The aim of this study is to evaluate whether adding edoxaban to aspirin following femoropoplitealendovascular intervention will enable maintenance of vessel patency and prevent restenosisrelative to current treatment with clopidogrel and aspirin.
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate 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.
- To evaluate re-stenosis/re-occlusion [defined as peak systolic velocity
(PSV) ratio >/= 2.4] at the treated segments(s) measured at 1, 3 and 6
months after randomization using color coded duplex ultrasonography
scanning (DUS).
Secondary outcome
- 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
AEs, SAEs, and other events of special interest (i.e., hepatic events).
- To characterize the PK and PD of edoxaban in PAD subjects.
Other objectives
To evaluate:
- Change in the peak systolic velocity (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; for ABI definition, see
Appendix 17.1.2.;
- Rutherford stage at 1, 3 and 6 months; for Rutherford stage classification,
see Appendix 17.1.1.;
- Symptomatic acute thrombosis;
- Target lesion revascularization (percutaneous or surgical);
- MACE (a composite of non-fatal myocardial infarction (MI)/non-fatal
stroke and death from cardiovascular causes);
- Fatal and non-fatal SEE;
- Amputations;
- All cause mortality.
Background summary
The current treatment post-infrainguinal intervention is DAPT [aspirin
indefinitely and
clopidogrel for 1 to 3 months]. However, current practice is not supported by
clinical
trial evidence.
As a consequence of endovascular intervention, platelets adhere to the
subendothelium
that is exposed after dilatation of the artery. The subendothelial collagen
activates
platelets and platelet aggregation is mediated via the fibrinogen receptor GP
IIb/IIIa. In
addition, subendothelial tissue factor (TF) is exposed and forms a complex with
Factor
VIIa (FVIIa) that circulates in plasma, triggering the activation of
coagulation factors and
the formation of fibrin. Thus, inhibition of platelet aggregation as well as
inhibition of
coagulation and fibrin formation may be the optimal strategy to prevent
thrombosis and
subsequent re-stenosis/re-occlusion after endovascular intervention.
Therefore this study proposes to use edoxaban 60 mg QD dosage for 3 months on a
background of aspirin to assess whether this regimen is effective in
maintaining vessel
patency following femoropopliteal endovascular intervention compared to
clopidogrel.
Study objective
The aim of this study is to evaluate whether adding edoxaban to aspirin
following femoropopliteal
endovascular intervention will enable maintenance of vessel patency and prevent
restenosis
relative to current treatment with clopidogrel and aspirin.
Study design
This study is a randomized, open-label, parallel-group, active-control,
multi-center, proof-of-concept study in
subjects with PAD, designed to assess the safety and potential efficacy of
either edoxaban/aspirin or current
treatment practice (dual antiplatelet therapy) with clopidogrel/aspirin
following femoropopliteal
endovascular intervention. Eligible subjects will include those with
symptomatic PAD who have
undergone successful intervention (with or without stent placement). Subjects
will be stratified during
randomization by clinical center/site, intervention with/without stent
placement and by factors requiring
edoxaban dosage adjustment. After confirmation that subjects meet all inclusion
criteria and do not meet any
exclusion criteria, and completion of written informed consent, subjects will
be randomized and dosed as
early as possible after adequate hemostasis (i.e., within 4 hours of
hemostasis) through an interactive
voice/web response system (IXRS) in a 1:1 ratio to either one of the two
treatment arms:
1. Edoxaban 60 mg once daily (QD) on a background therapy of aspirin 100 mg QD
regimen. (See Section 3.2.1.2 for instructions
on dose adjustments), or,
2. Clopidogrel 75 mg QD on a background therapy of aspirin 100 mg QD regimen.
The first dose of edoxaban 60 mg QD will be given as early as possible after
adequate hemostasis (i.e., within
4 hours of hemostasis) and once daily thereafter for 3 months. A loading dose
of clopidogrel 300 mg will be
given as the first dose (i.e., within 4 hours of hemostasis) followed by 75 mg
QD thereafter for 3
months; The subjects will undergo color coded DUS at 1, 3 and 6 months. These
ultrasound images will serve to
establish the primary efficacy endpoint (re-stenosis as defined by PSV ratio >=
2.4) in the treated segments(s)
measured at 1, 3 and 6 months.
Intervention
1. Edoxaban 60 mg once daily (QD) on a background therapy of aspirin 100 mg QD
regimen. (See Section 3.2.1.2 for instructions
on dose adjustments), or,
2. Clopidogrel 75 mg QD on a background therapy of aspirin 100 mg QD regimen.
Study burden and risks
The study takes 180 days ( 6 months) and the patient will be invited to the
clinic 7 times for the purposes of this study. The visits will last
approximately 2 hours. During these visits, the patient will undergo duplex
Ultrasound scans, a physical exam, vital signs will be checked, questions will
be asked, blood and urine will be collected and an electrocardiogram will be
taken.
Edoxaban has a rapid and predictable onset of anticoagulant action. It has the
potential to
be as efficacious as LMWH and vitamin K antagonists because it directly
inhibits FXa.
Additional advantages of edoxaban are that it is an oral agent and thus more
convenient
to use than anticoagulants that require intravenous (IV) or subcutaneous (SC)
injections.
Second, unlike vitamin K antagonists (VKA), edoxaban does not require regular
laboratory monitoring to control its anticoagulant effect and to minimize the
risk of
serious bleeding.
The aim of this study is to evaluate whether adding edoxaban to aspirin
following femoropopliteal
endovascular intervention will enable maintenance of vessel patency and prevent
restenosis
relative to current treatment with clopidogrel and aspirin.
The most common side effects seen with edoxaban are bleeding and changes in
liver blood tests. The most common side-effect of clopidogrel is bleeding, and
uncommonly can result in bleeding inside the head or brain (a rare condition
that causes a stroke or death). Aspirin (acetylsalicylic acid) may have
undesirable side effects. People who are allergic to acetylsalicylic acid, or
have asthma, persisting or recurring stomach problems (such as heartburn, upset
stomach, or stomach pain), ulcers, or bleeding problems should not take
aspirin, unless directed by a doctor.
Chiltern Place, Chalfont Park x
Gerrards Cross, Buckinghamshire SL9 0BG
GB
Chiltern Place, Chalfont Park x
Gerrards Cross, Buckinghamshire SL9 0BG
GB
Listed location countries
Age
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 also eligible if they have undergone additional successful endovascular intervention(s) during the index intervention;
8. Able to provide signed informed consent.
Exclusion criteria
1. Calculated creatinine clearance (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 preinterventional loading dose of clopidogrel or other P2Y12 receptor antagonists;
11. Treatment with cilostazol within 24h 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];
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 (ULN); total bilirubin (TBL) >= 1.5 ×ULN]; 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 thesubject at increased risk of harm if he/she participated in the study;
22. History of heparin-induced thrombocytopenia.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003009-88-NL |
| CCMO | NL42559.101.12 |