| 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 | 8.1 |
| 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 |
Stage 1 Dose Escalation
The primary objective of Stage 1 (Dose Escalation) of this study is to evaluate the safety of rivaroxaban in subjects with recent acute coronary syndrome (ACS) (including ST-segment elevation myocardial infarction [STEMI], nonST segment elevation myocardial infarction [NSTEMI], and unstable angina [UA]) who are treated with aspirin alone or aspirin plus a thienopyridine.
Stage 2: Dose Confirmation
The primary objective of Stage 2 (Dose Confirmation) of this study is to evaluate the ability of rivaroxaban to reduce the combined incidence of death, myocardial infarction (MI) or repeat myocardial infarction (reMI), stroke (ischemic, hemorrhagic or unknown), or severe recurrent ischemia requiring revascularization in subjects with recent ACS (including STEMI, NSTEMI, or UA) who are treated with aspirin alone or aspirin plus a thienopyridine after medical therapy or percutaneous coronary intervention (PCI) as acute treatment. |
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| E.2.2 | Secondary objectives of the trial |
Stage 1: Dose Escalation
Evaluation of: 1) primary and secondary efficacy endpoints to enable a benefit:risk assessment; 2) the pk/pd of rivaroxaban; 3) the ability to reduce thrombin generation; 4) the overall safety of treatment.
Stage 2: Dose Confirmation
Evaluate the ability of rivaroxaban to 1) reduce the composite of death, MI, or stroke through 6 months of treatment; 2) reduce the composite of death, MI, stroke, or severe recurrent ischemia through 6 months; 3) reduce each component of the primary efficacy endpoint; 4) reduce ischemia as measured by continuous ST segment monitoring; 5) reduce the incidence of LV thrombus at Day 10 to 14 after randomization in subjects presenting with anterior STEMI; 6) to assess the net clinical benefit by measuring the composite of death, MI, stroke, severe recurrent ischemia requiring revascularization, TIMI major bleed or TIMI minor bleed through 6 months; 7) to assess the overall safety of treatment. |
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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 |
The Holter (ambulatory ECG) monitoring and Echocardiography substudies are incorporated into this protocol.
At select sites during Stage 2 (Dose Confirmation), approximately 1,200 subjects will undergo Holter (ambulatory electrocardiogram [ECG]) monitoring. Holter monitoring will be applied after randomization but before the first dose of study medication and should be removed between Days 4 to 7 postrandomization. The hypothesis is that treatment with rivaroxaban will decrease the total duration of ischemia in the combined rivaroxaban groups compared with placebo.
At select sites during Stage 2 (Dose Confirmation), approximately 600 subjects with anterior STEMI will have echocardiograms performed. Randomized subjects confirmed by baseline echocardiogram to not have LV thrombus will have a follow-up echocardiogram between Days 10 to 14 to assess for the presence or absence of LV thrombus. The hypothesis of the echocardiography substudy is that in subjects with anterior STEMI, treatment with rivaroxaban will decrease the incidence of LV thrombus by echocardiography on Day 10 to 14 in the combined rivaroxaban groups compared with placebo. |
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| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study: - man or woman between 18 and 75 years of age, inclusive, for Stage 1. Subjects older than 75 years of age will be allowed to enroll in the 20-mg or lower total daily dose panels during Stage 1 assuming an acceptable safety profile is demonstrated, as determined by The Operations Committee in consultation with the IDMC Chair. For Stage 2, subjects over 75 years of age will be allowed to enroll assuming an acceptable safety profile is demonstrated in Stage 1.
- female subjects must be surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control before entry and throughout the study; female subjects of childbearing potential must have a negative urine β-hCG pregnancy test at screening.
- subjects must have signed an informed consent document.
- in countries where health authorities have approved the pharmacogenomic testing, subjects must have signed an informed consent for genetic testing indicating that they agree to participate in the genetic part of the study; participation in the genetic testing component is not mandatory for participation in the study.
- have symptoms suggestive of ACS that lasted at least 10 minutes at rest occurring within 7 days of randomization - have either a diagnosis of STEMI or a diagnosis of NSTEMI or UA with at least 1 of the follow:
- elevated cardiac enzyme marker (e.g., CK-MB or troponin I or T) - ≥1 mm ST-segment deviation (i.e., elevation or depression) - TIMI risk score ≥3 |
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| E.4 | Principal exclusion criteria |
Conditions that may increase the risk of bleeding:
- active internal bleeding, clinically significant bleeding, bleeding at a noncompressible site, or bleeding diathesis within 30 days of randomization
- platelet count <90,000/µL at the screening visit
- known pseudoaneurysm
- major surgery, biopsy of a parenchymal organ, eye surgery (including cataract surgery or vision correcting surgery), or serious trauma within 30 days before randomization
- clinically significant gastrointestinal bleeding within 6 months before the randomization visit
- have an INR known to be >1.5 at the time of screening
- abciximab bolus or infusion within the past 8 hours, or an eptifibatide or tirofiban bolus or infusion within the past 2 hours before randomization
- any other condition known to increase the risk of bleeding
Conditions that may increase the risk of intracranial hemorrhage:
- history of hemorrhagic stroke at any time or clinical presentation consistent with intracranial hemorrhage (e.g., severe headache or new neurologic deficit after fibrinolytic therapy)
- recent ischemic stroke or transient ischemic attack (TIA) of any etiology within 30 days of randomization
- recent head trauma. (i.e., within 30 days of randomization)
- known intracranial neoplasm, arteriovenous malformation, or aneurysm
- sustained uncontrolled hypertension: systolic blood pressure of ≥180 mmHg or diastolic pressure of ≥100 mmHg that persists for more than 1 hour at time of screening despite treatment
Required drugs or procedures:
- the need for continued treatment with anticoagulant drugs (e.g., warfarin)
- systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within 4 days before randomization or planned treatment during the time period of the study
- treatment with a strong inducer of cytochrome P450 3A4, such as rifampin/rifampicin within 4 days before randomization or planned treatment during time period of the study
- planned PCI or peripheral arterial intervention
Severe concomitant diseases such as:
- cardiogenic shock
- refractory ventricular arrhythmias
- calculated creatinine clearance <30 mL/min at the screening visit
- known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or ALT >3 times the ULN
- anemia (i.e., hemoglobin <10 g/dL) at the screening visit
- have received transfusion of red blood cells (RBCs), whole blood, or platelets within 7 days before randomization
- known human immunodeficiency virus (HIV) infection at the screening visit
- substance abuse (drug or alcohol) problem within the previous 3 years
- have any severe condition that would limit life expectancy to less than 6 months
General:
- known allergy to aspirin
- known allergy or hypersensitivity to any component of rivaroxaban or placebo excipients (includes lactose, microcrystalline cellulose, magnesium stearate, hypromellose, macrogol, croscarmellose sodium, sodium lauryl sulfate, titanium oxide)
- have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment
- is pregnant or breast-feeding or planning to become pregnant during the study
- have previously completed or withdrawn from this study or any other study of rivaroxaban
- employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1 (Dose Escalation)
The primary safety endpoint is the incidence of clinically significant bleeding (i.e., the presence of TIMI major bleeding, TIMI minor bleeding, or bleeding requiring medical attention)
Stage 2 (Dose Confirmation)
The primary composite endpoint is time to death (all cause), MI (or reMI), stroke (ischemic, hemorrhagic or unknown), or severe recurrent ischemia requiring revascularization through 6 months |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 175 |
| 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
| |
| 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 | 6 |
| 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 | 6 |
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