E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Peripheral artery disease |
|
E.1.1.1 | Medical condition in easily understood language |
Peripheral artery disease |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053375 |
E.1.2 | Term | Peripheral revascularization |
E.1.2 | System Organ Class | 100000004865 |
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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 |
To evaluate whether rivaroxaban added to acetylsalicylic acid (ASA) is superior to ASA alone in reducing the risk of major thrombotic vascular events (defined as myocardial infarction (MI), ischemic stroke, cardiovascular (CV) death, acute limb ischemia (ALI), and
major amputation of a vascular etiology) in symptomatic PAD patients undergoing lower extremity revascularization procedure.
To evaluate the overall safety and tolerability of rivaroxaban added to
ASA compared to ASA alone. |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate whether rivaroxaban + ASA is superior to ASA alone in reducing the risk of MI, ischemic stroke, coronary heart disease
mortality, ALI, and major amputation of a vascular etiology;
- To evaluate whether rivaroxaban + ASA is superior to ASA alone in reducing the risk of an unplanned index limb revascularization for recurrent limb ischemia (subsequent index leg revascularizations that were not planned or considered as part of the initial treatment plan at the time of randomization)
- To evaluate whether rivaroxaban + ASA is superior to ASA alone in reducing the risk of MI, ischemic stroke, all-cause mortality, ALI, and major amputation of a vascular etiology;
- To evaluate whether rivaroxaban + ASA is superior to ASA alone in reducing the risk of vascular hospitalizations for a coronary or peripheral event (either limb) of a thrombotic nature;
See Protocol section 4 for the full list of objectives |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥50
- Documented moderate to severe symptomatic lower extremity atherosclerotic peripheral artery disease
a. clinically, by functional limitations in walking activity, ischemic rest pain, or ischemic ulceration,
b. anatomically, by imaging evidence of peripheral artery disease distal to the external iliac artery in the index leg within 12 months prior to or at the time of the qualifying revascularization
AND
c. hemodynamically in either leg (within 12 months prior to, or at the time of, the qualifying revascularization) by:
* an ABI ≤ 0.80 or TBI ≤ 0.60 for patients without a prior history of limb revascularization,
OR
* an ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a prior history of limb revascularization;
- Technically successful peripheral revascularization distal to the external iliac artery (surgical and/or endovascular; for definition see Section 9.3.3) for symptomatic PAD within the last 10 days prior to
randomization
- Written informed consent by patient or his/her legal representative;
- Patient understands and is willing and able to comply with the study instructions and follow-up visit;
- Negative serum pregnancy test (in women of childbearing potential only);
- Women of reproductive potential must agree to use adequate contraception* when sexually active. This applies for the time period between signing of the informed consent form (ICF) to the last administration of study drug.
(*The definition of adequate contraception [with a failure rate of less than 1% per year] will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to: oral contraceptives, contraceptive injections, intrauterine device, double barrier method, male partner sterilization |
|
E.4 | Principal exclusion criteria |
- Patients undergoing revascularization for asymptomatic PAD or mild claudication without functional limitation of the index leg
- Patients undergoing revascularization of the index leg to treat an asymptomatic or minimally symptomatic restenosis of a bypass graft or target lesion restenosis
- Prior revascularization on the index leg within 10 days of the qualifying revascularization;
- Acute limb ischemia (ALI) within 2 weeks prior to the qualifying revascularization.
- Patients with major tissue loss (defined as significant ulceration/gangrene proximal to the metatarsal heads, i.e. heel or midfoot) in either leg;
Exclusion criteria related to concomitant and study treatment:
- Patients requiring treatment with ASA at doses >100 mg;
- Planned dual antiplatelet therapy (DAPT) use for the qualifying
revascularization procedure of clopidogrel in addition to ASA for >6 months after the qualifying revascularization procedure; it is strongly recommended that any course of clopidogrel is kept to the minimum necessary in accordance with local standard of care and international practice guidelines (typically 30 days, or up to 60 days for some drugcoated products or devices), and is only allowed for up to 6 months for complex procedures or devices that in the investigator's opinion require longer use; see section 8.1 for further guidance on clopidogrel;
- Planned* use of any additional antiplatelet agent other than
clopidogrel and ASA after the qualifying revascularization procedure
(*This exclusion criterion refers to the clinical condition at the time of randomization. The use of DAPT with ASA plus clopidogrel, for new indication(s) occurring after randomization is permitted);
Exclusion criteria related to bleeding risks or systemic conditions:
- Medical history or active clinically significant bleeding, lesions, or conditions within the last 6 months prior to randomization, considered to be a significant risk for major bleeding (this may include current
medically confirmed gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, current or recent brain or spinal injury, known esophageal varices, vascular aneurysms of the large arteries or major intraspinal or intracerebral vascular abnormalities);
Other exclusion criteria:
- Previous (within 30 days) or concomitant participation in another clinical study with investigational product (s);
- Close affiliation with the investigational site; e.g., a close relative of the investigator, dependent person (e.g., employee or student of the investigational site).
- Breast feeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Time from randomization to the first occurrence of any of the following major thrombotic vascular events: MI (Myocardial infarction), ischemic stroke, CV (Cardiovascular) death, ALI (Acute limb ischemia), and major amputation
2. Time from randomization to first occurrence of major bleeding events according to the Thrombolysis in Myocardial Infarction (TIMI) classification |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Time from randomization to first occurrence of an index limb revascularization
2. Time from randomization to the first occurrence of an index limb evascularization (subsequent index leg revascularization that was not planned or considered as part of the initial treatment plan at the time of
randomization)
3. Time from randomization to first occurrence of myocardial infarction, ischemic stroke, all-cause mortality,acute limb
ischemia, and major amputation of a vascular etiology
4. Time from randomization to first occurrence of hospitalization for a coronary or peripheral cause (either lower limb) of a thrombotic nature
5. Time from randomization to first occurrence of myocardial infarction, all-cause stroke, cardiovascular death, acute limb ischemia, and major amputation of a vascular etiology
6. Time from randomization to first occurrence of venous thromboembolic (VTE) events
7. Time from randomization to all-cause mortality |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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.8.2.4 | 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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 234 |
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 |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Slovakia |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Ukraine |
United Kingdom |
United States |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |