Peripheral Arterial Disease
Conditions
Brief summary
This study is a randomized, open-label, blinded endpoint, parallel-group, active-control, multi-center, proof-of-concept study in subjects with Peripheral Arterial Disease (PAD), designed to assess the safety and potential efficacy of adding edoxaban to aspirin following femoropopliteal endovascular intervention, with or without stent placement, relative to current treatment practice with clopidogrel and aspirin.
Interventions
DRUGedoxaban
DRUGClopidogrel
75mg tablet
DRUGAspirin
Sponsors
UMC Utrecht
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects older than the minimum legal adult age (country specific); * Rutherford stages 2-5 provided there are no ulcerations on the heel and/or exposed tendon and/or bone; * Superficial femoral above knee-popliteal ( 3 cm proximal to the medial femoral condyle) lesion and ≥ 50% stenosis or occlusion; * At least one run-off vessel to the foot with or without additional endovascular intervention; * Successful intervention, defined as angiographic confirmation of ≤ 30% residual stenosis and absence of flow limiting dissection; * Adequate hemostasis at the vascular access site within 24 hours of intervention; * A subject is also eligible if they have undergone additional successful endovascular intervention(s) during the index intervention; * Able to provide signed informed consent.
Exclusion criteria
* Calculated Creatinine Clearance \< 30 ml/min; * Femoral or popliteal aneurysm; * Adjunctive use of thrombolytics; * Any extravasation or distal embolization not successfully treated; * Uncontrolled hypertension as judged by the investigator (e.g., systolic blood pressure \> 170 mmHg or diastolic blood pressure \> 100 mmHg despite antihypertensives); * Aspirin intolerance; * Clopidogrel intolerance; * Contraindication for anticoagulants or antiplatelets and any other contraindication listed in the local labeling of aspirin and/or clopidogrel; * 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; * 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; * Treatment with cilostazol within 24 hours of randomization; * Subjects receiving prohibited concomitant medications \[fibrinolytics, chronic use of non steroidal anti-inflammatory drugs (NSAIDS) \> 4 days per week, and oral or parenteral non-aspirin NSAIDs and strong P-gp inhibitors\]; * Prior stroke or myocardial infarction (MI) or acute coronary syndrome within 3 months; * 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 Gilberts syndrome may be included in the study; * Prior history of a positive test for Hepatitis B antigen or Hepatitis C antibody; * 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; * Subjects previously randomized to an edoxaban (DU-176b) study; * 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; * 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; * 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); * 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; * History of heparin-induced thrombocytopenia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically Relevant Bleeding During Treatment | at 3 months | Percentage of participants with clinically relevant bleeding, defined as major bleeding or clinical relevant non-major bleeding, in the on-treatment period based on International Society of Thrombosis and Haemostasis (ISTH) |
| Percentage of Participants With First Re-stenosis / Re-occlusion | within 6 months | Percentage of participants with re-stenosis/re-occlusion during treatment within 6 months - only the first occurrence of re-stenosis / re-occlusion was counted for each participant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | within 3 months | The percentage of participants with major, clinically relevant non-major, and minor bleeding occurring during treatment, within 3 months |
| Safety Assessments | within 6 months | Number of participants with serious adverse events (SAEs) within 6 months Note: Based on changes to the database structure, clinically significant changes in physical or laboratory parameters are recorded as adverse events (AEs). Details of non-serious adverse events are reported at the 5% reporting threshold in the AE module, as is all-cause mortality. |
| Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period | within 6 months | Number of Adjudicated Major Adverse Cardiovascular Events (MACE) which is a composite of non-fatal myocardial infarction (MI), non-fatal stroke and cardiovascular death |
| Number of Participants With Amputations | within 6 months | Number of participants with amputations within 6 months |
Countries
Austria, Belgium, Germany, Israel, Netherlands, Switzerland, United States
Participant flow
Pre-assignment details
A total of 275 subjects were screened, of these 203 subjects were randomized into the study, with 101 subjects in the edoxaban group and 102 subjects in the clopidogrel group.
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel Open-label clopidogrel with aspirin | 102 |
| Edoxaban Open-label edoxaban with aspirin | 101 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Reason not provided | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | Clopidogrel | Edoxaban | Total |
|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 8.55 | 68 years STANDARD_DEVIATION 10.36 | 67.4 years STANDARD_DEVIATION 9.49 |
| Age, Customized 85 years of age and over | 1 Participants | 6 Participants | 7 Participants |
| Age, Customized Adults 18-64 years of age | 33 Participants | 30 Participants | 63 Participants |
| Age, Customized From 65 to 84 years of age | 68 Participants | 65 Participants | 133 Participants |
| Region of Enrollment Austria | 13 Participants | 15 Participants | 28 Participants |
| Region of Enrollment Belgium | 6 Participants | 9 Participants | 15 Participants |
| Region of Enrollment Germany | 11 Participants | 10 Participants | 21 Participants |
| Region of Enrollment Israel | 7 Participants | 5 Participants | 12 Participants |
| Region of Enrollment Netherlands | 5 Participants | 8 Participants | 13 Participants |
| Region of Enrollment Switzerland | 13 Participants | 12 Participants | 25 Participants |
| Region of Enrollment United States | 47 Participants | 42 Participants | 89 Participants |
| Sex: Female, Male Female | 24 Participants | 34 Participants | 58 Participants |
| Sex: Female, Male Male | 78 Participants | 67 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 101 | 3 / 100 |
| other Total, other adverse events | 23 / 101 | 32 / 100 |
| serious Total, serious adverse events | 30 / 101 | 31 / 100 |
Outcome results
Primary
Percentage of Participants With Clinically Relevant Bleeding During Treatment
Percentage of participants with clinically relevant bleeding, defined as major bleeding or clinical relevant non-major bleeding, in the on-treatment period based on International Society of Thrombosis and Haemostasis (ISTH)
Time frame: at 3 months
Population: Safety Analysis Set, defined as all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel | Percentage of Participants With Clinically Relevant Bleeding During Treatment | Including Access Site Bleeding (IASB) | 8 percentage of participants |
| Clopidogrel | Percentage of Participants With Clinically Relevant Bleeding During Treatment | Excluding Access Site Bleed (EASB) | 6 percentage of participants |
| Edoxaban | Percentage of Participants With Clinically Relevant Bleeding During Treatment | Including Access Site Bleeding (IASB) | 11 percentage of participants |
| Edoxaban | Percentage of Participants With Clinically Relevant Bleeding During Treatment | Excluding Access Site Bleed (EASB) | 6 percentage of participants |
Primary
Percentage of Participants With First Re-stenosis / Re-occlusion
Percentage of participants with re-stenosis/re-occlusion during treatment within 6 months - only the first occurrence of re-stenosis / re-occlusion was counted for each participant
Time frame: within 6 months
Population: Modified Intent-to-Treat (mITT), defined as all randomized subjects who received at least one dose of the study study and had at least one post-dose duplex scanning
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clopidogrel | Percentage of Participants With First Re-stenosis / Re-occlusion | 34.7 percentage of participants |
| Edoxaban | Percentage of Participants With First Re-stenosis / Re-occlusion | 30.9 percentage of participants |
Comparison: Treatment difference was edoxaban - clopidogrel. For the treatment difference, 95% Confidence interval was calculated using a normal approximation to the binomial distribution.95% CI: [-17.3, 9.5]
Secondary
Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period
Number of Adjudicated Major Adverse Cardiovascular Events (MACE) which is a composite of non-fatal myocardial infarction (MI), non-fatal stroke and cardiovascular death
Time frame: within 6 months
Population: mITT Set 1 (Safety Analysis Set), defined as the participants who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clopidogrel | Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period | 1 Participants |
| Edoxaban | Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period | 3 Participants |
Secondary
Number of Participants With Amputations
Number of participants with amputations within 6 months
Time frame: within 6 months
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clopidogrel | Number of Participants With Amputations | 3 Participants |
| Edoxaban | Number of Participants With Amputations | 1 Participants |
Secondary
Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment
The percentage of participants with major, clinically relevant non-major, and minor bleeding occurring during treatment, within 3 months
Time frame: within 3 months
Population: Safety Analysis Set, defined as all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB : Major Bleeding | 5 percentage of participants |
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB: CRNM Bleeding | 4 percentage of participants |
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB: Minor Bleeding | 20.8 percentage of participants |
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : Major Bleeding | 4 percentage of participants |
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : CRNM Bleeding | 3 percentage of participants |
| Clopidogrel | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : Minor Bleeding | 17.8 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : CRNM Bleeding | 5 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB : Major Bleeding | 1 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : Major Bleeding | 1 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB: CRNM Bleeding | 10 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | EASB : Minor Bleeding | 19 percentage of participants |
| Edoxaban | Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | IASB: Minor Bleeding | 20 percentage of participants |
Secondary
Safety Assessments
Number of participants with serious adverse events (SAEs) within 6 months Note: Based on changes to the database structure, clinically significant changes in physical or laboratory parameters are recorded as adverse events (AEs). Details of non-serious adverse events are reported at the 5% reporting threshold in the AE module, as is all-cause mortality.
Time frame: within 6 months
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clopidogrel | Safety Assessments | 30 Participants |
| Edoxaban | Safety Assessments | 31 Participants |