E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Myocardial Infarction with ST-segment elevation (STEMI) undergoing thrombolysis |
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E.1.1.1 | Medical condition in easily understood language |
Patients with myocardial infarction undergoing thrombolysis
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000891 |
E.1.2 | Term | Acute myocardial infarction |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that coronary microvascular function as assessed with the TIMI frame counting method is improved after ticagrelor administration compared to clopidogrel administration in eligible STEMI subjects undergoing thrombolysis.
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E.2.2 | Secondary objectives of the trial |
-To demonstrate that coronary microvascular function, as assessed with other angiographic outcomes, is improved after ticagrelor administration compared to clopidogrel administration in eligible STEMI subjects undergoing thrombolysis.
-To demonstrate that ticagrelor is associated with greater myocardial recovery than clopidogrel, as assessed by echocardiographic indexes, in eligible STEMI subjects undergoing thrombolysis.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
In a subgroup of 60 subjects (around 30 subjects per arm), enrolled at 2 of the hospitals, invasive indexes of stenosis severity and microcirculatory function will be measured pre- and post-PCI using a PressureWire (St Jude Medical). These coronary physiological indexes are the following: -Fractional Flow Reserve (FFR); -Coronary Flow Reserve (CFR), and -Index of Microcirculatory Resistance (IMR). More specifically, immediately after the completion of diagnostic coronary angiogram, an intracoronary pressure and temperature sensor-tipped guide wire (PressureWire, St Jude Medical) will be placed at the culprit vessel to measure distal coronary pressure and to derive thermodilution curves. Thermo dilution curves will be obtained (in triplicate) from a hand-held, 3-ml brisk (<0.25 seconds) injection of room temperature saline at baseline and at maximal hyperaemia. Maximal hyperaemia will be achieved by infusion of 140 μg/kg/min of adenosine via a central vein. Mean transit time (Tmn) at baseline and maximal hyperaemia will be derived from thermo dilution curves. Simultaneous recordings of mean aortic pressure (from the guiding catheter) and mean distal coronary pressure (from the distal pressure sensor) will be also obtained at baseline and during maximal hyperaemia. The CFR will be calculated from the ratio of hyperaemic to baseline Tmn. The IMR will be calculated from the ratio of the mean distal coronary pressure at maximal hyperaemia to the inverse of mean hyperaemic Tmn. All measurements will be repeated immediately after performing PCI to the culprit vessel. FFR will be calculated from the ratio of distal to proximal pressures at maximal hyperaemia only before PCI. In case that culprit vessel is totally occluded, all measurements will be performed only after successful reopening PCI is performed. |
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E.3 | Principal inclusion criteria |
1) Provision of informed consent prior to any study specific procedures.
2) Male and female subjects, 18-75 years of age (both inclusive).
3) STEMI eligible for thrombolysis
4) Inability to perform primary PCI, because of transport time in centers carrying out primary PCI lasting more than two hours
5) Ability of transportation in 3-24 hours after thrombolysis in order to perform coronary angiography and PCI. This period may be extended for reasons of extreme importance up to 72 hours at the latest.
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E.4 | Principal exclusion criteria |
1)Inability to give informed consent.
2)Pre-treatment with any P2Y12 inhibitor within the 7-day period prior to randomization.
3)Cardiogenic shock – Killip class 4.
4)Suspicion or evidence of mechanical complication, including mitral valve dysfunction, ventricular septal rupture, and rupture of the left ventricle.
5)Current use of warfarin or other anticoagulant drug.
6)Known multivessel coronary artery disease not suitable for revascularization. 7)Any contraindication to thrombolytic therapy -Central nervous system damage or neoplasms or atrioventricular malformation -Recent major trauma/surgery/head injury (within the preceding 3 weeks) -Gastrointestinal bleeding within the past month -Known bleeding disorder (excluding menses) -Aortic dissection -Non-compressible punctures in the past 24 hours (e.g. liver biopsy, lumbar puncture). 8)Other bleeding diathesis, or considered by Investigator to be at high risk for bleeding.
9)Any kind of stroke in the past year or haemorrhagic stroke ever.
10)Severe uncontrolled hypertension (>180/110 mmHg) prior to randomisation. 11)Prolonged or traumatic cardiopulmonary resuscitation (> 10 minutes) in the last 2 weeks.
12)Known thrombocytopenia defined as platelet count of <100,000/mm3.
13)Known anemia (hemoglobin [Hb] <10 gr/dL).
14)Subjects receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors that cannot be discontinued for the duration of the study.
15)Chronic dialysis or known chronic renal failure (glomerular filtration rate (GFR)<30 ml/min/1.73m2).
16)Known moderate or severe hepatic impairment.
17)Severe uncontrolled chronic obstructive pulmonary disease.
18)Concomitant use of potent Cytochrome P450 3A4 (CYP3A4) inhibitors (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole, grapefruit juice over 1 litre daily), CYP3A substrates with narrow therapeutic indices (cyclosporine, quinidine), or inducers (carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, and rifapentine).
19)Concomitant use of drugs that are metabolized through CYP2C19 (omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol).
20)Increased risk of bradycardic events (e.g. known sick sinus syndrome or third degree AV block or previous documented syncope suspected to be due to bradycardia unless treated with a pacemaker).
21)Any known contraindication to clopidogrel, ASA, or ticagrelor.
22)Current pregnancy, active lactation or parturition (childbirth) within the previous 30 days; women of childbearing potential must have a negative urine pregnancy test, or use a medically accepted method of birth control.
23)Treatment with other investigational agents (including placebo) or devices within 30 days prior to randomization or planned use of investigational agents or devices prior to the completion of study participation.
24)Any non-cardiac condition with life expectancy less than 1 year.
25)Inability to adhere to the follow-up requirements or any other reason or condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated.
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E.5 End points |
E.5.1 | Primary end point(s) |
The difference in Post PCI CTFC between the ticagelor and clopidogrel treatment arms. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1)The rates of TMPG and the difference in the incidence of normal TMPG (3) following PCI between the ticagelor and clopidogrel treatment arms.
2)The rates of Pre and Post PCI TFG and the difference in the incidence normal epicardial flow (TFG 3) following PCI between the ticagelor and clopidogrel treatment arms.
3)The rates of full, partial and failed perfusion as assessed by the APS and the between treatment difference.
4)The rates of TIMI thrombus grades Pre and Post PCI and the difference in the incidence of thrombus grade ‘0’ following PCI between the ticagelor and clopidogrel treatment arms. 5)The mean GLS and RLS within 48 hours and at 30 and 90 days following PCI in the ticagelor and clopidogrel treatment arms, and the between treatment difference.
6)The mean LVEF within 48 hours and at 30 and 90 days following PCI in the ticagelor and clopidogrel treatment arms, and the between treatment difference. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |