCULATION OF VARIABLES ................................ 28 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........... 28 
12.1 
Description of analysis sets ................................................................................ 28 
12.1.1 
Efficacy analysis set ........................................................................................... 28 
12.1.2 
Safety analysis set .............................................................................................. 28 
12.2 
Methods of statistical analyses ........................................................................... 28 
12.2.1 
Interim analyses ................................................................................................. 29 
12.3 
Determination of sample size ............................................................................. 29 
12.4 
Data monitoring committee ................................................................................ 29 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .............................................................................................. 30 
13.1 
Pregnancy .......................................................................................................... 30 
13.2 
Overdose ............................................................................................................ 30 
14. 
LIST OF REFERENCES ................................................................................... 32 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
Abbreviation or 
special term 
Explanation 
PPCI 
Primary Percutaneous Coronary Intervention 
STEMI 
ST elevation myocardial infarction 
LD 
Loading Dose 
ODT 
OroDispersable Tablets 
AE 
Adverse Events 
OAE 
Other Adverse Events 
PRO 
Patient Reported Outcome 
 
 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
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1. 
INTRODUCTION 
1.1 
Background 
Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for 
patients with acute ST-segment elevation myocardial infarction (STEMI). Additional 
antithrombotic therapy prior or during intervention plays an important role in the short- and 
long-term outcomes after PPCI (1,2). Oral antiplatelet therapy including a platelet P2Y12 
receptor inhibitors is a  cornerstone of antithrombotic  treatment in patients with STEMI. 
Prasugrel and Ticagrelor have been shown to be superior to clopidogrel in patients with 
 
STEMI in reduction of ischemic complication without any increase in the bleeding risk and 
 
with a significant reduction in the stent thrombosis rate (3,4). Current guidelines strongly 
 
recommend Prasugrel and Ticagrelor over Clopidogrel in patients with STEMI undergoing 
 
PPCI (1,2); nevertheless Prasugrel administration is contraindicated in patients over 75 years 
 
of age, weighing less than 60 kg, with history of TIA/stroke, and patients pretreated with 
 
clopidogrel. These reasons, together with the need of taking six coated pills to reach 60 mg of 
 
prasugrel loading dose, limit prasugrel use in a considerable portion of patients and make 
 
ticagrelor more employed than prasugrel in routine clinical practice. 
 
In STEMI patients, pharmacodynamic studies showed prasugrel and ticagrelor loading dose 
(LD) provided a suboptimal platelet inhibition in the first hours after LD, and at least 4 hours 
are required to achieve and effective platelet aggregation inhibition in the majority of patients. 
A several hours vulnerable window of suboptimal antithrombotic therapy exists in which 
patients are at high risk of thrombotic events (5,6). Increasing ticagrelor loading dose has been 
shown to be not effective to limit this phenomenon (7, 8). 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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All P2Y12 receptor antagonists routinely used at the present time in STEMI treatment are 
only available in the oral form. In absence of liquid dosage form, tablets or pills can be 
crushed and suspended in a vehicle before administration. Theoretically, Tmax is likely to be 
shortened since gastric disintegration phase does not occur. The administration of clopidogrel 
in crushed form resulted in its faster and greater bioavailability and this fact could have 
widespread clinical implications (9, 10). In a recent pharmacodynamics study in STEMI 
patients, Parodi et al. demonstrated that crushed ticagrelor tablets provided a faster platelet 
inhibition as compared with Ticagrelor integral tablets (11). A pharmacokinetic study 
confermed these findings (12). 
Orodispersible tablet (ODT) is a different tablet formulation that disperse upon contact with 
the moist mucosal surfaces of the oral cavity and quickly release its components before 
swallowing; thus drug dissolution and absorption as well as onset of clinical effect can be 
obtained conveniently easily and quickly (13-16). Recently, Ticagrelor 90 mg ODT has 
become available and bioequivalence studies on healthy volunteers documented its 
effectiveness with consequent approval by European Medicine Agency of this formulation 
which is currently available on the market. 
In patients with difficulties in swallowing (elderly, previous stroke, sedated and intubated 
patients) ODTs represent an easy way of drug administration. While, in the clinical settings 
(ambulance for example) without access to water, ODTs might represent the only way of oral 
drug administration. Finally, ODT administration might represent the most convenient way of 
treating lying supine STEMI patients in the ambulance, emergency room or in the cath lab if 
efficacy data will be provided in real life acute coronary syndrome patients. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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Recently, opioids-antiplatelet interaction has been documented (17, 18, 19); in particular in 
patients with STEMI morphine use is associated with a delayed onset of action of the oral 
antiplatelet agents. Vomit may frequently occur in STEMI patients, especially in those 
receiving morphine. Moreover, gastric absorption may be impaired in patients with acute 
myocardial infarction and/or haemodinamic compromise due to sympathetic nervous 
activation, nausea, hypotension, and cardiogenic shock. It is unknown whether ODTs might 
be an effective route of drug administration in STEMI patients. 
1.2 
Research hypothesis 
Thus, the aim of the present study is to evaluate the superiority in platelet inhibition with 180 
mg Ticagrelor loading dose (LD) administered as ODTs as compared with standard 
formulation, among patients with STEMI or very high-risk NSTEMI undergoing immediate 
PCI. 
 
1.3 
Rationale for conducting this study 
In patients with difficulties in swallowing (elderly, previous stroke, sedated and intubated 
patients) ODTs represent an easy way of drug administration. In a scenario without access to 
water the clinical settings (like in ambulance), ODTs might represent the only way of oral 
drug administration. Finally, ODT administration might represent the most convenient way of 
treating lying supine STEMI patients in the ambulance, emergency room or in the cath lab if 
efficacy data will be provided in real life acute coronary syndrome patients. 
Moreover, the administration of morphine, used to relieve pain and anxiety in patients with 
ongoing myocardial infarction, is associated with a delayed onset of action of the oral 
antiplatelet agents. Furthermore, gastric absorption may be impaired in patients with acute 
myocardial infarction and/or haemodinamic compromise due to sympathetic nervous 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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activation, nausea, hypotension, and cardiogenic shock. It is unknown whether ODTs might 
be an effective route of drug administration in STEMI patients. 
1.4 
Benefit/risk and ethical assessment 
The main risk after antiplatelet drug administration is related to bleeding events. Common 
measure of good clinical practice will be adopted to minimize this risk, including the 
limitation to heparin dose during and after procedure, and discouraging drug cross-over. 
Moreover use of GPI will be not allowed according to the study protocol. Use of transradial 
access for coronary angiography and PCI will be strongly encouraged according to the most 
recent recommendations of the European Society of Cardiology. 
Of note, ODT administration of ticagrelor loading dose would not lead to an overuse of 
ticagrelor, which is already the P2Y12 receptor inhibitor most widely employed at our Centre 
among patients with acute myocardial infarction treated with PCI due to the reasons explained 
in “Background” paragraph. The most evident advantages of ODT loading dose over coated 
pills formulation would derive mainly from easier and quicker administering of the drug by 
the catheter laboratory nurses and by the simpler assumption by the patients, who may find 
this alternative formulation objectively less complex than swallowing two coated pills, 
especially if sedated, elderly, or dysphagic. 
 
 
2. 
STUDY OUTCOMES 
Thus, the aim of the present study is to evaluate the superiority in platelet inhibition with 180 
mg Ticagrelor loading dose (LD) administered as ODTs as compared with standard 
formulation, among patients with STEMI or very high-risk NSTEMI undergoing immediate 
PCI. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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2.1 
Primary endpoint 
- 
Platelet reactivity evaluated by Platelet Reactivity Units (PRU) VerifyNow 1 hour 
after Ticagrelor LD. 
 
2.2 
Secondary Efficacy Endpoints 
- 
The percent of patients with a high residual platelet reactivity (PRU > 208) 1 hour after 
Ticagrelor LD. 
- 
PRU at 2, 4 and 6 hours. 
 
- 
PRU area-under the curve (AUC) between baseline and 6 hours from LD 
 
2.3 
Secondary Safety Endpoints 
Safety objective will be major bleeding events across the two different regimens of Ticagrelor 
administration. 
 
2.4 
Exploratory objectives 
- 
Potential morphine-ticagrelor interaction will be assessed by stratified randomization 
according to morphine use. 
- 
Combined ticagrelor administration-related adverse events defined as in-hospital ≥2 
BARC bleedings, dyspnea, ventricular pauses, allergic reactions, or vomit 
- 
Comparison of time necessary for preparation and administering of either formulation 
 
of ticagrelor loading dose by the catheter laboratory nursing personnel. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
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3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
Ticagrelor Administered as Standard Tablet or 
orodispersiblE foRmulation (TASTER) Study 
 
0 
1 
2 
4 
6 
 
Blood samples: PRU (VerifyNow) 
Primary endpoint: PRU 1 hour after LD 
 
 
 
 
 
3.2 
Rationale for study design, doses and control groups 
See the Background section 
 
4. 
SUBJECT SELECTION CRITERIA 
All patients enrolled in the study will have to strictly respect the following inclusion and 
exclusion criteria. 
STEMI/ very high-risk NSTEMI diagnosis and 
randomization 
(n = 130) 
Morphine use (n=34) 
No-morphine use (n=66) 
TICAGRELOR 180 mg 
Loading dose 
Standard Tablets 
(n = 44) 
TICAGRELOR 180 mg 
Loading dose 
Orodispersable Tablets 
(n = 86) 
Primary PCI 
- Radial or Femoral Approach 
- UFH (No GPI) 
- Ticagrelor LD in the ER or Cath Lab 
- DES 
hours 


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4.1 
Inclusion criteria 
1. 
Patients presenting within 12 hours from the onset of symptoms with STEMI or 
very high-risk NSTEMI referred for immediate (< 2 hours) angiography. Very high- 
risk NSTEMI patients include patients with haemodynamic instability 
or 
cardiogenic shock, heart failure, life-threatening arrhythmias or resuscitated cardiac 
arrest, intermittent ST-segment elevation, or ongoing chest pain. 
2. 
Informed, written consent 
 
3. 
Male or female patients, aged ≥ 18 years old 
 
 
 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. 
Age < 18 years 
 
2. 
Active bleeding; bleeding diathesis; coagulopathy 
 
3. 
History of gastrointestinal or genitourinary bleeding <2 months 
 
4. 
Major surgery in the last 6 weeks 
 
5. 
History of intracranial bleeding or structural abnormalities 
 
6. 
Suspected aortic dissection 
 
7. 
Administration in the week before the index event of clopidogrel, ticlopidine, 
prasugrel, ticagrelor, thrombolytics, bivalirudin, low-molecular weight heparin or 
fondaparinux. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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8. 
Concomitant oral or IV therapy with strong CYP3A inhibitors or strong CYP3A 
inducers, CYP3A with narrow therapeutic window 
9. 
Known relevant hematological deviations: Hb <10 g/dl, Thromb. <100x10^9/l 
 
10. 
Use of warfarin or new oral anticoagulant derivatives within the last 7 days 
 
11. 
Known severe liver disease, severe renal failure 
 
12. 
Allergy or hypersensitivity to ticagrelor or any of the excipients. 
 
13. 
Pregnancy or lactation 
 
 
5. 
STUDY CONDUCT 
 
5.1 
Restrictions during the study 
It is mandatory that the patients enrolled in the present study have not to simultaneously 
participate to other studies. 
5.2 
Subject enrollment <<and randomization>> <<and initiation of 
investigational product>> 
5.2.1 
Procedures for randomization 
Allocation to treatment will be made by means of sealed opaque envelopes containing a 
computer-generated sequence; this will be done immediately after establishing the indication 
for PCI. Patients who meet all of the inclusion criteria and none of the exclusion criteria will 
be randomized in the order that they qualify. Patients will be allocated to each of the two 
treatment groups in equal proportions. Randomization will be stratified according to morphine 
use. We plan to enrol 44 patients with and 86 patients without morphine treatment. The two 
treatment groups will be studied concurrently. Patients will be considered enrolled in the study 
and eligible for the final intention to treat analysis at the time of PCI. 


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Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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5.3 
Procedures for handling subjects incorrectly enrolled<< or 
randomized>> <<or initiated on investigational product>> 
5.4 
Blinding and procedures for unblinding the study 
5.4.1 
Methods for ensuring blinding 
Site investigators performing platelet function tests will be blinded regarding patient 
randomization arm and the blood samples will be fully anonymized. 
 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor 
90 mg standard tablets 
AstraZeneca 
Ticagrelor 
90 mg orodispersable tablets 
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Ticagrelor 180 mg loading dose standard (coated) tablets 
Ticagrelor 180 mg loading dose orodispersable tablets 
5.5.3 
Additional study drug 
1) Aspirin: 500 mg LD followed by 100 mg daily maintenance dose 
 
2) UFH 80-100 U/Kg endovenous bolus during PCI, additional intraprocedural bolus 
depending on ACT values 
3) Morphine: from 0 to 10 mg according to the attending physician preference in the 
ambulance, emergency room or cath lab. Once the patient will be allocated to study arm 
(stratified according to morphine use) opioids will be no more allowed 
4) B-blockers, ACE-Inhibitors or Angiotensin II receptor blockers, Statins, Proton Pump 
Inhibitors and other drugs according to the current guidelines of patients with STEMI 
and NSTEMI 


Clinical Study Protocol: TASTER 
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Study Number: ESR-17-13174 
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5) Glycoprotein IIb/IIIa inhibitors are not allowed. In the case of bail out use of 
glycoprotein IIb/IIIa inhibitors the patient will be excluded by the final primary end- 
point analysis. 
5.5.4 
Labeling 
The label will include the following information: patient’s initials, date of birth, identification 
code of the patient. 
 
5.5.5 
Storage 
Standard storage protocol will be followed for study drugs. 
 
5.6 
Concomitant and post-study treatment(s) 
After the Ticagrelor loading dose administration in orodispersable vs. standard coated tablets 
all patients in both study arms will receive maintenance dose of 90 mg b.i.d. given as standard 
coated tablets. After the 30-days follow-up the patients will continue DAPT regimen (aspirin 
and standard ticagrelor) according to international guidelines. Associated drugs will be 
prescribed following current international guidelines. 
 
5.7 
Treatment compliance 
All interventions during hospitalization are administrated and monitored directly by 
caregivers. After discharge, daily assumption of therapy will be recommended, patients will 
be educated on the potential catastrophic consequences of premature interruption especially of 
antiplatelet drugs. 
 
5.8 
Discontinuation of investigational product 
Study drug should be discontinued in case of: 
 
1. serious uncontrolled bleeding 
 
2. need for emergency surgery 


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3. anaphylaxis to study drug 
 
4. serious drug-related side effects 
 
The reason for discontinuation of the study treatment and the exact duration of the infusion of 
study drug should be reported on the Case Report Forms (CRF). These complications should 
be treated according to local standards and the type of treatment and should also be reported 
on the Adverse Event Form (AEF). 
5.9 
Withdrawal from study 
Patients can be withdrawn from the study at every time from the enrolment if any of the 
following criteria occurs: withdrawal of informed consent, non-compliance, safety issue (i.e. 
unexpected risk related to study procedure), premature interruption of the study, presence of 
any exclusion criteria that was not known at the time of enrolment. 
 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
Source data must be available at the site to document the existence of the study participants. 
Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the participant. Source documents include demographic data, 
visit dates, participation in study and Informed Consent Forms, randomization number, SAEs, 
AEs and concomitant medication, and results of relevant examinations. The investigator 
assures that source documents are appropriately stored and completed. The patient’s file will 
reveal that this patient is a study participant by entering the following details: study name, 
protocol number, date of enrolment, informed consent obtained prior to any study specific 
procedure. Each follow up visit will be reported in the source data and should at least contain 
the information required according the protocol. The investigator assures that medical files 


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and Case Record Forms are accessible for inspection by authorities and monitoring visits. All 
study data must be archived for a minimum of 10 years after study termination or premature 
termination of the clinical trial. All data will be stored at the main site at Sassari University 
Hospital. 
 
6.2 
Data collection at enrolment and follow-up 
6.2.1 
Enrollment procedures 
Enrollment procedures will last for 12 months. 
 
6.2.2 
Follow-up procedures 
After enrollment, follow-up visit is scheduled at 1 month. This visit will include detailed 
anamnesis (comprehensive of questions about eventual bleeding events), 
physical 
examination, electrocardiogram and transthoracic echocardiogram. 
 
6.3 
EFFICACY 
6.3.1 
Efficacy variable 
The platelet reactivity test reports at each time point (as reported on the table at paragraph 9.3) 
will be collected in the patient’s medical records. 
 
6.4 
SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. For what concerns the main safety issues related to 
ticagrelor administration, during the hospital stay and at 30-days follow-up visit detailed 
anamnesis will focus on eventual bleeding events referred by the patients. Routine blood 
samples comprehensive of hemoglobin will be drawn at various time points (as reported on 
the table at paragraph 9.3). In addition, all the patients will receive continuous vital signs 
monitoring and ECG telemetric recording during the first 48h after myocardial infarction; this 


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will allow assessing eventual ventricular pauses. Moreover, 12-leads ECG will be recorded 
also at discharge and at 30-days follow-up visit. 
 
6.4.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
 
6.4.2 
Definitions of serious adverse event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
wash-out, follow-up), that fulfils one or more of the following criteria: 
 
Results in death 
 
 
Is immediately life-threatening 
 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
 
Is a congenital abnormality or birth defect 
 
 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
19 
 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
Serious Adverse event occurrence should be reported to Principal Investigator and to 
AstraZeneca as soon as possible, ideally within 24 hours. 
 
 
Follow-up of unresolved serious adverse events 
SAEs will be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination will be further followed up until recovery or until stabilisation of the disease 
after termination. 
The following variables will be collected for each AE: 
 
 
AE (verbatim) 
 
 
The date and time when the AE started and stopped 
 
Whether the AE is serious or not 
 
Investigator causality rating against the Investigational Product (yes or no) 
 
Action taken with regard to investigational product 
 
AE caused subject’s withdrawal from study (yes or no) 
 
Outcome. 
In addition, the following variables will be collected for SAEs: 
 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE is serious due to 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
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Edition Number 4 
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 
Date of hospitalization 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s) 
 
Causality assessment in relation to Other medication 
 
Causality assessment in relation to Additional Study Drug 
 
Description of AE. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
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Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated, e.g. laboratory values or vital 
signs,   should therefore only be reported as AEs if they fulfill any of the SAE criteria or are 
the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non- 
mandated parameters should be reported as AE(s s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Reporting of serious adverse events 
Investigators and other site personnel must inform the Competent Authorities, via appropriate 
form, of any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of CT-3, and will concurrently forward all such reports to AZ.   A copy of the 
report must be faxed to AstraZeneca at the time the event is reported to the Competent 
Authorities.   It is the responsibility of the investigator to compile all necessary information 
and ensure that the Competent Authorities receive a report according to the reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time, at the following contacts: 
 
fax number: +46 31 776 37 34 / +1 302 886 4114; 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
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e-mail: AEMailboxClinicalTrialTCS@astrazeneca.com (to be used if a secure e-mail is 
available). 
 
* A cover page should accompany the form indicating the following: 
 
 
Investigator Sponsored Study esr) 
 
CT number 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ESR reference number 
* Investigative site must also indicate, either in the SAE report or the cover page, the causality 
 
of events in relation to all study medications. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the Competent Authorities. 
Serious adverse events that do not require expedited reporting to the Competent Authorities 
need to be reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events. This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly. 
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the randomization code/ code break information or unblind those SAEs which require 
expedited reporting. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product. All SAEs will be documented. The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
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Non-serious adverse events and SAEs will be collected from the time consent is given, 
throughout the treatment period and up to and including the 30 day follow-up period. After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 30 
calendar days after the last dose of trial drug and/or until event resolution. All new AEs 
occurring during that period must be recorded (if SAEs, then they must be reported to the 
Competent Authorities and AstraZeneca). All study-related toxicities/ SAEs must be 
followed until resolution, unless in the Investigator’s opinion, the condition is unlikely to 
resolve due to the patient’s underlying disease. 
Non serious adverse event should be communicated to AstraZeneca periodically (quarterly) by 
line-listing. 
 
7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
For each patient participating to the study 25 ml of blood samples will be collected. 
 
7.2 
Handling, storage and destruction of biological samples 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples 
Pharmacodynamic samples will be analyzed shortly after withdrawal and will be destructed 
after use. Due to economic reason, pharmacokinetic samples will be not obtained. 
 
 
7.3 
Labeling of biohazard samples 
Biological samples will be labeled using the identification code of the patient. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
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Edition Number 4 
Date 7 January 2019 
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7.4 
Chain of custody of biological samples 
Biological samples will be strictly shield in a dedicated room and destructed after analysis. 
 
7.5 
Withdrawal of informed consent for donated biological samples 
The patients will be able to retire their consent for the donated biological sample to the study 
in every moment. 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
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8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study adhered to the ethical principles of the Declaration of Helsinki, specifications of the 
International Conference of Harmonisation, and Good Clinical Practice. 
 
8.2 
Ethics and regulatory review 
The ethics of the study protocol will be submitted for approval by an independent ethics 
committee and by local ethics committee. 
 
8.3 
Informed consent 
Patients provided written informed consent before they were randomly assigned to treatment. 
 
8.4 
Changes to the protocol and informed consent form 
Substantial amendments are only implemented after approval of the CEC. 
 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and 
well-being of human subjects may proceed without prior approval of the sponsor and the 
CEC. Such deviations shall be documented and reported to the sponsor and the CEC as soon 
as possible. All non-substantial amendments are communicated to the CEC within the Annual 
Safety Report (ASR). 
8.5 
Audits and inspections 
The study site may be subject to audits and inspections to verify that the rights and well-being 
of the patients are protected, the trial is conducted according to Good Clinical Practices (GCP) 
and ISO14155, and that the protocol is followed. The study documentation and the source 
data/documents should be accessible to auditors/inspectors (also CEC) and questions should 


Clinical Study Protocol: TASTER 
Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
26 
 
 
be answered during inspections. All involved parties must keep the participant data strictly 
confidential. 
 
 
 
 
9. 
STUDY MANAGEMENT 
9.1 
Training of study site personnel 
Principal investigator is responsible for the training of the study site personnel. 
 
9.2 
Monitoring of the study 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. Monitoring will verify that the rights and 
well-being of the patients are protected, the trial is conducted according to Good Clinical 
Practices (GCP) and ISO14155, and that the protocol is followed. The dates of the visits will 
be recorded by the monitor in a log kept at the site. The source data/documents should be 
accessible to monitors and questions should be answered during monitoring. The Local 
Investigator and their relevant personnel should be available during monitoring visit and 
possible audits and sufficient time should be devoted to the process. The progress of the study 
will be monitored by: 
- 
Informed Consent Forms for each study participant; 


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- 
Ensuring completed eCRFs match source documents, and resolution of any discrepancies. 
Direct access to complete source documents must be made available during monitoring 
visits for verification of eCRF data. 
- 
Periodic on-site visits and, if necessary, remote monitoring of data. 
 
 
 
9.2.1 
Source data 
The study participant’s contact information will be securely stored at the clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
 
9.3 
Study timetable and end of study 
 
Study Periods 
Enroll 
ment 
Treatment, Intervention Period 
In-hospital 
Follow 
-up 
Time point 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Time 
0 
Ticagrelor 
LD 
1 h 
2 h 
4 h 
6h 
24 hrs 
48 hrs 
Discharge 
30 
days 
Patient 
Information 
and Informed Consent 
x 
Demographics 
x 
Medical History 
x 
In- /Exclusion Criteria 
x 
Physical Examination 
x 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomisation 
x 
12-leads 
ECG/ 
telemetry 
ECG 
monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transthoracic 
echocardiogram 
x 
x 
x 
x 
Administer 
Study 
Medication 
x 
Variables for primary 
endpoint 
x 
x 


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Variables 
for 
secondary 
efficacy 
endpoints 
x 
x 
x 
x 
x 
Routine 
laboratory 
tests (complete blood 
count 
with 
haemoglobin, 
creatinine, 
cardiac 
troponin) 
x 
x 
x 
x 
x 
Concomitant Therapy, 
Intervention 
x 
x 
Adverse Events 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
10. 
DATA MANAGEMENT 
 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1 
Calculation or derivation of pharmacodynamic variable(s) 
Calculation and/or derivation of pharmacodynamic variables, including PRU AUC will be 
performed off-line during data analysis. 
 
11.1.1 
Population analysis of pharmacokinetic/pharmacodynamic variables 
One-hundred and 30 patients will be used for pharmacodynamic analyses. 
 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1.1 
Efficacy analysis set 
This evaluation is designed on the basis of the superiority principle. 
 
12.1.2 
Safety analysis set 
Not performed. 
 
12.2 
Methods of statistical analyses 
Categorical variables such as demographics and medical history data will be summarized 
using frequencies and proportions and will be compared using the chi-square test or Fisher’s 
exact test, as appropriate. Continuous data will be summarized using mean ± standard 


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deviation or median [25th, 75th percentiles] and will be compared using Student t test or 
nonparametric Wilcoxon rank-sum test. All tests will be two-sided and an alpha level of 0.05 
will be considered statistically significant. All analyses will be performed in a blinded manner 
regarding the randomly assigned treatment and on an intention-to-treat basis. Unblinding of 
the study groups will be done after completion of the statistical analyses regarding the primary 
endpoint. 
 
 
12.2.1 
Interim analyses 
Interim analysis is planned after the enrollment of 50% of the entire study population (n=65 
patients). 
 
12.3 
Determination of sample size 
The study will comprise a sample size of 130 patients. This evaluation is designed on the basis 
of the superiority principle. We hypothesized that OTD Ticagrelor would be superior as 
compared with standard ticagrelor tablets. Based on the result of the MOJITO study (11), and 
considering a) the inclusion of only 44 morphine-treated patients, b) the inclusion of high-risk 
NSTEMI patients, and c) the expected lower PRU standard deviation with Ticagrelor OTD, as 
compared with hand-crushed ticagrelor, we assumed a PRU of 230±90 in the Ticagrelor 
standard tablet group and of 185±90 in the Ticagrelor OTD group. The enrollment of 126 
patients provides 80% power. We planned to enroll 130 patients in order to account for 
potential missing values. 
 
12.4 
Data monitoring committee 
Data monitoring committee will include 3 physicians and will be activated before the 
beginning of study patient enrolment. 


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Pregnancy 
Pregnancy and lactation will be study exclusion criteria. All outcomes of pregnancy will be 
reported to AstraZeneca using contacts listed at Par.6.4.3. 
 
13.2 
Overdose 
An overdose of study medication is defined as intake of more than 360 mg 
ticagrelor/ticagrelor placebo per day. 
 
In the event of an overdose of study medication ascertain the time and extent of the overdose 
regardless of severity. Determine the causative circumstance and whether haemorrhagic or 
toxic complications have occurred or are likely to do so. Depending on these facts it has to be 
decided if the patient should be hospitalised for observation or not. Bleeding is one of the 
most likely pharmacological effects of excessive ticagrelor dosing, and appropriate supportive 
measures such as volume replacement, local haemostatic measures (eg, compression), and 
decompression or drainage may be required depending on the localisation, extent of bleeding 
or volume of blood lost. Patients with overdose-related bleeding should be cautioned to avoid 
unnecessary activity, mechanical tissue stress, and minor trauma for at least 24 hours after the 
bleeding has stopped. The IB documents other symptoms that can be expected after an 
overdose of ticagrelor. 
 
 An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 


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Study Number: ESR-17-13174 
Edition Number 4 
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 An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
 
For overdoses associated with SAE, standard procedure. 


Clinical Study Protocol: TASTER 
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Study Number: ESR-17-13174 
Edition Number 4 
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14. 
LIST OF REFERENCES 
 
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Management of ST-Elevation Myocardial Infarction: Executive Summary A 
Report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines AHA/ACC STEMI guidelines 
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3) Montalescot G, Wiviott SD, Braunwald E, et al; TRITON-TIMI 38 investigators. 
 
Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary 
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Ticagrelor versus clopidogrel in patients with acute coronary sindrome. N Engl J 
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5) Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor 
loading doses in ST-segment elevation myocardial infarction patients: RAPID 
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Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
33 
 
 
6) Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of 
ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment- 
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Drug Substance: ODT 
Study Number: ESR-17-13174 
Edition Number 4 
Date 7 January 2019 
34 
 
 
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