E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of stroke and non-CNS systemic embolism in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention |
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E.1.1.1 | Medical condition in easily understood language |
Nonvalvular atrial fibrillation patients who undergo percutaneous coronary intervention procedure |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
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 |
The primary objective of this study is to assess the safety of 2 rivaroxaban treatment strategies and a dose-adjusted VKA treatment strategy after PCI (with stent placement) in subjects with paroxysmal, persistent, or permanent non-valvular AF, based on the composite of TIMI major bleeding, minor bleeding, and bleeding requiring medical attention events (known collectively as clinically significant bleeding) after 12 months of therapy. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to explore the differences between the treatment strategy groups in
terms of:
TIMI major bleeding, minor bleeding, and bleeding requiring medical attention events
the composite and each component of adverse cardiovascular events (cardiovascular death, MI, and stroke)
stent thrombosis events
TIMI major bleeding, minor bleeding, and bleeding requiring medical attention events, and the composite and each component of adverse cardiovascular events (cardiovascular death, MI, stroke) at the end of intended DAPT period |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Have a documented medical history of paroxysmal, persistent, or permanent non-valvular AF
Have undergone PCI procedure (with stent placement) for primary atherosclerotic disease
Be willing and able to adhere to the prohibitions and restrictions specified in this protocol
If a woman, before entry she must be:
- Postmenopausal, defined as
>45 years of age with amenorrhea for at least 18 months
- Menstrual
a. Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
b. If heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel), or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study, or
c. Not heterosexually active
Note: women who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study.
Women must agree to continue using these methods of contraception throughout the study.
If a woman of childbearing potential, she must have a negative urine β-human chorionic gonadotropin (-hCG)] pregnancy test at screening. Serum pregnancy testing may be performed if required by local regulation. |
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E.4 | Principal exclusion criteria |
1. Has 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 before randomization
● platelet count <90,000/μL at screening or prerandomization
● history of intracranial hemorrhage
● clinically significant gastrointestinal bleeding within 12 months before randomization
● except for subjects who are taking a VKA at the time of screening, a PT or INR test result that is higher than the upper limit of normal at the time of screening or prerandomization that suggests underlying coagulation disorder
● any other condition known to increase the risk of bleeding
● INR does not drop to 2.5 or below by 72 hours after sheath removal following the index PCI procedures
2. Has a history of stroke or TIA
3. Has cardiogenic shock at the time of randomization
4. Has ventricular arrhythmias refractory to treatment at the time of randomization
5. Has calculated CrCl <30 mL/min at screening or prerandomization
6. Has known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis), or liver function test (LFT) abnormalities at screening (confirmed with repeat testing): alanine transaminase (ALT) >5 times the upper limit of normal or ALT >3 times the upper limit of normal plus total bilirubin >2 times the upper limit of normal
7. Has anemia of unknown cause with a hemoglobin level <10 g/dL (<6.21 mmol/L) at screening or prerandomization
8. Has a known clinical history of human immunodeficiency virus (HIV) infection
9. Has a current substance abuse (drug or alcohol) problem or a history within the previous 6 months
10. Has any severe condition that would limit life expectancy to less than 12 months
11. Has had major surgery, biopsy of a parenchymal organ, or serious trauma (including head trauma) within the past 30 days.
12. Has a suspected or documented stent thrombosis during the index procedure
OR
Has a PCI with stent placement for a previously stented lesion (stent within a stent) during the index procedure or within the previous 12 months
13. Has an incomplete staged PCI procedure (once the completion of the staged procedure has occurred, the final PCI may become the index event and is allowed)
14. Has a CABG planned
16. Has contraindications to the use of VKAs, ASA, or P2Y12 platelet inhibitors (clopidogrel, prasugrel, or ticagrelor), per prescribing information.
17.Has transient AF caused by a reversible disorder (eg, thyrotoxicosis, pulmonary embolism, recent surgery)
18. Has condition(s) other than paroxysmal, persistent, or permanent non-valvular AF requiring long-term anticoagulation with VKAs during the conduct of the study, including but not limited to moderate to severe mitral valve stenosis, mechanical heart valves, deep vein thrombosis, pulmonary embolism, or left ventricular thrombus
19. Is receiving systemic treatment with strong inhibitors of both CYP3A4 and p-glycoprotein (P-gp; eg, the azole-antimycotic ketoconazole and the HIV-protease inhibitor ritonavir). Treatment with the azole-antimycotic fluconazole is allowed.
20. Has known allergies, hypersensitivity, or intolerance to rivaroxaban or its excipients (refer to Investigator's Brochure)
21. Uses disallowed therapies.
22. Has an anticipated need for chronic (more than 4 weeks) therapy with nonsteroidal anti-inflammatory drugs
23. Has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study drug or is currently enrolled in an investigational study
24. Is a woman who is pregnant or breast-feeding or planning to become pregnant while enrolled in this study
25. Has any active malignancy
26. Has any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments
27. Is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, 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) |
The primary safety endpoint for this study is the occurrence of the composite of TIMI major bleeding, minor bleeding, and bleeding requiring medical attention events (known collectively as clinically significant bleeding) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Percutaneous Coronary Intervention procedure to Month 12. |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints for this study are the proportions of subjects at the end of DAPT and at
Month 12 with the following events:
· Each component of the TIMI clinically significant bleeding composite (TIMI major bleeding, minor bleeding, and bleeding requiring medical attention)
· The composite of adverse cardiovascular events (cardiovascular death, MI, and stroke)
· Cardiovascular death
· Myocardial infarction
· Stroke
· Stent thrombosis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Percutaneous Coronary Intervention procedure to the end of DAPT period (by prespecified duration of 1, 6, or 12 months) and at Month 12. |
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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 | 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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Vitamin K Antagonist (VKA) |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 150 |
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 | No |
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 |
Argentina |
Belgium |
Canada |
Chile |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Russian Federation |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |