| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Acute Coronary Syndrome in medically managed subjects enrolled within 7 days of the unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) index event. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051592 |
| E.1.2 | Term | Acute coronary syndrome |
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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 |
The primary objective of this study is to test the hypothesis that prasugrel and aspirin is superior to clopidogrel and aspirin in the treatment of medically managed subjects enrolled within 7 days of the unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) index event. Superiority will be assessed by the reduction in risk of the composite endpoint of first occurrence of cardiovascular (CV) death, myocardial infarction (MI), or stroke throughout the study.
The primary analysis will be conducted in a hierarchical manner, with evaluation of the primary endpoint performed first in medically managed UA/NSTEMI subjects < age 75 years. Conditional on successfully establishing superiority in the primary analysis, the same composite endpoint will be evaluated in the entire population.
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| E.2.2 | Secondary objectives of the trial |
| The following secondary endpoints will be analyzed in both the population of medically managed UA/NSTEMI subjects age <75 years and the entire medically managed UA/NSTEMI population (subjects < age 75 years and subjects ≥ age 75 years). |
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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 |
Three substudies will be performed in Study TABY. Both cohorts (population <75 years of age and the population ≥75 years of age) will be eligible for participation in these substudies.
1. Platelet Function Substudy (IPA substudy) part of main protocol (06February2008, H7T-MC-TABY(a)). The IPA substudy will not be run in all countries participating in the main study. Subjects who participate in the platelet function substudy will be assessed for each of the substudy objectives:
Pharmacodynamic Objectives
Platelet aggregation will be measured by the Accumetrics VerifyNow® P2Y12 and aspirin assays. The key platelet function objectives are:
• To demonstrate a lower risk of the composite endpoint of CV death, MI, or stroke in subjects with greater attenuation of platelet aggregation, irrespective of baseline treatment.
• To compare the prasugrel and clopidogrel groups with respect to degree of platelet aggregation.
• To compare the prasugrel and clopidogrel groups with respect to intra- and inter-subject variability in platelet aggregation during maintenance dosing.
• To assess the incidence of bleeding events by degree of platelet aggregation.
Genomic Objectives
• To assess the interaction between treatment groups and the presence of genetic variation in drug metabolizing enzymes and transporters on platelet function.
• To assess the interaction between treatment group and the presence of genetic variation in drug metabolism enzymes and transporters on clinical efficacy and/or safety outcomes.
Other Objectives
•To assess the effect of the prasugrel and clopidogrel groups on biomarkers of inflammation (high-sensitivity C-reactive protein [hsCRP]) and hemodynamic stress (N-terminal prohormone brain natriuretic peptide [NT-proBNP] or brain natriuretic peptide [BNP]).
2. Health Outcome Substudy Objectives. Part of main protocol (06February2008, H7T-MC-TABY(a))
Health outcome objectives are:
• To compare the prasugrel and clopidogrel treatment arms with respect to:
a) Major healthcare resource use, cumulative medical costs, and incremental cost effectiveness.
b) Health-related quality of life.
• To examine healthcare costs and resource use as a function of both treatment assignment and degree of platelet aggregation.
Other Objectives
Other prespecified and exploratory analyses will be conducted, as specified in the statistical analysis plan (SAP), to include repeating the primary and all secondary analyses in the age ≥ 75 year population
3. Protocol Sample Banking Addendum (30August2007, H7T-MC-TABY(1))
For sites not participating in the IPA substudy
Protocol Sample Banking Addendum(30August2007, H7T-MC-TABY(2))
For Sites in IPA Substudy
Sample banking is an optional part of this study. DNA banked samples will be anonymized and stored. DNA from banked samples may be used to further explore genetic relationships between disease susceptibility, disease outcomes, and drug responses.
There is a slight difference in the collection of samples for sites which are participating in the DNA banking and performing IPA substudy.
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| E.3 | Principal inclusion criteria |
1. Have had a UA/NSTEMI index event within 7 days (168 hours) prior to randomization (based on the disease diagnostic criteria in Section 4.1.1).
2. Have had a medical management strategy decision made with reasonable certainty; that is, neither PCI nor CABG is planned for treatment of the index event.
• For subjects whose medical management decision and randomization occurs no later than 24 hours following onset of the index event, prior clopidogrel treatment is not a consideration for eligibility.
• For subjects with a medical management decision who are randomized beyond 24 hours of onset of the index event, commercial clopidogrel must have been received according to standard of care practice guidelines no later than 24 hours following the onset of the index event (as defined in Section 4.1.2).
3. Have had at least 1 of the following 3 high-risk features at the time of the UA/NSTEMI event:
• Age ≥60 years
• Prior MI evidenced by pre-existing Q waves, or demonstration of infarction on imaging studies, or prior documentation of elevated cardiac markers.
• Diabetes Mellitus - defined by concomitant treatment with an oral hypoglycemic agent and/or insulin.
4. Have at least 1 native coronary artery stenosis >50% (applies only to those subjects who undergo diagnostic coronary angiography within 7 days of the onset of the index event but do not undergo PCI or CABG after angiography is performed).
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| E.4 | Principal exclusion criteria |
Cardiovascular Exclusion Criteria
5. Decision for medical management >24 hours after the onset of the index event without commercial clopidogrel treatment within 24 hours following the onset of the index event (Note: commercial clopidogrel treatment must continue daily thereafter until randomization).
6. Previous or planned (during the index hospitalization or thereafter) PCI or CABG as treatment for the index event.
7. PCI or CABG within the previous 30 days.
8. STEMI as the index event.
9. Cardiogenic shock within the previous 24 hours (defined as a systolic blood pressure <90 mm Hg associated with clinical evidence of end-organ hypoperfusion, or hypotension requiring vasopressors to maintain systolic blood pressure over 90 mm Hg and associated with clinical evidence of end-organ hypoperfusion).
10. Refractory ventricular arrhythmias within the previous 24 hours.
11. Symptoms of New York Heart Association (NYHA) Class IV congestive heart failure (CHF) within the previous 24 hours (see Attachment TABY.4 for NYHA CHF classifications).
Exclusion Criteria Related to Bleeding
12. Contraindicated for antiplatelet therapy.
13. Received fibrinolytic therapy as initial treatment for the index event.
14. Any history of bleeding diathesis.
15. Clinical findings associated, in the judgment of the investigator, with an unacceptably high risk of bleeding.
16. Any of the following:
• History of ischemic or hemorrhagic stroke
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• History of any TIA symptoms.
17. International Normalized Ratio (INR) known to be >1.5 at the time of screening.
18. Platelet count of <100,000/mm3 at the time of screening.
19. Anemia (hemoglobin [Hgb] <10 gm/dL) at the time of screening.
20. History of spontaneous gastrointestinal bleeding requiring in-hospital treatment.
21. History of spontaneous non-gastrointestinal internal bleeding requiring in-hospital treatment.
22. Currently receiving hemodialysis or peritoneal dialysis.
Prior/Concomitant Therapy Exclusion Criteria
23. History of intolerance or allergy to aspirin or approved thienopyridines (ticlopidine or clopidogrel).
24. Treated with ticlopidine within 5 days of randomization.
25. Receiving prasugrel treatment at the time of screening.
26. Receiving oral anticoagulants at the time of screening or are anticipated to require oral anticoagulants therapy during the course of the study.
27. 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 NSAIDs or COX2 inhibitors during the study.
General Exclusion Criteria
28. Unwilling to provide or not sufficiently mentally competent to provide written informed consent.
29. Study site personnel directly affiliated with the study or are immediate family of study site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
30. Employed by Eli Lilly and Company, Ube Industries Limited, Daiichi Sankyo Pharma Inc, the academic research organization (ARO), or the contract research organization (CRO) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly employees may participate in Lilly-sponsored clinical studies, but are not permitted to participate at a Lilly facility. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
31. Previously completed or withdrawn from this study or any other study investigating prasugrel.
32. Received treatment within the last 30 days with a drug or device that has not received regulatory approval for any indication at the time of study entry or are presently enrolled in another interventional drug or device study.
33. Females who are known to be pregnant, who have given birth within the past 90 days, or who are breastfeeding.
34. Females of childbearing potential (that is, females who are not surgically or chemically sterilized and who are between menarche and 1 year post menopause) and do not agree to use a reliable method of birth control during the study.
35. Concomitant medical illness (for example, terminal malignancy) that, in the opinion of the investigator, is associated with reduced survival over the expected treatment period.
36. Known severe hepatic dysfunction (that is, with cirrhosis or portal hypertension).
37.Conditions associated with poor treatment compliance, including alcoholism, mental illness, or drug dependence.
38. Unable to cooperate with protocol requirements and follow-up procedures.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Measure
The primary efficacy endpoint is the time to the first occurrence of the composite of CV death, MI, or stroke defined as follows.
1) Cardiovascular Death (CV Death):
Death due to documented cardiovascular cause. Additionally, death not clearly attributable to noncardiovascular causes will be considered CV death.
2) Myocardial Infarction (MI):
The definition of MI is adapted from the universal definition of MI (Thygesen et al. 2007) and is dependent on the clinical timing of the event in relation to presenting syndrome and cardiovascular procedures. A subject who experiences any one of the following after randomization will qualify as having had an MI:
• Elevation or re-elevation of the ST segment AND either ischemic chest pain ≥20 minutes in duration, or hemodynamic decompensation.
• CK-MB fraction or troponin >ULN, AND either ischemic chest pain (or anginal equivalent) ≥20 minutes in duration, or ST-segment deviation ≥1 mm in one or more leads. If at the onset of the suspected event, the ischemic biomarker was still elevated as a result of the index event, then there must be demonstration of a falling biomarker level prior to the onset of the suspected event, and the subsequent peak of the ischemic biomarker must be 1.5 times the value prior to the onset of the suspected event. These criteria do not need to be met if the ischemic biomarker is not elevated prior to the onset of the suspected event.
•CK-MB >3 times ULN on at least 1 sample within 24 hours following PCI (for subjects requiring emergent, urgent, or elective PCI at any time after randomization).
•CK-MB >5 times ULN on at least 1 sample within 24 hours following CABG (for subjects requiring emergent, urgent, or elective CABG surgery at any time after randomization).
•New Q waves ≥0.04 seconds or pathology distinct from that of the index event and thought to be new since randomization.
In order to detect periprocedural MI in subjects undergoing PCI or CABG during the course of the study, it is recommended that 4 blood samples for CK-MB be drawn: 1 prior to the procedure and 3 within the first 24 hours after PCI/CABG. The second sample should be drawn at least 6 hours after PCI. The third sample should be at least 6 hours later (6 to 8 hours recommended), and the fourth sample should be drawn at least 6 hours after the third sample (6 to 8 hours recommended).
In the rare circumstances where CK-MB testing is not available, a troponin >3 times ULN on at least 1 sample within 24 hours following PCI (for subjects requiring emergent, urgent, or elective PCI at any time after randomization) or a troponin >5 times ULN on at least 1 sample within 24 hours following CABG (for subjects requiring emergent, urgent, or elective CABG surgery at any time after randomization) may be used to define and adjudicate a periprocedural MI in place of CK-MBs levels.
3) Stroke:
The rapid onset of new, persistent neurologic deficit lasting more than 24 hours. In the case of clinical diagnosis of stroke, computed tomography (CT) or magnetic resonance imaging (MRI) is strongly recommended, but not required. Computed tomography or MRI scans will be considered by the CEC to support the clinical impression. Available supplemental information from head CT or MRI scans will assist in the determination if there is a demonstrable lesion compatible with an acute stroke. Furthermore, all strokes will be classified as either “ischemic” or “hemorrhagic” based on imaging data, if available, or “uncertain cause” if imaging data are not available.
Primary endpoint events must be reported to the sponsor or designee within 24 hours after the site staff learns of the clinical event.
All primary endpoints will be adjudicated by the CEC. Study sites should send the required documents that include the relevant completed endpoint CRFs and the requested source documentation to the CEC in a timely fashion for adjudication of the event. Additional details are available in the CEC charter.
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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 | 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 250 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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