ePAD: Edoxaban in Peripheral Arterial Disease

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01802775
• Collaborator: UMC Utrecht (Other)
• Enrollment: 203
• Locations: 42
• Arms: 2
• Actual Duration (Months): 21.8
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Arterial Disease	Drug: edoxaban; Drug: Clopidogrel; Drug: Aspirin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 203 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Parallel-Group, Multi-Center Study Of Adding Edoxaban Or Clopidogrel To Aspirin To Maintain Patency In Subjects With Peripheral Arterial Disease Following Femoropopliteal Endovascular Intervention
• Actual Study Start Date: Feb 6, 2013
• Actual Primary Completion Date: Dec 3, 2014
• Actual Study Completion Date: Dec 3, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: edoxaban/aspirin Open label edoxaban will be provided. Subjects randomized to this treatment arm will receive edoxaban 60 mg once daily (QD) (two 30 mg tablets) for a total of approximately 3 months on a background of aspirin 100 mg QD.	Drug: edoxaban; Drug: Aspirin
Active Comparator: clopidogrel/aspirin Open label clopidogrel will be provided. Subjects randomized to this treatment arm will receive clopidogrel 75 mg QD (one 75 mg tablet) for a total of approximately 3 months on a background of aspirin 100 mg QD. A loading dose of clopidogrel 300 mg (four 75mg tablets) will be given to subjects as the first dose as early as possible after adequate hemostasis (i.e., within 4 hours of hemostasis).	Drug: Clopidogrel; 75mg tablet; Other Names: Plavix ; Drug: Aspirin

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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 Outcome Measures

1. 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

2. 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.

3. 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

4. Number of Participants With Amputations [within 6 months]

   Number of participants with amputations within 6 months

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 Gilbert"s 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Beverly Hills	California	United States
4		Los Angeles	California	United States
5		Orange	California	United States
6		New Haven	Connecticut	United States
7		Hollywood	Florida	United States
8		Jacksonville	Florida	United States
9		Aurora	Illinois	United States
10		Iowa City	Iowa	United States
11		New Orleans	Louisiana	United States
12		Lewiston	Maine	United States
13		Boston	Massachusetts	United States
14		Flint	Michigan	United States
15		Ypsilanti	Michigan	United States
16		Teaneck	New Jersey	United States
17		New York	New York	United States
18		Raleigh	North Carolina	United States
19		Wilmington	North Carolina	United States
20		Cleveland	Ohio	United States
21		Columbus	Ohio	United States
22		Camp Hill	Pennsylvania	United States
23		Columbia	South Carolina	United States
24		Greenville	South Carolina	United States
25		Austin	Texas	United States
26		San Antonio	Texas	United States
27		Graz		Austria
28		Innsbruck		Austria
29		Wien		Austria
30	Edgem	Edegem		Belgium
31		Ghent		Belgium
32		Leuven		Belgium
33		Bad Krozingen		Germany
34		Leipzig		Germany
35		Afula		Israel
36		Jerusalem		Israel
37		Tel Aviv		Israel
38		Tel Hashomer		Israel
39		Rotterdam		Netherlands
40		Utrecht		Netherlands
41		Bern		Switzerland
42		Zurich		Switzerland

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• UMC Utrecht

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT01802775
• Other Study ID Numbers: DU176b-E-U210; 2012-003009-88
• First Posted: Mar 1, 2013
• Last Update Posted: Feb 26, 2019
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases; Aspirin; Edoxaban; Clopidogrel

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Period Title: Overall Study
STARTED	102	101
Received Drug (Safety Analysis Set)	101	100
COMPLETED	96	89
NOT COMPLETED	6	12

Baseline Characteristics

Arm/Group Title	Clopidogrel	Edoxaban	Total
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin	Total of all reporting groups
Overall Participants	102	101	203
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.7 (8.55)	68 (10.36)	67.4 (9.49)
Age, Customized (Count of Participants)
Adults 18-64 years of age	33 32.4%	30 29.7%	63 31%
From 65 to 84 years of age	68 66.7%	65 64.4%	133 65.5%
85 years of age and over	1 1%	6 5.9%	7 3.4%
Sex: Female, Male (Count of Participants)
Female	24 23.5%	34 33.7%	58 28.6%
Male	78 76.5%	67 66.3%	145 71.4%
Region of Enrollment (Count of Participants)
Austria	13 12.7%	15 14.9%	28 13.8%
Netherlands	5 4.9%	8 7.9%	13 6.4%
Belgium	6 5.9%	9 8.9%	15 7.4%
United States	47 46.1%	42 41.6%	89 43.8%
Israel	7 6.9%	5 5%	12 5.9%
Switzerland	13 12.7%	12 11.9%	25 12.3%
Germany	11 10.8%	10 9.9%	21 10.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Clinically Relevant Bleeding During Treatment
Description	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

Outcome Measure Data

Analysis Population Description

Safety Analysis Set, defined as all participants who received at least one dose of study drug

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	101	100
Including Access Site Bleeding (IASB)	8 7.8%	11 10.9%
Excluding Access Site Bleed (EASB)	6 5.9%	6 5.9%

2. Primary Outcome

Title	Percentage of Participants With First Re-stenosis / Re-occlusion
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	95	94
Number [percentage of participants]	34.7 34%	30.9 30.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clopidogrel, Edoxaban
	Comments	Treatment difference was edoxaban - clopidogrel. For the treatment difference, 95% Confidence interval was calculated using a normal approximation to the binomial distribution.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 95%; -17.3 to 9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment
Description	The percentage of participants with major, clinically relevant non-major, and minor bleeding occurring during treatment, within 3 months
Time Frame	within 3 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set, defined as all participants who received at least one dose of study drug

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	101	100
IASB : Major Bleeding	5 4.9%	1 1%
IASB: CRNM Bleeding	4 3.9%	10 9.9%
IASB: Minor Bleeding	20.8 20.4%	20 19.8%
EASB : Major Bleeding	4 3.9%	1 1%
EASB : CRNM Bleeding	3 2.9%	5 5%
EASB : Minor Bleeding	17.8 17.5%	19 18.8%

4. Secondary Outcome

Title	Safety Assessments
Description	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

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	101	100
Count of Participants [Participants]	30 29.4%	31 30.7%

5. Secondary Outcome

Title	Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period
Description	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

Outcome Measure Data

Analysis Population Description

mITT Set 1 (Safety Analysis Set), defined as the participants who received at least 1 dose of study drug

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	101	100
Count of Participants [Participants]	1 1%	3 3%

6. Secondary Outcome

Title	Number of Participants With Amputations
Description	Number of participants with amputations within 6 months
Time Frame	within 6 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Clopidogrel	Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin	Open-label edoxaban with aspirin
Measure Participants	101	100
Count of Participants [Participants]	3 2.9%	1 1%

Adverse Events

Time Frame	From the first dose to the end of the study (6 months)
Arm/Group Title	Clopidogrel		Edoxaban
Arm/Group Description	Open-label clopidogrel with aspirin		Open-label edoxaban with aspirin
All Cause Mortality
	Clopidogrel		Edoxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/101 (0%)		3/100 (3%)
Serious Adverse Events
	Clopidogrel		Edoxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/101 (29.7%)		31/100 (31%)
Blood and lymphatic system disorders
ANAEMIA	0/101 (0%)		1/100 (1%)
IRON DEFICIENCY ANAEMIA	1/101 (1%)		0/100 (0%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	0/101 (0%)		2/100 (2%)
ANGINA PECTORIS	1/101 (1%)		1/100 (1%)
ATRIAL FIBRILLATION	1/101 (1%)		1/100 (1%)
BRADYCARDIA	1/101 (1%)		1/100 (1%)
CARDIAC FAILURE ACUTE	0/101 (0%)		1/100 (1%)
CARDIO-RESPIRATORY ARREST	0/101 (0%)		1/100 (1%)
CARDIOGENIC SHOCK	1/101 (1%)		0/100 (0%)
CORONARY ARTERY DISEASE	1/101 (1%)		2/100 (2%)
CORONARY ARTERY STENOSIS	0/101 (0%)		1/100 (1%)
Gastrointestinal disorders
INTESTINAL ISCHAEMIA	1/101 (1%)		0/100 (0%)
General disorders
CHEST PAIN	2/101 (2%)		2/100 (2%)
NECROSIS	1/101 (1%)		0/100 (0%)
Hepatobiliary disorders
CHOLELITHIASIS	0/101 (0%)		1/100 (1%)
Infections and infestations
CELLULITIS	0/101 (0%)		1/100 (1%)
CLOSTRIDIUM COLITIS	1/101 (1%)		0/100 (0%)
GANGRENE	1/101 (1%)		2/100 (2%)
INFECTED SKIN ULCER	0/101 (0%)		1/100 (1%)
LOCALISED INFECTION	1/101 (1%)		0/100 (0%)
PNEUMONIA	0/101 (0%)		1/100 (1%)
UROSEPSIS	1/101 (1%)		0/100 (0%)
Injury, poisoning and procedural complications
ARTERIAL RESTENOSIS	0/101 (0%)		1/100 (1%)
FEMUR FRACTURE	0/101 (0%)		1/100 (1%)
PERIPHERAL ARTERY RESTENOSIS	1/101 (1%)		3/100 (3%)
POST PROCEDURAL HAEMATOMA	1/101 (1%)		0/100 (0%)
POST PROCEDURAL HAEMORRHAGE	2/101 (2%)		0/100 (0%)
VASCULAR PSEUDOANEURYSM	0/101 (0%)		4/100 (4%)
WOUND	1/101 (1%)		0/100 (0%)
Metabolism and nutrition disorders
FLUID OVERLOAD	1/101 (1%)		0/100 (0%)
Musculoskeletal and connective tissue disorders
COMPARTMENT SYNDROME	1/101 (1%)		1/100 (1%)
PAIN IN EXTREMITY	1/101 (1%)		1/100 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
LUNG NEOPLASM MALIGNANT	1/101 (1%)		0/100 (0%)
PANCREATIC CARCINOMA METASTATIC	0/101 (0%)		1/100 (1%)
Nervous system disorders
CAROTID ARTERY STENOSIS	1/101 (1%)		0/100 (0%)
HAEMORRHAGIC STROKE	0/101 (0%)		1/100 (1%)
PRESYNCOPE	1/101 (1%)		0/100 (0%)
Psychiatric disorders
ALCOHOL ABUSE	0/101 (0%)		1/100 (1%)
Renal and urinary disorders
HAEMATURIA	0/101 (0%)		1/100 (1%)
RENAL FAILURE ACUTE	0/101 (0%)		1/100 (1%)
RENAL TUBULAR NECROSIS	1/101 (1%)		0/100 (0%)
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/101 (0%)		1/100 (1%)
EPISTAXIS	1/101 (1%)		0/100 (0%)
Skin and subcutaneous tissue disorders
SKIN ULCER	1/101 (1%)		1/100 (1%)
Vascular disorders
FEMORAL ARTERY OCCLUSION	0/101 (0%)		2/100 (2%)
HAEMORRHAGE	0/101 (0%)		1/100 (1%)
HYPERTENSION	1/101 (1%)		0/100 (0%)
INTERMITTENT CLAUDICATION	4/101 (4%)		2/100 (2%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	3/101 (3%)		1/100 (1%)
PERIPHERAL ARTERY STENOSIS	2/101 (2%)		2/100 (2%)
PERIPHERAL ARTERY THROMBOSIS	2/101 (2%)		3/100 (3%)
PERIPHERAL EMBOLISM	1/101 (1%)		0/100 (0%)
PERIPHERAL ISCHAEMIA	2/101 (2%)		1/100 (1%)
Other (Not Including Serious) Adverse Events
	Clopidogrel		Edoxaban
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/101 (22.8%)		32/100 (32%)
Gastrointestinal disorders
Nausea	4/101 (4%)		6/100 (6%)
Injury, poisoning and procedural complications
Post procedural haematoma	3/101 (3%)		6/100 (6%)
Investigations
Creatinine renal clearance decreased	3/101 (3%)		6/100 (6%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/101 (2%)		6/100 (6%)
Pain in extremity	7/101 (6.9%)		9/100 (9%)
Nervous system disorders
Dizziness	1/101 (1%)		5/100 (5%)
Headache	0/101 (0%)		5/100 (5%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	7/101 (6.9%)		7/100 (7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A study site may not publish results of a study until after a coordinated multicenter publication has been submitted for publication or until one year after the study has ended, whichever occurs first. The site may publish the results with proper regard to the protection of subjects' identities, provided that sponsor (including legal and intellectual property) has had the opportunity to review and comment on the proposed publication prior to its being submitted for publication.