Clinical Trials Register

Summary
EudraCT Number:	2008-007290-20
Sponsor's Protocol Code Number:	TMC-BIV-08-03
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-02-16
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

Netherlands - Competent Authority

A.2

EudraCT number

2008-007290-20

A.3

Full title of the trial

European Ambulance Acute Coronary Syndrome Angiox Trial: EUROMAX

A.3.1

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

Comparing the effectiveness of the study drug bivalirudin to the standard of care in patients suffering from heart

A.3.2

Name or abbreviated title of the trial where available

EUROMAX

A.4.1

Sponsor's protocol code number

TMC-BIV-08-03

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 UK Ltd.
B.1.3.4	Country	United Kingdom
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 UK Ltd.
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Krakow Cardiovascular Research Institute
B.4.2	Country	Poland
B.4.1	Name of organisation providing support	DIAGRAM B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	DIAGRAM BV
B.5.2	Functional name of contact point	A. Kloosterman
B.5.3	Address:
B.5.3.1	Street Address	v Nahuysplein 6
B.5.3.2	Town/ city	Zwolle
B.5.3.3	Post code	8011 NW
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031384262996
B.5.5	Fax number	0031384262990
B.5.6	E-mail	a.kloosterman@diagram-zwolle.nl

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
D.2.1.1.2	Name of the Marketing Authorisation holder	The Medicines Company UK Limited
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 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.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	Any unfractionated heparin with marketing authorisation in the Netherlands for anticoagulation in patients with STE-ACS can be used as comparator for this trial
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	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.3.10	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 presenting with ST-Segment Elevation Acute Coronary Syndrome (STE-ACS) planned for a primary Percutaneous Coronary Intervention (PCI) management strategy

E.1.1.1

Medical condition in easily understood language

Patients suffering from heart attack planed for primary Percutaneous Coronary Intervention (PCI) management strategy

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10051592
E.1.2	Term	Acute coronary syndrome
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10041894
E.1.2	Term	ST segment elevation
E.1.2	System Organ Class	100000004848

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 primary objectives of the trial are to show that, when compared with standard anti-thrombotic therapies other than bivalirudin (which includes treatment with unfractionated heparin and optional Glycoprotein IIb/IIIa Inhibitor [GPI]) that at 30 days:
• Bivalirudin is superior to control at reducing a composite of death, re-infarction (Myocardial Infarction [MI]) or non-Coronary Artery Bypass Grafts (CABG)-related protocol major bleeding.

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

ST SEGMENT RESOLUTION SUB-ANALYSIS, appendix to the protocol, same date and version as the protocol.
This sub-study hypothesizes that routine pre-hospital bivalirudin is non-inferior to routine pre-hospital Unfractionated Heparin (UFH) and GPI with regard to the extent of myocardial reperfusion (ST segment resolution) in patients with STE-ACS, intended for treatment with primary PCI.

E.3

Principal inclusion criteria

The decision to randomise patients must be made by a qualified physician or paramedic who is present at the time.
Subjects may be included in the study if they present either via ambulance or to a centre where PCI is not performed and meet all of the following criteria:

1. Provide written informed consent before initiation of any study related procedures. Patients randomised in the ambulance may initially sign an abridged version.
2. Be aged ≥18 years at the time of randomisation.
3. Have a presumed diagnosis of a STE-ACS with onset of symptoms of >20 minutes and <12 hours with one or more of the following:
• ST segment elevation of ≥1 mm in ≥2 contiguous leads
• Presumably new left bundle branch block
• An infero-lateral MI with ST segment depression of ≥1 mm in ≥2 of leads V1-3) with a positive terminal T wave
4. All patients must be scheduled for angiography +/- PCI (if indicated) <2 hours after first medical contact

E.4

Principal exclusion criteria

Subjects will be excluded from the study if any of the following exclusion criteria apply prior to randomisation:
1. Any bleeding diathesis or severe haematological disease or history of intra-cerebral mass, aneurysm, arterio-venous malformation, haemorrhagic stroke, intra-cranial haemorrhage or gastrointestinal or genitourinary bleeding within the last 2-weeks.
2. Patients who have undergone recent surgery (including biopsy) within the last two weeks.
3. Patients on warfarin (not applicable if INR known to be <1.5).
4. Patients who have received UFH, LMWH or bivalirudin immediately before randomisation.
5. Thrombolytic therapy within the last 48 hours.
6. Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast or to any of the study medications including aspirin or clopidogrel.
7. Contraindications to angiography, including but not limited to severe peripheral vascular disease.
8. If it is known pregnant or nursing mothers. Women of child-bearing age will be asked if they are pregnant or think that they may be pregnant.
9. If it is known a creatinine clearance <30 mL/min or dialysis dependent.
10. Previous enrolment in this study.
11. Treatment with other investigational drugs or devices within the 30 days preceding randomisation or planned use of other investigational drugs or devices in this trial.
12. Patients may not be enrolled if the duration of randomised investigational medicinal product (IMP) anti-thrombin infusion is likely to be less than 30 minutes from the time of onset to the commencement of angiography.
13. Patients may not be enrolled within a primary PCI capable hospital (unless at the time of randomisation the catheter laboratory is not available and the patient requires transfer to another primary PCI capable hospital).
14. Estimated body weight of >120 kg.

E.5 End points

E.5.1

Primary end point(s)

• A composite of death, and non-CABG-related protocol major bleeding

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint of this trial at 30 days is:

E.5.2

Secondary end point(s)

• Death or re-infarction (MI) at 30 days
• Death at 30 days and 365 days
• Re-infarction (MI) at 30 days
• IDR at 30 days
• Death, re-infarction (MI) or IDR at 30 days
• Death, re-infarction (MI) or non-CABG-related protocol major bleeding at 30 days
• Major bleeding at 30 days (protocol, TIMI and GUSTO)
• Minor bleeding at 30 days (protocol, TIMI, and GUSTO)
• Incidence of thrombocytopenia post index procedure and at 30 days
• Stent thrombosis (ARC definition) within 30 days
• Stroke at 30 daysARC definition) within at 30 days
• Stroke at 30 days

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days and 365 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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

last visit of the last subject undergoing the trial

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:

1104

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2576

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 2010-02-16.

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

Yes

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

600

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3680

F.4.2.2

In the whole clinical trial

3680

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)

To be included in the study all patients should receive as soon as logistically feasible a European Society of Cardiology (ESC) guideline recommended dose of:
• Aspirin at an initial dose of 150-325 mg orally (or 250-500 mg IV) followed by 75-100 mg/day for at least 1 year.
• A loading dose of an approved P2Y12 receptor blocker such as clopidogrel, prasugrel or ticagrelor that should be continued as per ESC guidelines (preferably for one year) in all patients.

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

2010-02-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-05-31

P. End of Trial
P.	End of Trial Status	Completed

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