E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Edoxaban is being investigated for use in PAD subjects after femoropopliteal endovascular interventions with/without stent placement for the maintenance of patency and prevention of re-intervention. |
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E.1.1.1 | Medical condition in easily understood language |
Circulatory problem in which narrowed arteries reduce blood flow to the limbs causing pain and requiring intervention to open the vessels and allow blood flow and consequently relieving pain. |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067825 |
E.1.2 | Term | Peripheral arterial disease |
E.1.2 | System Organ Class | 100000004866 |
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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 clinically relevant bleeding (i.e., major or clinically relevant nonmajor bleeding) occurring during treatment or within 3 days of interrupting or stopping study drug.
- To evaluate re-stenosis/re-occlusion [defined as peak systolic velocity (PSV) ratio >/= 2.4] at the treated segment(s) measured at 1, 3 and 6 months after randomization using color coded duplex ultrasonography scanning (DUS). |
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E.2.2 | Secondary objectives of the trial |
-To evaluate any bleeding (major, clinically relevant non-major, and minor bleeding) occurring during treatment or within 3 days of interrupting or stopping study drug.
- To evaluate all other clinical and laboratory safety assessments including adverse events (AEs), serious adverse
events (SAEs), and other events of special interest (i.e., hepatic events).
- To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban in PAD subjects. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects older than the minimum legal adult age (country specific);
2. Rutherford stages 2-5 provided there are no ulcerations on the heel
and/or exposed tendon and/or bone;
3. Superficial femoral, above-knee popliteal (3 cm proximal to the medial
femoral condyle) lesion and ≥ 50% stenosis or occlusion;
4. At least one run-off vessel to the foot with or without additional endovascular intervention;
5. Successful intervention, defined as angiographic confirmation of ≤ 30% residual stenosis and absence of flow limiting dissection;
6. Adequate hemostasis at the vascular access site within 24 hours of intervention;
7. A subject is eligible if they have undergone additional successful
endovascular intervention(s) during the index intervention;
8. Able to provide signed informed consent. |
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E.4 | Principal exclusion criteria |
1. Calculated CrCL < 30 ml/min;
2. Femoral or popliteal aneurysm;
3. Adjunctive use of thrombolytics;
4. Any extravasation or distal embolization not successfully treated;
5. Uncontrolled hypertension as judged by the investigator (e.g., systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg
despite antihypertensives);
6. Aspirin intolerance;
7. Clopidogrel intolerance;
8. Contraindication for anticoagulants or antiplatelets and any other contraindication listed in the local labeling of aspirin and/or clopidogrel
(see Appendix 17.8 for US and EU labeling);
9. Active bleeding or known high risk for bleeding or history of intracranial, or spontaneous intraocular, spinal retroperitoneal or intra-articular bleeding; overt gastrointestinal (GI) bleeding or active ulcer within the previous year;
10. Subjects receiving dual antiplatelet or anticoagulant therapy at the time of randomization; subjects receiving pre-interventional loading dose of clopidogrel or other P2Y12 receptor antagonists; see Appendix 17.5. for details;
11. Treatment with cilostazol within 24 hours of randomization;
12. Subjects receiving prohibited concomitant medications [fibrinolytics,
chronic use of non steroidal anti-inflammatory drugs (NSAIDS) > 4 days per week, and oral or parenteral non-aspirin NSAIDs and strong P-gp inhibitors]; see Appendix 17.5 for list of prohibited concomitant medications;
13. Prior stroke or MI or acute coronary syndrome within 3 months;
14. Chronic liver disease [alanine transaminase (ALT) and/or aspartate
transaminase (AST) ≥ 2 × upper limit of normal; total bilirubin (TBL) ≥
1.5 × upper limit of normal]; however, subjects whose elevated TBL is
due to known Gilbert's syndrome may be included in the study;
15. Prior history of a positive test for Hepatitis B antigen or Hepatitis C antibody;
16. Subjects who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period;
17. Subjects previously randomized to an edoxaban (DU-176b) study;
18. Women of childbearing potential without proper contraceptive measures (i.e. a method of contraception with a failure rate < 1 % during the course of the study including the observational period) and women who are pregnant or breast feeding;
Note: These methods of contraception according to the note for guidance on nonclinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner;
19. Subjects with the following diagnoses or situations:
- Active malignancy except for adequately treated non-melanoma skin cancer or other non-invasive or in-situ neoplasm (e.g., cervical cancer in situ);
- Concurrent treatment with cancer therapy (drugs, radiation, and/or surgery);
- Other significant active concurrent medical illness or infection;
- Life expectancy < 12 months;
20. Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study);
21. Subjects with any condition that, in the opinion of the Investigator, would place the subject at increased risk of harm if he/she participated in the study;
22. History of heparin-induced thrombocytopenia. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Endpoint:
The primary safety endpoint is clinically relevant bleeding (i.e., major or clinically relevant non major bleeding) occurring during treatment or within 3 days of interrupting or stopping study drug.
Primary Efficacy Endpoint:
The primary efficacy endpoint is re-stenosis/reocclusion
(as defined by PSV ratio >= 2.4) at the treated segment(s) measured at 1, 3 and 6 months, using color-coded DUS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Safety Endpoint:
During treatment or within 3 days of interrupting or stopping study drug.
Primary Efficacy Endpoint:
measured at 1, 3 and 6 months. |
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E.5.2 | Secondary end point(s) |
· Change in PSV ratio in the treated segment(s) at 3 and 6 months compared to 1 month;
· Change from baseline ABI at 3 and 6 months;
· Rutherford stage at 1, 3 and 6 months;
· Symptomatic acute thrombosis;
· Target lesion revascularization (percutaneous or surgical);
· MACE;
· SEE (fatal and non-fatal)
· All cause mortality;
· Amputations;
· PK: Plasma concentrations of edoxaban and its metabolite (D21-2393) on Days 30 and 90;
· Pharmacodynamics (PD): Plasma concentrations of PD biomarkers on Days 30 and 90 (anti-FXa activity, intrinsic FX, aPTT, PT/INR, D-dimer, sP-selectin, CRP and TGA). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PSV ratio - 3 and 6 months and 1 month - used as comparison
Change from baseline ABI - 1, 3 and 6 months
Rutherford stage - screening, 1, 3 and 6 months
PK – Days 30 and 90
PD – Days 30 and 90
All other secondary endpoints – throughout the study
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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 | 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) | Yes |
E.8.2.2 | Placebo | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Austria |
Belgium |
Germany |
Israel |
Netherlands |
Switzerland |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |