E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardiovascular disease- Acute coronary syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Heart disease- heart attack |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
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 |
OBSERVATIONAL REGISTRY OF SCREENED PATIENTS
To identify the proportion of patients who are good responders to routine doses of Clopidogrel and compare the events of death at 30 days.
RANDOMISED PATIENTS
To evaluate if reloading with Prasugrel compared to a high dose regimen of Clopidogrel results in more patients having a low platelet reactivity. Patients will be identified who have poor platelet response to previous Clopidogrel and have undergone an invasive procedure (PCI) to treat their narrowed or blocked heart vessels.
SUBSTUDIES
1. Title: APACS-HPR genetic substudy
To determine the relevant influence of genetic heritage on response variability to the Clopidogrel and Prasugrel antiplatelet treatment.
2) Title: APACS-HPR biomarker substudy
To determine the variability of platelet inhibition to Clopidogrel or Prasugrel treatment if this is influenced by the inflammatory condition and the extent of platelet activation and blood flow to the heart muscle. |
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E.2.2 | Secondary objectives of the trial |
(i) To compare the proportion of patients with improved platelet response between the treatment arms at hospital discharge/7 days and at 30 days.
(ii) To compare the amount of damage to heart muscle using blood marker (CK, troponin) at 24 hours between the treatment arms.
(iii) To compare the rate of major adverse events (death, myocardial infarction, stroke, repeated revascularization) at 30 days between the treatment arms.
(iv) To compare the safety rate of major bleedings at 30 days between the treatment arms. |
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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 |
1. APACS-HPR genetic substudy
Objective: There is a relevant influence of genetic heritage on response variability to thienopyridine treatment. Polymorphic variants of genes encoding for platelet proteins and enzymes involved in drug metabolism have been
previously linked to the platelet function phenotype and clinical outcome under clopidogrel treatment. Particular candidate genes include single nucleotide polymorphism of genes encoding for different cytochrome P450 isoenzymes (CYP 2C19*2, CYP2C19*3, CYP3A4/5), multidrug resistance gene (ABCB1) and Paraoxonase-1 (PON1). The primary objective of the genetic substudy is to investigate the impact of candidate SNP´s involved in thienopyridine metabolism and efficacy on differences in the primary endpoint between the two randomised arms and
to investigate their effects on clinical outcome in clopidogrel treated patients in the registry study.
2. APACS-HPR biomarker substudy
Objective: Variability of platelet inhibition under thienopyridine treatment is influenced by the inflammatory condition and the extent of platelet activation and myocardial ischemia in the course of acute coronary events. The primary objective of the biomarker substudy is to investigate the association of C-reactive
protein (hsCRP) and inflammatory cytokines and chemokines (RANTES, Interleukins, TNFalpha, MCP-1, SDF-1, adiponectin) and differences in platelet reactivity between the treatment arms. Additionally, levels of biomarkers monitoring myocardial ischemia and plaque destablization (high sensitivity Troponin, soluble glycoprotein 6, Copeptin, heart-type fatty acid binding protein, myeloperoxidase) and platelet activation (soluble P-selectin, CD40 ligand) will be determined to elucidate mechanisms of differences in platelet response to antiplatelet therapy. |
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E.3 | Principal inclusion criteria |
PATIENT INCLUSION CRITERIA REGISTRY
a) ACS patients with intent for PCI <72 hours from admission.
b) Prior clopidogrel loading within 24h before planned PCI or chronic (>24 hours) treatment with clopidogrel
c) Low platelet reactivity (HPR) PA <400 AU min by multiplate analyser (“good responders”). Blood sample to be taken
at least 2 hrs after prior clopidogrel loading.
d) Consent.
PATIENT INCLUSION CRITERIA FOR RANDOMISED APACS STUDY
a) ACS patients with intent for PCI <72 hours from admission.
b) Prior clopidogrel loading within 24h before planned PCI or chronic (>24 hours) treatment with clopidogrel.
c) High platelet reactivity (HPR) PA ≥400 AU min by multiplate analyser (“poor responders”).
d) Initial platelet function sample at least 2 hours after pre PCI loading dose
e) Consent. |
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E.4 | Principal exclusion criteria |
PATIENT EXCLUSION CRITERIA RANDOMISED APACS STUDY
a) Patients <18 years and ≥75 years
b) Body weight <60kg
c) Pretreatment with prasugrel within 7 days of randomisation
d) History of stroke or transient ischaemic attack
e) Patients with increased bleeding risk e.g.
• recent major trauma or surgery
• gastrointestinal bleeding or active peptic ulceration
• Platelet count <100,000 / mm3 at the time of screening
• Internationally Normalized Ratio (INR)> 1.5 at the time of screening
f) Hb<10g/dL
g) Intracranial neoplasm, arteriovenous malformation or aneurysm.
h) Severe hepatic impairment (Child Pugh class C)
i) Intention to use the following medications
• oral anticoagulation
• other antiplatelet therapy (including GPIIb/IIIa inhibitors) besides aspirin
• nonsteroidal antiinflammatory
drugs (NSAIDs) or cyclooxygenase2 (COX2) inhibitors
j) Female patients who are pregnant, planning pregnancy, not using reliable contraception or who are breastfeeding
k) Known allergy, hypersensitivity or other contraindications to prasugrel or clopidgrel |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will compare the proportion of patients with improved platelet response (i.e. decreased platelet reactivity under the cutoff value of 400 Au.min) in the prasugrel reloading arm compared to the clopidogrel reloading arm at 4 hours after randomization in patients with initial high platelet reactivity. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
4 hours post randomisation. |
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E.5.2 | Secondary end point(s) |
a) To compare the proportion of patients with improved platelet response between the treatment arms at hospital discharge/7 days and at 30 days.
b) To compare the AUC for CK and troponin at 24 hours between the treatment arms
c) To compare the rates major adverse events (death, myocardial infarction, stroke, repeated revascularization) at 30 days between the treatment arms
d) To compare the rate of major bleedings at 30 days between the treatment arms. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Between hospital discharge/7 days and at 30 days
b) 24 hours
c) 30 days
d) 30 days
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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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The trial will end when the last patient randomised has completed 30+/-7 days of follow up. |
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |