E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | PT |
E.1.2 | Classification code | 10011078 |
E.1.2 | Term | Coronary artery disease |
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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 objectives of the study are to investigate the safety and tolerability of E5555 at three dose levels in patients admitted to hospital with symptoms of ACS. This will be assessed for a period of up to 16 weeks (112 days). |
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E.2.2 | Secondary objectives of the trial |
To determine the effect of E5555 on major adverse cardiac events (MACE), which include cardiovascular death, myocardial infarction, stroke or refractory ischemia To provide data that can be used to help determine the safe and effective clinical dose range. To determine the effect of E5555 on the incidence of transient ischemia (a predictor of MACE) assessed by continuous (Holter) ECG monitoring for the initial 48 hours following randomization. To describe the pharmacokinetics (PK) of E5555 and its active metabolites in the patient population using an appropriate parametric PK model, and to obtain an evaluable dataset of individual patient exposures for exploration of exposure-response relationships with safety, efficacy and pharmacodynamic (PD) outcomes. Additional exploratory analyses aim to identify significant patient-specific covariates with PK variables and determine the relationships between E5555 PK exposure and PD parameters. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Men and women (women of child-bearing potential must use adequate contraception) •Presenting with features of non-ST segment elevation ACS (unstable angina or MI without persistent ST elevation). There must be new onset or a worsening pattern of characteristic ischemic chest pain or ischemic symptoms occurring at rest or with minimal activity (lasting longer than 5 minutes or requiring sublingual nitroglycerin for relief of the pain) •Randomisation and treatment possible within 72 hours of the onset of symptoms. Every effort should be made to randomise and treat eligible subjects as soon after hospital admission as possible. •Age 18–80 years inclusive and at least one of the following two criteria on admission: - Troponin T or I ≥ ULN or CKMB ≥ ULN for the local institution - ECG changes compatible with ischemia (i.e. ST depression at least 1 mm in 2 contiguous leads or T wave inversion > 3 mm or any dynamic ST shift or transient ST elevation)
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E.4 | Principal exclusion criteria |
•Unwilling or unable to provide informed consent •History of acquired or congenital bleeding disorder, coagulopathy or platelet disorder •Recent trauma or major surgery (within the 30 days prior to screening/baseline) •Recent (within 14 days prior to screening/baseline) significant infection or history of chronic infections with a recurrence < 14 days prior to screening/baseline visit and/or requiring continuous antibiotic treatment •Evidence of active pathological bleeding at screening/baseline or history of bleeding (such as gastrointestinal or genitourinary) within the last 6 months prior to screening/baseline visit, unless the cause has been definitely corrected •History of intracranial bleeding e.g. hemorrhagic stroke, subdural hematoma, subarachnoid hemorrhage) or history of hemorrhagic retinopathy •History of ischemic stroke or transient ischemic attack, within the past year prior to screening/baseline or known structural cerebral vascular lesion (eg, arteriovenous malformation [AVM], aneurysm) •Haematological abnormalities: platelet count <100 x 103 / μL, haemoglobin < 10 g/dL at screening/baseline visit (day 1) •History of NYHA class III or IV congestive heart failure or history of severe, uncontrolled cardiac arrhythmias at screening/baseline •Patients with ST-segment changes at baseline attributed to left ventricular hypertrophy with repolarisation changes, bundle branch block and digoxin will be excluded. •Percutaneous cardiac intervention or coronary artery surgery in the previous 12 weeks prior to the current hospital admission. •Significant (as determined by the investigator) cardiovascular events (such as a Q wave MI) within the past 30 days prior to the screening/baseline visit •Planned elective surgical operation or major invasive procedures planned from 30 days prior to screening to completion of the study (the decision of what constitutes a major invasive procedure will be at the discretion of the investigator in conjunction with review and approval by the Medical Monitor) •Unstable diabetes requiring frequent adjustments to medications (other than insulin) in the 30 days prior to the screening/baseline visit •Documented history of chronic liver disease and/or screening/baseline ALT or AST > 3 x ULN or total bilirubin > 1.5 x ULN (unless the abnormal bilirubin is secondary to Gilbert’s syndrome) •History of rheumatologic or autoimmune diseases •Significant renal impairment, defined as creatinine clearance of < 30mL/min •History of cancer (other than basal cell carcinoma, cervical carcinoma in situ, or low-grade prostate cancer), unless adequately treated with no evidence of disease recurrence for at least 2 years •Use of any of the following drugs in the 30 days prior to the screening / baseline visit and for the duration of the study: -Oral antiplatelets other than aspirin (daily aspirin dose of 325 mg or lower) and/or clopidogrel (75 mg chronically; loading dose allowed) and/or Ticlopidine (250mg BID) -Oral anticoagulants (e.g. acenocoumarol, warfarin) -Fibrinolytics (eg, tPA, streptokinase, urokinase) -NSAIDs, (including COX-2 inhibitors) other than occasional use -Potent and moderate CYP 3A4 inhibitors -Selected CYP 2D6 substrates -Herbals with anti-platelet properties:Gingko biloba, Horse chestnut (Aesculus hippocastanum) •Use of another investigational drug or device within previous 30 days (12 weeks for investigational devices, eg, unapproved stents) prior to sceening/baseline visit •Pregnant or nursing women •Use of illicit drugs or alcohol abuse 3 months prior to the screening or during the course of the study •A Marked prolongation of QT/QTc interval (>500 ms) at the screening/baseline visit (Day 1)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will be proportions of patients with CEC-adjudicated major bleeds. Cross-classification tables of CEC-adjudicated major bleeds versus treatment group will be created.
Safety and tolerability will be determined by comparison of incidences of treatment-emergent SAEs, treatment-emergent AEs, treatment-emergent abnormal lab values and changes in ECGs in the safety population.
Two main secondary endpoints will be used to assess efficacy issues between the treatment groups. The first will be the proportion of patients with CEC-adjudicated MACEs.The second efficacy endpoint will be the proportion of subjects with 24-h Holter-detected ischemia as defined by a ST-segment shift ≥ 0.1 mV below/above the baseline, ≥ 1 minute in duration, and separated from other episodes of ST segment shift by ≥ 1 minute. |
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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 | Yes |
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) | 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) | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |