Clinical Trials Register

Summary
EudraCT Number:	2014-005569-58
Sponsor's Protocol Code Number:	BAY59-7939/17454
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-26
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2014-005569-58

A.3

Full title of the trial

An international, multicenter, randomized, double-blind, placebo-controlled phase 3 trial investigating the efficacy and safety of Rivaroxaban to reduce the risk of major thrombotic vascular events in patients with symptomatic peripheral artery disease undergoing lower extremity revascularization procedures

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities.

A.3.2

Name or abbreviated title of the trial where available

VOYAGER PAD

A.4.1

Sponsor's protocol code number

BAY59-7939/17454

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bayer AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer AG
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Janssen Research & Development, LLC
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bayer AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	-
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 30 300139003
B.5.6	E-mail	clinical-trials-contact@bayer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xarelto 2.5 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rivaroxaban 2.5mg
D.3.2	Product code	BAY 59-7939
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.2	Current sponsor code	BAY 59-7939
D.3.9.4	EV Substance Code	SUB29263
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10053375
E.1.2	Term	Peripheral revascularization
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

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

E.3

Principal inclusion criteria

- Age ≥50

- Documented moderate to severe symptomatic lower extremity atherosclerotic peripheral artery disease as evidenced by ALL of the following:
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

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

Approximately 2 years

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 revascularization (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

E.5.2.1

Timepoint(s) of evaluation of this end point

Approximately 2 years

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

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

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

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

2210

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

4290

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

480

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3000

F.4.2.2

In the whole clinical trial

6500

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-01-09

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