| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PCI-related myocardial infarction (MI type 4) or injury (I) within 48 hours (or at hospital discharge if earlier than 48 hours) of elective PCI/stent |
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| E.1.1.1 | Medical condition in easily understood language |
| PCI-related myocardial infarction (MI type 4) or injury (I) within 48 hours (or at hospital discharge if earlier than 48 hours) of elective PCI/stent |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028596 |
| E.1.2 | Term | 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 |
Primary Efficacy Objective
The purpose of this study is to demonstrate the superiority of the new P2Y12 inhibitor ticagrelor over clopidogrel on PCI-related myocardial infarction (MI type 4) or major myocardial injury (I) within 48 hours (or at hospital discharge if earlier) of elective PCI/stent.
Primary Safety Objective
The primary safety objective is to compare the new P2Y12 inhibitor ticagrelor over clopidogrel on major bleeding events as assessed by the BARC criteria 19 (BARC type 3 or 5) at 48 hours (or discharge if it occurs earlier).
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Primární cíl
- Prokázat superioritu ticagreloru oproti clopidogrelu v kontextu vzniku infarktu myokardu souvisejícího s PCI (typ 4) nebo závažným poškozením myokardu v průběhu 48 hodin (nebo při propuštění, pokud proběhne dříve) od provedení elektivní PCI/implantace stentu.
Primární cíl
- Porovnat bezpečnost ticagreloru a clopidogrelu v kontextu výskytu závažných krvácení dle BARC (typ 3 nebo 5) kritérií po 48 hodinách (nebo při propuštění, pokud proběhne dříve) od provedení elektivní PCI/implantace stentu. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives are to demonstrate :
- the superiority of the new P2Y12 inhibitor ticagrelor over clopidogrel on
- myocardial infarction (MI) both at 48 hours (or at hospital discharge if earlier) and 30 days of elective PCI/stent.
- death (any) or myocardial infarction (MI) both at 48 hours (or at hospital discharge if earlier) and 30 days of elective PCI/stent.
- on death (any), MI/I, urgent revascularization or recurrent ischemia requiring catheterization at 48 hours and 30 days.
- on PCI-related myocardial infarction (MI type 4) or any type of injury (major or minor) within 48 hours (or at hospital discharge if earlier) of elective PCI/stent.
Secondary Safety Objectives are to assess the rates of :
- major bleeding events as assessed by the BARC criteria19 (BARC type 3 or 5) at 30 days follow-up,
- nuisance or minor bleeding (BARC type 1 or 2) at 48h and 30 day,
- any bleeding (BARC 1, 2, 3, 4, 5) at 48h and 30 days,
- stroke at 48h and 30 days. |
- Prokázat superioritu ticagreloru oproti clopidogrelu po 48 hodinách (nebo při propuštění, pokud proběhne dříve) a zároveň po 30 dnech od provedení elektivní PCI/implantace stentu v kontextu:
> vzniku infarktu myokardu
> úmrtí (jakákoliv příčina) a infarktu myokardu
- Prokázat superioritu ticagreloru oproti clopidogrelu v kontextu vzniku infarktu myokardu (typ 4) souvisejícího s PCI nebo jakéhokoliv poškození myokardu v průběhu 48 hodin (nebo při propuštění, pokud proběhne dříve) od provedení elektivní PCI/implantace stentu.
- Určit četnost:
> příhod závažného krvácení dle BARC kritérií (typ 3 nebo 5) po 30 dnech.
> obtíží nebo nezávažných krvácení dle BARC kritérií (typ 1 nebo 2) po 48 hodinách a po 30 dnech.
> jakéhokoliv krvácení (BARC 1, 2, 3, 4, 5) po 48 hodinách a po 30 dnech.
> cévní mozkové příhody po 48 hodinách a po 30 dnech |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female ≥ 18 years of age
- Having at least one high-risk feature (Age > 75, Renal insufficiency (Clearance below 60ml/min calculated with Cockcroft-Gault formula), Diabetes Mellitus, Overweight (BMI >30), History of ACS (in the past 12 months) including UA/NSTEMI and STEMI, LVEF < 40% and/or prior episode of heart failure, Multivessel disease (2 or 3 V), Multiple stents needed defined as i) more than one stent implanted in one vessel or ii) more than 2 stents in 2 or more vessels, or iii) total stent length envisioned > 30mm, Left main stenting, Bifurcation stenting (whatever the technique), ACC/AHA type B2 or C lesion , Stenting of venous or arterial coronary graft).
- Undergoing non-emergent single or multiple sites/vessels PCI during the same procedure).
- Negative troponin (hs-Tn preferably) or decreasing troponin in case of hs-Tn above the ULN and within the grey zone of the laboratory (or <3XULN if the grey zone is not defined) before enrolment according to local measurement, during hospitalization for coronary angiogram or PCI.
-Informed consent obtained in writing at enrolment into the study
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- Muž nebo žena, věk ≥ 18 let
- Splňuje alespoň jeden ukazatel vysokého rizika (Věk > 75; renální nedostatečnost (clearance pod 60 ml/min počítaná Cockcroft-Gaultovým vzorcem); diabetes mellitus; obezita (BMI > 30); historie ACS v posledních 12 měsících vč. UA/NSTEMI a STEMI; LVEF < 40% a/nebo předchozí epizoda srdečního selhání; postižení více tepen (2 nebo 3); potřeba více stentů definovaná jako: i) více než jeden stent implantovaný v jedné tepně, ii) více než 2 stenty ve 2 nebo více tepnách , iii) stent s délkou > 30 mm; stent levé tepny; stent bifurkace; ACC/AHA typu B2 nebo C léze; stent žilního nebo arteriálního koronárního štěpu)
- Podstupuje non-emergentní PCI na jednom či více místech/tepnách během jedné procedury
- Negativní troponin (hs-Tn přednostně) nebo klesající troponin v případě hs-Tn nad horní limit normálních hodnot (ULN) a v rámci šedé zóny laboratoře (nebo <3×ULN, pokud není šedá zóna definována) před zařazením na základě lokálních zvyklostí, během hospitalizace pro koronární angiogram nebo PCI
- Podepsaný informovaný souhlas |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
- Women of child-bearing potential (ie, those who are not chemically or surgically sterilised or who are not post-menopause) who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator OR women who have a positive pregnancy test at randomisation OR women who are breast-feeding
- Thrombolytic therapy within the previous 24 hours
- Undergoing primary PCI for ongoing STEMI
- Undergoing rescue PCI after failed thrombolysis
- Any other elective PCI scheduled within the following 30 days after the index PCI
- History of intracranial haemorrhage at any time.
- Increased bleeding risk: intracranial tumor or aneurysm; recent trauma or major surgery (< 1 month) (including bypass surgery), active gastrointestinal, active bleeding
- Uncontrolled arterial hypertension (defined as a systolic BP ≥ 180 mmHg and/or diastolic BP ≥ 100 mmHg)
- Recent (<48 hours) or planned spinal/epidural anesthesia or puncture
- Impaired haemostasis such as known International Normalized Ratio (INR) >1.5; past or present bleeding disorder (including congenital bleeding disorders such as von Willebrand's disease or hemophilia, acquired bleeding disorders, and unexplained clinically significant bleeding disorders), thrombocytopenia (platelet count <100,000/µL)
- Known severe and moderated hepatic impairment
- Treatment with oral anticoagulant therapy within 72 hours prior to inclusion or current need for oral anticoagulant therapy in the next month.
- Use of abciximab within the previous 7 days or, tirofiban or eptifibatide within the past 12 hours of index PCI
- Prohibited treatments (see section 8.3)
- Inability to give informed consent or high likelihood of being unavailable for follow-up
- Participation in another clinical research protocol with other investigational agents or devices within the previous 30 days, planned use of investigational drugs or devices, or previous enrolment in this trial (routine care authorized)
- Known intolerance to clopidogrel or ticagrelor
- Hypersensitivity to ticagrelor or its excipients
- Hypersensitivity to clopidogrel or its excipients
- Patient on prasugrel or ticagrelor before the procedure |
- Ženy ve fertilním věku bez adekvátní kontracepce, nebo ženy, které měly při randomizaci pozitivní těhotenský test, nebo kojící ženy
- Trombolytická léčba během posledních 24 hodin
- Podstupující primární PCI pro probíhající STEMI
- Podstupující záchranou PCI po selhání trombolýzy
- Indikace k další PCI během následujících 30 dnů po indexové PCI
- Historie intrakraniální hemorhagie
- Zvýšené riziko krvácení: intrakraniální tumor nebo aneurysma; nedávné trauma nebo operace (méně než 1 měsíc) (zahrnující bypass), aktivní gastrointestinální krvácení
- Nekontrolovaná arteriální hypertenze (systolický krevní tlak ≥ 180 mmHg a/nebo diastolický krevní tlak ≥ 100 mmHg)
- Nedávná (<48 hodin) nebo plánovaná spinální/epidurální anestezie nebo punkce
- Porucha hemostázy jako INR >1,5; krvácivé stavy v minulosti nebo aktuálně (vč. kongenitálních krvácivých stavů jako je von Willebrandova choroba, hemofilie, získané krvácivé stavy a nezdůvodněné klinicky významné krvácivé stavy); trombocytopenie (počet destiček <100 000/µl)
- Známé závažné nebo středně závažné poškození jater
- Léčba orálními antikoagulancii během 72 hodin před zařazením do studie, nebo potřeba léčby orálními antikoagulancii během následujícího měsíce
- Užití abciximabu v posledních 7 dnech, nebo užití tirofibanu nebo eptifibatidi v posledních 12 hodinách před indexovým PCI
- Nedovolená léčba (prasugrel, cangrelor, simvastatin, lovastatin a inhibitory a aktivátory CYP3A4 v rameni ticagreloru)
- Nemožnost udělení informovaného souhlasu nebo vysoká pravděpodobnost nemožnosti dalšího sledování
- Účast v jiné klinické studii za použití jiných sledovaných přípravků nebo pomůcek v předchozích 30 dnech, plánované použití výzkumných léčivých přípravků nebo pomůcek, nebo předchozí zařazení do této studie
- Známá intolerance clopidogrelu nebo ticagreloru
- Přecitlivělost na ticagrelor nebo jeho excipienty
- Přecitlivělost na clopidogrel nebo jeho excipienty
- Léčba prasugrelem nebo ticagrelorem předcházející sledovanou událost |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PCI-related myocardial infarction (MI type 4) or major myocardial injury (I) within 48 hours (or at hospital discharge if earlier) of elective PCI/stent. MI-4/I at 48 hours will include the following events (according to the third universal definition of MI)
The primary safety endpoint including the rate of major bleeding events (BARC 3 or 5) will be evaluated from randomization to 48 hours of elective PCI/stent or hospital discharge if earlier.
Bleeding will be defined by the BARC classification (type 1 to 5) although only types 3 and 5 will be considered as major bleeding and types 1 and 2 as minor/nuisance bleedings. We are not expecting any BARC bleeding type 4 by trial design.
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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/ Myocardial infarction (MI) both at 48 hours (hospital discharge if earlier) and 30 days of elective PCI/stent. MI will include the following events (according to the third universal definition of MI)
2/ Death (any) or myocardial infarction (MI) both at 48 hours (hospital discharge if earlier) and 30 days of elective PCI/stent. MI will include the following events (according to the third universal definition of MI18)
3/ Death (any), MI/I, urgent revascularization or recurrent ischemia requiring catheterization at 48 hours and 30 days.
4/ PCI-related myocardial infarction (MI type 4) or any type of injury (I) (major or minor) within 48 hours (or at hospital discharge if earlier) of elective PCI/stent. MI-4/I will include the following events (according to the third universal definition of MI)
The secondary safety endpoints will be evaluated from randomization to 48 hours of elective PCI/stent or hospital discharge if earlier and at 30 days and will includes:
o the rate of major bleeding events (BARC 3 or 5) at 30 days
o Nuisance or minor bleeding (BARC type 1 or 2)
o Any bleeding (BARC 1, 2, 3, 4, 5)
o Any stroke. |
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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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 | Yes |
| 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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Members of the CEC are and will not be aware of the investigator's point of view. The CEC will assess all endpoints according to the definitions stated in the protocol. This will be a blinded evaluation. It is intended that the CEC meets to assess the clinical endpoints; several times during monitoring, after the finalization of the trial to assess the 48 hours followup. Clinical endpoint adjudication will be performed using blinded source data that are
provided by CRAs to the CEC. |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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