Clinical Trials Register

Summary
EudraCT Number:	2011-000430-11
Sponsor's Protocol Code Number:	RFBU11-I
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-12-23
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-000430-11

A.3

Full title of the trial

Minimizing Adverse haemmhorragic events by TRansradial access site and systemic Implementation of angioX (MATRIX)

Accesso Radiale versus Femorale e bivalirudina versus eparina non frazionata con o senza inibitori delle glicoproteine IIb/IIIa come strategia globale per minimizzare le complicanze emorragiche in pazienti con sindrome coronarica acuta soggetti a trattamento invasivo (MATRIX)

A.3.1

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

Minimizing Adverse haemmhorragic events by TRansradial access site and systemic Implementation of AngioX

Accesso Radiale versus Femorale e bivalirudina versus eparina non frazionata con o senza inibitori delle glicoproteine IIb/IIIa per verificare le complicanze emorragiche in pazienti con sindrome coronarica acuta soggetti a trattamento di angioplastica coronarica.

A.3.2

Name or abbreviated title of the trial where available

MATRIX

A.4.1

Sponsor's protocol code number

RFBU11-I

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	G.I.S.E. - SOCIETA'' ITALIANA CARDIOLOGIA INVASIVA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The Medicine Company
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dimensione Ricerca
B.5.2	Functional name of contact point	Maria Salomone
B.5.3	Address:
B.5.3.1	Street Address	Viale Parioli 12
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00197
B.5.3.4	Country	Italy
B.5.4	Telephone number	06 89763854
B.5.5	Fax number	06 80693521
B.5.6	E-mail	m.salomone@dimensione-ricerca.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*EV 10F 250MG
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	Italy
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	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.3.9.2	Current sponsor code	B01AE06
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	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 SODIC
D.3.9.1	CAS number	9005-49-6
D.3.9.4	EV Substance Code	SUB30021
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Real world ACS both Non-ST segment elevation and ST-segment elevation patients undergoing coronary angiography±PCI.

Pazienti con sindrome coronarica acuta (ACS) con o senza elevazione del tratto ST che vengono sottoposti ad angiografia coronarica ± angioplastica (PCI).

E.1.1.1

Medical condition in easily understood language

Patients with ACS, both Non-ST segment elevation and ST-segment elevation undergoing coronary angiography and, if necessary, to PCI.

Pazienti con infarto miocardico acuto con o senza elevazione del tratto ST che vengono sottoposti a coronografia e, se il caso, ad angioplastica coronarica.

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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management. 2) To demonstrate that bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors are associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

Dimostrare che il sito di accesso trans-radiale o l’infusione di bivalirudina rispetto all’accesso femorale o alla terapia standard consistente in eparina non frazionata e utilizzo provisional di inibitori delle glicoproteine IIb/IIIa sono associati ad una minor incidenza dell’endpoint composito di morte, infarto miocardico e ictus entro 30 giorni dalla randomizzazione in pazienti con sindrome coronarica acuta soggetti a trattamento invasivo precoce.

E.2.2

Secondary objectives of the trial

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

PHARMACOGENETIC:
Vers:2
Date:2011/06/07
Title:GENEMATRIX-Customized Choice of P2Y12 oral receptor blocker based on an integration of clopidogrel loss of function allele and phenotype assessment via Point of care testing
Objectives:To demonstrate in ACS patients undergoing early percutaneous intervention that an algorithm to select the most proper oral P2Y12 blocker integrating both gentotype and phenotype information will result in a lower composite endpoint of cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2 or 3 at 1 year follow-up compared to standard of care.

FARMACOGENETICA:
Vers:2
Data:2011/06/07
Titolo:GENEMATRIX-Scelta personalizzata dell’inibitore del recettore piastrinico P2Y12 in base all’integrazione di genotipo (alleli associati a perdita di funzione del citocromo P450-2C19 e della proteina ABCB1) e fenotipo (reattività piastrinica testata con il point-of-care VerifyNow)”
Obiettivi:Dimostrare che in pazienti con Sindrome Coronarica Acuta (SCA) sottoposti a Procedura di Rivascolarizzazione Percutanea (PCI), la scelta dell’inibitore orale del recettore P2Y12 più adeguato, in funzione del genotipo e del fenotipo del paziente, riduce l’incidenza dell’endpoint composito di morte cardiovascolare, re-infarto, ictus e bleeding di tipo 2 o 3 (classificazione BARC) a un anno dalla PCI rispetto allo standard of care.

E.3

Principal inclusion criteria

Patients with all of the following criteria will be eligible: (1) history consistent with new, or worsening ischemia, occurring at rest or with minimal activity; (2) enrolment within 7 days of the most recent symptoms; (3) planned coronary angiography with possible indication to PCI; (4) at least 2 of the following criteria: 1. Aged 60 years or older, 2. Troponin T or I or creatine kinase MB above the upper limit of normal; 3. Electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts; (5)chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block, or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment. 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 P2Y12 receptor blocker such as clopidogrel at a loading dose of 600 mg followed by 75 mg daily or prasugrel at a lading dose of 60 mg followed by 10 or 5 mg daily or ticagrelor (if and when commercially available) at a loading dose of 180 mg followed by 90 mg b.i.d daily. This should be continued as per ESC guidelines (preferably for one year) in all patients. Enrolment of patients will be stratified based on type of ACS (STEMI vs NSTEMI-troponin positive vs. NSTEACS-troponin negative), Intended or ongoing use of prasugrel and final treatment (i.e. PCI vs. non PCI).

Tutti i pazienti con sindrome coronarica acuta (ACS) che vengono sottoposti ad angiografia coronarica ± angioplastica (PCI) saranno arruolati su base consecutiva. ACS con o senza elevazione del tratto ST sono eleggibili ad essere trattate con entrambi i siti di accesso trans-radiale e trans-femorale. Secondo le linee guida della Società Europea di Cardiologia (ESC) tutti i pazienti, per essere inclusi nello studio, devono ricevere non appena logisticamente possibile una dose di: • Aspirina a una dose iniziale di 150-325 mg per via orale (o 250-500 mg IV) seguita da 75-100 mg/die per almeno 1 anno. • un bloccante del recettore P2Y12 come clopidogrel in dose di carico di 600 mg seguita da 75 mg/die o prasugrel in dose di carico di 60 mg seguita da 10 or 5 mg/die. Questo dovrebbe essere continuato come da linee guida ECS (preferibilmente per 1 anno) in tutti i pazienti. L’arruolamento dei pazienti sarà stratificato in base al tipo di ACS (STEMI vs NSTEMI-troponina positiva vs. NSTEACS-troponina negativa), uso pianificato o già iniziatro di prasugrel, operatore che effettua la procedura e trattamento finale (i.e. PCI vs. non PCI).

E.4

Principal exclusion criteria

1. Patients who can not give informed consent or have a life expectancy of <30 days 2. Allergy/intolerance to Bivalirudin or unfractionated heparin. 3. Stable or silent CAD as indication to coronary angiography 4. Treatment with LWMH within the past 6 hours 5. Treatment with any GPI in the previous 3 days 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 12. Randomisation or planned use of other investigational drugs or devices in this trial. 13. Severe uncontrolled hypertension (defined as persistent systolic blood pressure higher than 220 mmHg despite medical treatment). 14. Subacute bacterial endocarditis

1.Pazienti non in grado di dare il consenso informato o con un'aspettativa di vita inferiore ai 30 anni 2.Pazienti con allergia o intolleranza alla bivalirudina o all'eparina non frazionata 3.Pazienti con CAD stabile o silente come indicazione per la Coronografia 4.Pazienti in trattamento con eparina a basso peso molecolare nelle precedenti 6 ore 5. Pazienti in trattamento con GPI nei precedenti 3 giorni 6.Assoluta controindicazione o allergia al liquido di contrasto o ai farmaci in studio inclusi aspirina e/o clopidogrel che non possono essere pre-medicati 7.Controindicazione alla coronografia incluso ma non limitate a malattie vascolari periferiche gravi 8.Donne in gravidanza o allattamento 9.Pazienti con Clearance della creatinina < 30mL/min o in dialisi 10.Pazienti con Ipertensione grave non controllata definita come pressione sistolica persistente > 220 mmHg nonostante l'assunzione di farmaci antipertensivi 11.Pazienti con endocardite batterica acuta 12.Pazienti sottoposti ad angioplastica nei precedenti 30 giorni

E.5 End points

E.5.1

Primary end point(s)

A composite of death, re-infarction (MI) or stroke

End point composito di Morte, re-infarto (MI) o ictus

E.5.1.1

Timepoint(s) of evaluation of this end point

30 Days

30 Giorni

E.5.2

Secondary end point(s)

A composite of death, non-fatal MI, stroke or BARC-defined type 3 and 5 major bleeding complications at 30 days.

L’accesso radiale combinato all’ uso della bivalirudina riduce il tasso di morte, infarto non fatale, ictus o BARC definito di tipo 3 e le complicanze dei sanguinamenti maggiori.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days and 1 year

30 giorni e 1 anno

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

Yes

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	6800
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	6800
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
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 2011-12-23.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	Yes
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	6650
F.4.2	For a multinational trial
F.4.2.1	In the EEA	6700
F.4.2.2	In the whole clinical trial	6800

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

2011-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-01-27

P. End of Trial
P.	End of Trial Status	Ongoing

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