Trial document




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  DRKS00005441

Trial Description

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Title

PROSPECTIVE, RANDOMIZED TRIAL OF TICAGRELOR VERSUS PRASUGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

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Trial Acronym

ISAR-REACT 5

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URL of the Trial

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Brief Summary in Lay Language

The hypothesis to be tested is that ticagrelor is superior to prasugrel in patients with acute coronary syndrome (ACS) in terms of clinical outcomes. This will be achieved by means of a randomized, open label trial; a total of 4000 patients will be recruited by several national and international hospitals.

Patients with acute coronary syndrome need in addition to their therapy with aspirin another substance for platelet inhibition. This medicine is to prevent platelets from adhering to the treated vessel section and to prevent the development of a blood clot with subsequent closure of the vessel.

In patients with acute coronary syndrome a superiority of the two drugs used in this study, ticagrelor and prasugrel in combination with ASA, has been shown in large clinical trials compared with the previous substance clopidogrel (Plavix or Iscover). To date, no direct head-to-head comparison of the impact of Ticagrelor and Prasugrel, tested by a randomized clinical Trial, exists.

ACS patients continue to have an excess risk of ischemic events. Therefore, the study focuses on these events during and after therapy with ticagrelor or prasugrel; the primary endpoint therefore will be the composite of death, myocardial infarction or stroke at 12 months after randomization.

Patients with acute coronary syndrome undergoing a planned invasive treatment strategy receive a therapy with ticagrelor/aspirin or prasugrel/aspirin in tablet form. The randomization will be in a 1:1 ratio, therefore the probability of attribution to the one or the other group is 50%.

The follow-up takes place during hospital stay as well as 30 days, 6 months and 12 months after discharge by calling respectively by letter of the study staff to the patient or by a patient's office visit in the clinic. Thereby, the staff will ask questions concerning the drugs taken by the patient, and with regard to the patient's state of health.
A long term follow-up is planned at 3 years after inclusion. A Re-presentation in the hospital is not mandatory.

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Brief Summary in Scientific Language

In patients with acute coronary syndromes (ACS) – including unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) – a dual antiplatelet treatment regimen with a platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist in addition to the cyclooxygenase inhibitor acetylsalicylic acid (ASA) has become the cornerstone of treatment to prevent subsequent thrombotic vascular events. The 3rd generation thienopyridine prasugrel and the cyclopentyl-triazolo-pyrimidine ticagrelor provide a greater, more rapid and consistent platelet inhibition compared to the predecessor thienopyridine clopidogrel. While prasugrel – like clopidogrel – blocks the ADP binding site of the P2Y12 receptor irreversibly, ticagrelor reversibly inhibits binding of ADP to the P2Y12 receptor in a non-competitive manner declining about 12 hours after intake. Both drugs have been tested against clopidogrel in large, randomized, double blind clinical trials of ACS patients. In the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial of patients with ACS undergoing PCI, prasugrel compared to clopidogrel resulted in a significant reduction in the combined ischemic endpoint of cardiovascular death, myocardial infarction and stroke. In the PLATelet inhibition and patient Outcomes (PLATO) trial of ACS patients treated either conservatively or with an invasive strategy, ticagrelor compared to clopidogrel was also associated with a significant reduction in the composite of death from vascular causes, myocardial infarction or stroke. Based on the advantages of ticagrelor and prasugrel over clopidogrel in the two landmark studies, both drugs received a class I recommendation for their use in ACS patients including patients with STEMI and NSTE-ACS. The predecessor ADP receptor blocker clopidogrel is currently only recommended if prasugrel or ticagrelor are either not available or contraindicated.
In STEMI patients both ADP receptor blockers were administered before coronary angiography and provided superior outcome compared to clopidogrel, whereas the use and benefits of the two new ADP receptor blockers in NSTE-ACS deserve special consideration. The advantage of prasugrel in NSTE-ACS patients in the TRITON TIMI 38 trial was achieved by study drug administration after diagnostic angiography in patients undergoing PCI. The A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction (ACCOAST) study aimed at the evaluation of pre-catherization administration of prasugrel in NSTE-ACS. The trial was stopped prematurely due to an excessive bleeding rate. (Reportedly) The TaRgetetd platelet Inhibition to cLarify the Optimal strategy to medically manage Acute Coronary Syndromes (TRILOGY ACS) trial compared prasugrel with clopidogrel in patients with NSTE-ACS not undergoing revascularization. In that study prasugrel did not provide significant benefit in terms ischemic protection compared to clopidogrel. Due to the specific design of the TRITON TIMI 38 trial, the number of patients undergoing CABG for the index procedure was negligible (1%).

On the other hand, the PLATO trial also included ACS patients with conservative treatment strategy and a higher number of patients undergoing CABG. This was allowed by the design of the trial which included enrolment and study drug administration before angiography. Of note, ticagrelor was superior to clopidogrel not only in PCI treated patients but also in patients intended for conservative treatment and CABG. Finally, ticagrelor has been ascribed additional, adenosine mediated beneficial cardiovascular effects. Therefore a larger proportion of ACS patients might benefit from ticagrelor than from prasugrel.
Although both drugs provided superior efficacy compared to clopidogrel in the pivotal randomized trials, ACS patients continue to have an excess risk of ischemic events. Moreover, both drugs were shown to increase bleeding. Due to different ACS populations and conditions investigated the relative merits of prasugrel and ticagrelor in the treatment of ACS patients with planned invasive strategy cannot be reliably estimated from independent trials alone. To date, no direct head-to-head comparison of the two new P2Y12 receptor antagonists prasugrel and ticagrelor in terms of clinical outcome exists. The hypothesis to be tested will therefore be that ticagrelor is superior to prasugrel in terms of clinical outcomes. This will be achieved by means of a randomized, open label, multicentre trial. The primary endpoint will be the composite of death, myocardial infarction and stroke at 12 months after randomisation.

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Organizational Data

  •   DRKS00005441
  •   2013/11/18
  •   2013/09/13
  •   yes
  •   Approved
  •   5849/13, Ethik-Kommission der Fakultät für Medizin der Technischen Universität München
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Secondary IDs

  •   2013-002272-40 
  •   NCT01944800  (ClinicalTrials.Gov)
  •   GE-IDE-No.00113  (Sponsor-Code)
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Health Condition or Problem studied

  •   I20.0 -  Unstable angina
  •   I21 -  Acute myocardial infarction
  •   I24.9 -  Acute ischaemic heart disease, unspecified
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Interventions/Observational Groups

  •   Medication therapy with Brilique, substance ticagrelor, tablet 90 mg, oral intake, 2 x / day; duration of therapy: 12 months
  •   Medication therapy with Efient, substance prasugrel, tablet 10 mg (respectively 5 mg for patients > 75 years or < 60 kg), oral intake, 1 x / day; duration of therapy: 12 months
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control
  •   Treatment
  •   Parallel
  •   IV
  •   No
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Primary Outcome

Composite of death, myocardial infarction or stroke at 12 months after randomization

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Secondary Outcome

Safety endpoint: Bleeding according to BARC criteria (BARC class 3-5) at 12 months after randomization; the individual components of the primary endpoint at 12 months after randomization;
Stent thrombosis according to ARC criteria (definite and probable) at 12 months after randomization

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Countries of Recruitment

  •   Germany
  •   Italy
  •   United States
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Locations of Recruitment

  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2013/09/16
  •   4000
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   99   Years
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Additional Inclusion Criteria

Patients presenting with ACS and planned invasive strategy; Informed, written consent

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Exclusion Criteria

Active bleeding; History of stroke or TIA;
Need for oral anticoagulation;
Chronic renal insufficiency requiring dialysis;
Moderate or severe hepatic dysfunction

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Addresses

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    • Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen
    • Lazarettstr. 36
    • 80636  München
    • Germany
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    • ISAResearch Center, Deutsches Herzzentrum München
    • Ms.  Barbara  von Merzljak 
    • Lazarettstr. 36
    • 80636  München
    • Germany
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    • Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen
    • Ms.  Dr.  Stefanie  Schulz 
    • Lazarettstr. 36
    • 80636  München
    • Germany
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    • Deutsches Herzzentrum München, ISAResearch Center
    • Ms.  Nonni  Rifatov 
    • Lazarettstr. 36
    • 80636  München
    • Germany
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Sources of Monetary or Material Support

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    • Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen
    • Mr.  Prof.  Adnan  Kastrati 
    • Lazarettstr. 36
    • 80636  München
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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