| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Reduction of composite cardio-vascular end-point in patients who have successfully undergone elective percutaneous coronary intervention with placement of at least one drug-eluting stent. |
|
| MedDRA Classification |
| 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 estimate the relative risk of the composite endpoint of Clinical Events Committee (CEC) adjudicated cardiovascular (CV) death or myocardial infarction (MI) through 6 months of maintenance treatment with prasugrel plus aspirin compared to clopidogrel plus aspirin after loading with 600-mg clopidogrel and successful elective PCI with placement of at least one drug-eluting stent (DES) in subjects with high platelet reactivity as assessed by the VerifyNow® device (P2Y12 reaction units [PRU] >208) after the first MD (75-mg) of clopidogrel.
The intent of this study is to demonstrate that prasugrel is superior to clopidogrel in preventing the composite endpoint in this population. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
To compare prasugrel with clopidogrel through 6 months: risk of CV death, MI, or UTVR; CV death, MI, or stroke; CV death, MI, stroke, or rehospitalization for cardiac ischemic events; definite or probable stent thrombosis according to ARC criteria; all cause death or MI; all cause death, MI, or UTVR...
Safety
To evaluate the incidence of non-CABG surgery-related TIMI Study Group major bleeding, of life-threatening bleeding, of non-CABG-related TIMI major or TIMI minor bleeding, to evaluate safety based on clinical findings, laboratory values, and the occurrence of TEAEs
Pharmacodynamic
To demonstrate a lower risk of the composite endpoint of CV death or MI in subjects with lower platelet reactivity
To compare intrasubject and intersubject variability in platelet aggregation.
To assess the incidence of bleeding events by degree of platelet aggregation
Genetic
Variation in DNA related to drug metabolism and transport
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Subjects with coronary artery disease and clinical indication for PCI
with implantation of at least one DES, and in whom PCI of all treated
lesions is successful (diameter stenosis <30% with TIMI 3 flow in all
treated vessels) without major complications (definition s. excl. crit.)
One or more bare metal stents (BMS) may be implanted, and other
lesions may be treated without stenting, as long as at least one DES is
implanted. However, the procedure must be successful and
uncomplicated for all lesions (DES + BMS + non stent).
[2] Standard of care clopidogrel 600-mg LD must have been given
between 24 hours before, and the time of, PCI. A non-study-related
standard of care clopidogrel 75-mg MD must have been administered
in the morning of the day following PCI. (Administration of an
additional non-study-related standard of care clopidogrel 75-mg MD in
the evening of PCI should be avoided but is permitted if this is
standard of care at the institution).
[3] VerifyNow™ PRU >208, measured 2 to 7 hours after a clopidogrel
MD received the morning after successful PCI.
[4] Aspirin use prior to PCI: A non-study-related dose of at least 250-mg
(IV or oral) within 24 hours prior to PCI, and the time of PCI.
[5] Only stents that are CE marked for approval may be used in this study.
[6] PCI must have been performed with unfractionated or low molecular
weight heparin, or bivalirudin as the procedural antithrombin.
[7] Are of a legal age (and at least 18 years of age) and competent mental
condition to provide written informed consent before entering the
study. Informed consent must be signed by the study participant or
authorized representative, according to local rules and regulations.
[8] For women of child-bearing potential only (that is, women who are not
surgically or chemically sterilized and who are between menarche and
1 year postmenopause), test negative for pregnancy (based on a urine
or serum pregnancy test to be performed before randomization) and
agree to use a reliable method of birth control (Pearl Index < 1%)
during the study. A highly effective method of birth control is defined
as those which result in a low failure rate (i.e., ≤1% per year)
when used consistently and correctly such as implants, injectables,
combined oral contraceptives, some IUDs, sexual abstinence or
vasectomised partner. |
|
| E.4 | Principal exclusion criteria |
[9] Subjects with non-ST-segment elevation myocardial infarction
(NSTEMI) within 14 days prior to randomization. NSTEMI is defined
as a history of chest discomfort or ischemic symptoms of ≥10 minutes
duration at rest, with no evidence of persistent ST-segment elevation
and with troponin T or I greater than the upper limit of normal (ULN).
[10] Subjects with ST-segment elevation myocardial infarction (STEMI)
within 14 days prior to randomization. STEMI is defined as a history
of chest discomfort or ischemic symptoms of >20 minutes duration at
rest with one of the following present on at least one ECG prior to
PCI:
(a) ST-segment elevation ≥1 mm in two or more contiguous ECG
leads.
(b) New or presumably new left bundle branch block (LBBB).
(c) ST-segment depression ≥1 mm in two anterior precordial leads
(V1 through V4) with clinical history and evidence suggestive of
true posterior infarction.
[11] Subjects with known major complications after PCI and prior to
randomization defined as:
(a) ST-segment elevation myocardial infarction (STEMI).
(b) Stent thrombosis.
(c) Large non-ST-segment elevation myocardial infarction (NSTEMI)
defined as an increase in CK >5 x ULN with concomitant rise in
CK-MB.
(d) Major bleeding at the vascular access site (drop in Hgb of ≥5g/dL
or requiring transfusion).
(e) False aneurysma.
[12] Have cardiogenic shock at the time of randomization (systolic blood
pressure <90 mm Hg associated with clinical evidence of end-organ
hypoperfusion, or subjects requiring vasopressors to maintain systolic
blood pressure over 90 mm Hg and associated with clinical evidence
of end-organ hypoperfusion).
[13] Have refractory ventricular arrhythmias.
[14] Have New York Heart Association (NYHA) Class IV congestive heart
failure (CHF; see Attachment TACW.3).
[15] Have received fibrin-specific fibrinolytic therapy <24 hours prior to
randomization.
[16] Have received nonfibrin-specific fibrinolytic therapy <48 hours prior
to randomization.
[17] Have active internal bleeding or history of major bleeding diathesis.
[18] Have clinical findings, in the judgment of the investigator, associated
with an increased risk of bleeding.
[19] Non-cardiac surgery within 4 weeks prior to PCI.
[20] Have any of the following:
(a) Prior history of hemorrhagic or ischemic stroke, a transient
ischemic attack, or sub-arachnoid hemorrhage.
(b) Intracranial neoplasm, arteriovenous malformation, or aneurysm.
[21] Have an International Normalized Ratio (INR) >1.5 at the time of
evaluation.
[22] Have a platelet count of <100,000/mm3 at the time of screening.
[23] Have known anemia (Hgb <10 gm/dL) at the time of screening.
[24] Have a body weight <60 kg.
[25] Have an age of >80 years.
[26] Have received GPIIb/IIIa inhibitors eptifibatide or tirofiban within 24
hours before or during PCI or abciximab within 10 days before or
during PCI.
[27] Are receiving or will receive oral anticoagulation or other antiplatelet
therapy besides aspirin that cannot be safely discontinued for the
duration of the study.
[28] Are receiving daily treatment with nonsteroidal anti-inflammatory
drugs (NSAIDs) or cyclooxygenase-2 (COX2) inhibitors that cannot
be discontinued or are anticipated to require >2 weeks of daily
treatment with NSAID or COX2 inhibitors during the study.
[29] Are employed by Eli Lilly and Company, Ube Industries Limited, or
Daiichi Sankyo Company, Ltd.
[30] Investigator site, ARO or CRO personnel directly affiliated with this
study and/or their immediate families. Immediate family is defined as
a spouse, parent, child, or sibling, whether biological or legally
adopted.
[31] Have received treatment within the last 30 days with a drug that has
not received regulatory approval for any indication at the time of study
entry or are presently enrolled in another drug or device study.
[32] Have previously completed or withdrawn from this study or any other
study investigating prasugrel.
[33] Are women who are known to be pregnant, who have given birth
within the past 90 days, or who are breastfeeding.
[34] Have a concomitant medical illness (for example, terminal
malignancy) that in the opinion of the investigator is associated with
reduced survival over the expected treatment follow-up period (6
months).
[35] Have cardiac or extra-cardiac surgery planned within the expected
treatment respective follow-up period (6 months).
[36] Have known severe hepatic dysfunction (that is, with cirrhosis or
portal hypertension, Child-Pugh Class C).
[37] Have a condition associated with poor treatment compliance, including
alcoholism, mental illness, drug dependence, or are elderly and frail.
[38] Have a history of intolerance or allergy to aspirin or approved
thienopyridines (ticlopidine, clopidogrel or prasugrel).
[39] May be unable to cooperate with protocol requirements and follow-up
procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the composite of CV death or MI in the ITT population(defined as all randomized subjects). The primary analysis will be the time from randomization to the onset of the first occurrence of the primary endpoint using a two-sided log-rank test. Corresponding survival curves will be estimated by the Kaplan-Meier method and twosided 95% confidence intervals for the average hazard ratio will be provided with the use of the Cox proportional hazards assumption. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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.8.3 |
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 | 22 |
| 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 | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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