A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Multicenter Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with a Recent Acute Coronary Syndrome The ATLAS ACS 2 TIMI 51 Trial (The second trial of Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome) Amendment INT-2 - The ATLAS ACS 2 TIMI 51 Trial

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2008-002708-25-BG
• Date of registration: 26/01/2009
• Prospective Registration: No
• Primary sponsor: Janssen-Cilag International N.V.
• Public title: A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Multicenter Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with a Recent Acute Coronary Syndrome The ATLAS ACS 2 TIMI 51 Trial (The second trial of Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome) Amendment INT-2 - The ATLAS ACS 2 TIMI 51 Trial
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Multicenter Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with a Recent Acute Coronary Syndrome The ATLAS ACS 2 TIMI 51 Trial (The second trial of Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome) Amendment INT-2 - The ATLAS ACS 2 TIMI 51 Trial
• Date of first enrolment: 22/01/2009
• Target sample size: 16000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-002708-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Belgium, Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Latvia, Lithuania, Netherlands, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
Potential subjects must satisfy the following criteria to be enrolled in the study:
• Man or woman 18 years of age or older
• Currently receiving ASA therapy (75 to 100 mg/day) alone or in combination with a thienopyridine (clopidogrel or ticlopidine per national dosing recommendation)
• Have been hospitalized for symptoms suggestive of ACS that lasted at least 10 minutes at rest, and occurred 48 hours or less before hospital presentation or who develop ACS while being hospitalized for indication other then ACS,and have a diagnosis of:
– STEMI:
elevation of ST-segment more than 0.1 millivolt (mV) in 2 or more continuous ECG leads, or new left bundle branch block, or ST segment depression 0.1 mV or greater in 2 of the precordial leads V1-V4 with evidence suggestive of true posterior infarction, all with elevated biomarkers of myocardial necrosis (creatinine kinase muscle and brain isoenzyme [CK-MB] or troponin)
– NSTEMI:
Elevated biomarkers of myocardial necrosis (creatinine kinase-muscle and brain isoenzyme [CK-MB] or troponin) plus one of the following:
- Transient ST-segment elevation, or ST-segment depression, or T wave changes consistent with myocardial ischemia,
or
- Identification of a culprit lesion at angiography demonstrating recent, active, intracoronary athero-thrombosis (for example, thrombus or an ulcerated plaque)
– UA with at least 1 of the following:
– transient or persistent ST-segment deviation 0.1 mV or greater in 1 or more ECG leads
or
– TIMI risk score of =4.
• Subjects who are 18 to 54 years of age inclusive must also have either diabetes mellitus or a prior MI in addition to the presenting ACS event.
• Women must be:
– postmenopausal (for at least 2 years), or
– surgically sterile, (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
– abstinent (at the discretion of the investigator/per local regulations), or
– if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study.
• Women of childbearing potential must have a negative urine ß-human chorionic gonadotropin (ß-hCG) pregnancy test at screening. Serum pregnancy testing may be performed if required by local regulation.
• Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Bleeding risk
• Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding, such as, but not limited to, the following:
– 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 screening
– history of intracranial hemorrhage
– major surgery, biopsy of a parenchymal organ, or serious trauma within 30 days before randomization
– clinically significant gastrointestinal bleeding within 12 months before randomization
– have an International Normalized Ratio (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

Severe concomitant diseases such as:
• Cardiogenic shock at the time of randomization
• Ventricular arrhythmias refractory to treatment at the time of randomization
• Calculated creatinine clearance <30 mL/min at screening
• Known significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis), or liver function test (LFT) abnormalities (confirmed with repeat testing) which would require study drug discontinuation, i.e., ALT >5 x ULN or ALT >3 x ULN plus total bilirubin >2 x ULN
• A prior ischemic stroke or TIA in subject who are planned to be included in stratum 2 (ASA plus thienopyridine). (Note: Subjects with a prior ischemic stroke or TIA are eligible for inclusion in the study only if they are intended to be treated with ASA only). Subjects with prior hemorrhagic stroke are excluded completely from the study.
• Anemia (i.e., hemoglobin <10 g/dL) at screening
• Known clinical history of HIV infection at screening
• Substance abuse (drug or alcohol) problem within the previous 6 months
• Any severe condition that would limit life expectancy to less than 6 months

General:
• Systemic treatment with strong CYP 3A4 and P-gp inhibitors (e.g., certain azoleantimycotics, such as ketoconazole and HIV protease inhibitors, such as ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp.
•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)
• Known aspirin allergy
• Atrial fibrillation excluded except for the subjects younger than 60 years of age who have no clinical or echocardiographic evidence of cardiopulmonary disease and who had only a single episode of atrial fibrillation that occurred more than 2 years ago.
• Other conditions requiring long-term anticoagulation
• Use of disallowed therapies (see Section 8, Prestudy and Concomitant Therapy)
• Received an investigational drug or used an investigational medical device within 30 days before the planned start of treatment, or are currently enrolled in an investigational study
• Anticipated need for chronic (more than 4 weeks) therapy with non steroidal anti-inflammatory drugs (NSAIDs)
• Is pregnant or breast-feeding or planning to become pregnant during the study
• Have previously completed or withdrawn from this study
• Any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subjec

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Acute Coronary Syndrome (ACS)
MedDRA version: 13.1 Level: PT Classification code 10051592 Term: Acute coronary syndrome System Organ Class: 10007541 - Cardiac disorders

Intervention(s)

Product Name: Rivaroxaban
Product Code: Bay 59-7939 (JNJ-39039039)
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Rivaroxaban
CAS Number: 366789-02-8
Current Sponsor code: BAY 59-7939 (JNJ-39039039)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Rivaroxaban
Product Code: Bay 59-7939 (JNJ-39039039)
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Rivaroxaban
CAS Number: 366789-02-8
Current Sponsor code: Bay 59-7939 (JNJ-39039039)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5.0-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): The primary objective of the study is to determine whether rivaroxaban in addition to standard care reduces the risk of the composite of CV death, MI, or stroke in subjects with a recent ACS compared with placebo in addition to standard care.

Secondary Objective: • To determine whether rivaroxaban reduces the risk of the composite of all cause death, MI, or stroke in subjects with a recent ACS compared with placebo in addition to standard care
• To examine the effect of rivaroxaban on net clinical outcome, defined as the composite of CV death, MI, ischemic stroke, or a Thrombolysis in Myocardial Infarction (TIMI) major bleeding event not associated with coronary artery bypass graft (CABG) surgery
• To determine whether rivaroxaban reduces the risk of the composite of CV death, MI, stroke, or severe recurrent ischemia requiring revascularization in subjects with a recent ACS compared with placebo in addition to standard care
• To determine whether rivaroxaban reduces the risk of the composite of CV death, MI, stroke, or severe recurrent ischemia leading to hospitalization in subjects with a recent ACS compared with placebo in addition to standard care

Main Objective: The primary objective of the study is to determine whether rivaroxaban in addition to standard care reduces the risk of the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke in subjects with a recent ACS compared with placebo in addition to standard care.

Secondary ID(s)

RIVAROXACS3001 (BAY59-7939/13194)

2008-002708-25-SE