Clinical Trials Register

Summary
EudraCT Number:	2012-000632-26
Sponsor's Protocol Code Number:	TMC-BIV-11-02
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-04
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

Germany - BfArM

A.2

EudraCT number

2012-000632-26

A.3

Full title of the trial

Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3

A.3.1

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

Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3

A.3.2

Name or abbreviated title of the trial where available

BRAVO 2/3

A.4.1

Sponsor's protocol code number

TMC-BIV-11-02

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01651780

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	The Medicines Company
B.1.3.4	Country	Switzerland
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	The Medicines Company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Medicines Company
B.5.2	Functional name of contact point	Global Health Science Center
B.5.3	Address:
B.5.3.1	Street Address	8 Sylvan Way
B.5.3.2	Town/ city	Parsippany
B.5.3.3	Post code	NJ 07054
B.5.3.4	Country	United States
B.5.4	Telephone number	0080084363326
B.5.5	Fax number	+19736561929
B.5.6	E-mail	medical.information@themedco.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	Angiox 250 mg powder for concentrate for solution for injection or infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	The Medicines Company UK Ltd
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.3.4	Pharmaceutical form	Powder for concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BIVALIRUDIN
D.3.9.1	CAS number	128270-60-0
D.3.9.4	EV Substance Code	SUB05862MIG
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	250
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Unfractionated heparin
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Unfractionated Heparin
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Heparin Sodium
D.3.9.1	CAS number	01/08/9041
D.3.9.3	Other descriptive name	HEPARIN SODIUM
D.3.9.4	EV Substance Code	SUB02478MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients undergoing transcatheter aortic valve replacement (TAVR) procedures performed via the transfemoral approach.

E.1.1.1

Medical condition in easily understood language

Patients undergoing transcatheter aortic valve replacement (TAVR) procedures performed through a large artery in the thigh (transfemoral approach)

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10002916
E.1.2	Term	Aortic valve replacement
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of this study is to assess the safety and efficacy of using bivalirudin instead of unfractionated heparin (UFH) in transcatheter aortic valve replacements (TAVR).

E.2.2

Secondary objectives of the trial

There is no secondary objective.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

BRAVO ECONOMIC SUBSTUDY - appended to 'Effect of BivaliRudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)' -
Protocol No. TMC-BIV-11-02 - Version 1 - 14 March 2012
Objective: to assess and compare the in-hospital (index hospitalization) and 30-day costs of patients undergoing TAVR with bivalirudin versus UFH.

BRAVO MRI SUBSTUDY - appended to 'Effect of BivaliRudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)' -
Protocol No. TMC-BIV-11-02 - Version 1 - 14 March 2012
Objective: To compare the rate of new cerebral emboli evident on MRI in patients undergoing TAVR with bivalirudin versus UFH.

E.3

Principal inclusion criteria

Patients may be included in the study if they meet all of the following criteria:
1. ≥ 18 years of age
2. High risk (Euroscore ≥18, or considered inoperable) for surgical aortic valve replacement
3. Undergoing TAVR via transfemoral arterial access
4. Provide written informed consent before initiation of any study related procedures

E.4

Principal exclusion criteria

Patients will be excluded from the study if any of the following exclusion criteria apply prior to enrollment:
1. Any known contraindication to the use of bivalirudin (except presence of severe renal impairment [GFR<30 ml/min] since these patients will be included in the trial - please see protocol section 8.1.1) or UFH
2. Refusal to receive blood transfusion
3. Mechanical valve (any location) or mitral bioprosthetic valve
4. Extensive calcification of the common femoral artery, or minimal luminal diameter < 6.5 mm
5. Use of elective surgical cut-down for transfemoral access
6. Concurrent performance of percutaneous coronary intervention with TAVR
7. International normalized ratio (INR) ≥ 2 on the day of TAVR procedure, or known history of bleeding diathesis
8. History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass or aneurysm, or arteriovenous malformation
9. Severe left ventricular dysfunction (left ventricular ejection fraction<15%)
10. Severe aortic regurgitation or mitral regurgitation (4+)
11. Hemodynamic instability (e.g. requiring inotropic or IABP support) within 2 hours of the procedure
12. Dialysis dependent
13. Administration of thrombolytics, glycoprotein IIb/IIIa inhibitors, or warfarin in the 3 days prior to the procedure
14. Acute myocardial infarction, major surgery or any therapeutic cardiac procedure (other than balloon aortic valvuloplasty) within
30 days
15. Percutaneous coronary intervention within 30 days
16. Upper gastrointestinal or genitourinary bleed within 30 days
17. Stroke or transient ischemic attack within 30 days
18. Any surgery or biopsy within 2 weeks
19. Administration of: a. UFH within 30 minutes of the procedure, b. Enoxaparin within 8 hours of the procedure c. Fondaparinux or other LMWHs within 24 hours of the procedure d. Dabigatran, rivaroxaban or other oral anti-Xa or antithrombin agent within 48 hours of the procedure e. Thrombolytics, GPI, or warfarin within 72 hours of the procedure
20. Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast
21. Contraindications or allergy to aspirin or clopidogrel
22. Known or suspected pregnant women, or nursing mothers. Women of child-bearing potential will be asked if they are pregnant and will be tested for pregnancy.
23. Previous enrolment in this study
24. Treatment with other investigational drugs or devices within the 30 days preceding enrollment or planned use of other investigational drugs or devices before the primary endpoint of this study has been reached

Patients excluded for any of the above reasons may be re-screened for participation at any time if the exclusion characteristic has changed.

E.5 End points

E.5.1

Primary end point(s)

The primary end point will be major bleeding defined as Bleeding Academic Research Consortium (BARC) type ≥3b at 48 hours or hospital discharge whichever occurs first. BARC type 3b bleeding includes bleeds that are evident clinically, or by laboratory or imaging results, which result in in surgical intervention or administration of intravenous vasoactive drugs; overt bleeds with a hemoglobin drop of at least 5g/dL; and bleeding that causes cardiac tamponade. BARC 3c bleeding includes intracranial or intraocular bleeds that compromise vision. BARC type 4, CABG related bleeding, includes perioperative intracranial bleeding within 48 hours; bleeds that result in reoperation following closure of sternotomy for the purpose of controlling bleeding; bleeds that result in treatment with transfusion of ≥5 units of whole blood or packed red blood cells within a 48 hour period; and chest tube output ≥2L within a 24 hour period. BARC type 5, fatal bleeding, describes bleeds that directly result in death with no other cause. The co-primary endpoint will be net adverse cardiac events (NACE) at 30 days that is the composite of major adverse cardiovascular events (MACE) + major bleeding (BARC type ≥3b). The composite of major adverse cardiovascular events (MACE) is defined as all-cause mortality, myocardial infarction, and stroke. All events will be adjudicated using source documents by an independent clinical events committee blinded to the antithrombotic agents. Each component of the co-primary endpoint will be tested in a hierarchical manner with a superiority test for bleeding followed by a non-inferiority and then superiority test for NACE.

E.5.1.1

Timepoint(s) of evaluation of this end point

primary endpoint: 48 hours or prior to hospital discharge (whichever occurs first)
co-primary endpoint: up to 30 days

E.5.2

Secondary end point(s)

The secondary endpoints of this trial are: (1) Major bleeding according to additional scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS); (2) Bleeding BARC ≥3; moderate bleeding BARC = 3a; minor bleeding (BARC type 1 and 2 and TIMI minor); (3) major adverse cardiac events (MACE) including death, non-fatal MI, and stroke; (4) the rates of the individual components of MACE; (5) transient ischemic attack; (6) acute kidney injury; (7) VARC major vascular complications; (8) acquired thrombocytopenia; (9) rate of new post-procedural atrial fibrillation/flutter; and (10) economic analysis of using bivalirudin in TAVR. All end points will be assessed at 48 hours post-procedure (or prior to hospital discharge, if that occurs earlier) and at up to 30-days. With respect to the economic analysis, the analysis timepoint will be fixed to the hospital discharge (but also include any subsequent hospitalizations).

E.5.2.1

Timepoint(s) of evaluation of this end point

48 hours or prior to hospital discharge (whichever occurs first)
and at up to 30 days

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

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

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

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

Canada

Switzerland

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:

261

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

609

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-06-04.

Yes

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

400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

738

F.4.2.2

In the whole clinical trial

870

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)

as per the protocol

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

2012-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-24

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