Clinical Trials Register

Summary
EudraCT Number:	2012-003125-24
Sponsor's Protocol Code Number:	Clopidogrel_NSTEACS
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:	2012-09-21
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

2012-003125-24

A.3

Full title of the trial

Evaluation of platelet functional response in relation to the bioavailability of clopidogrel in patients with acute coronary syndromes without ST-segment elevation (NSTEACS).

Valutazione della risposta funzionale piastrinica in relazione alla biodisponibilita'del Clopidogrel in pazienti con sindrome coronaria acuta senza sopraslivellamento del tratto ST (NSTEACS).

A.3.1

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

Evaluation of platelet functional response in patients with acute coronary syndromes without ST-segment elevation (NSTEACS)treated with clopidogrel.

Valutazione della risposta funzionale piastrinica in pazienti con sindrome coronaria acuta senza sopraslivellamento del tratto ST (NSTEACS) in trattamento con Clopidogrel.

A.4.1

Sponsor's protocol code number

Clopidogrel_NSTEACS

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	A.O. UNIVERSITARIA INTEGRATA DI VERONA
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	Regione Veneto
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	Azienda Ospedaliera Universitaria Integrata Verona
B.5.2	Functional name of contact point	U.O. Medicina Interna C
B.5.3	Address:
B.5.3.1	Street Address	P.le Scuro, 10
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37124
B.5.3.4	Country	Italy
B.5.4	Telephone number	045 8124414
B.5.5	Fax number	045 8027465
B.5.6	E-mail	pietro.minuz@univr.it

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.2.1.2	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	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	CLOPIDOGREL
D.3.9.1	CAS number	113665-84-2
D.3.9.4	EV Substance Code	SUB13395MIG
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	75
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	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.2.1.2	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	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	ASPIRIN
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB20435
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	100
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with acute coronary syndromes without ST-segment elevation (NSTEACS).

Pazienti con sindrome coronaria acuta senza sopraslivellamento del tratto ST (NSTEACS).

E.1.1.1

Medical condition in easily understood language

Unstable coronary condition prone to ischaemic recurrences and other complications that may lead to death or myocardial infarction in the short and long term.

Condizione coronarica instabile con episodi ischemici e altre complicazioni che possono portare a infarto nel breve e lungo termine

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	15.0
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 determine if surrogate pharmacodynamic tests (platelet function tests) predict the bioavailability of thienopyridine drugs as assesses by measuring plasma levels of clopidogrel and its active metabolite at different time points. To define usefulness and timing of pharmacodynamic assessment for the prediction of clopidogrel bioavailability.

Valutare se la biodisponibilità del metabolita attivo clopidogrel, intesa come log(AUC) del metabolita attivo riesca a spiegare l'indice di risposta piastrinica misurato negli istanti temporali diversi da Ts0

E.2.2

Secondary objectives of the trial

To assess whether log (AUC) of the prodrug can explain the index of platelet response measured in time instants different from Ts0; Measurement of pharmacodynamic response as platelet aggregation (AU/min) and PRI (%) at all points of the curve different from Ts0;Determination of the frequency of polymorphic variants of genes CYP2C19, ABCB1 and PON1;Evaluation of the difference in logAUC, PRI and platelet aggregation, in relation to the polymorphic variants of genes CYP2C19, ABCB1 and PON1 at all point of the curve;Measurement of the correlation between maximum intensity of platelet aggregation induced by ADP (AU%/min) and PRI(%);To measure the correlation between intensity of aggregation (AU%/min) at the end of the observation (ts17) , PRI (%) and pharmacokinetic parameters (AUC,logAUC,Cmax,Tmax).

Valutare se log(AUC)del profarmaco riesca a spiegare l'indice di risposta piastrinica misurato negli istanti temporali diversi da Ts0;Determinare la Cmax dei metaboliti attivi a cui si ottiene la max risp funzionale piastrinica in termini di PRI e di aggregazione piastrinica;Determinazione della frequenza delle varianti dei geni CYP2C19,PON1 e ABCB1;Valutare la differenza in termini di logAUC del metabolita attivo, in termini di PRI e differenza in aggregazione piastrinica (AU/min)utilizzando tutti i punti della curva in relazione alle varianti polimorfiche dei geni CYP2C19, PON1 e ABCB1;Misura della correlazione tra massima intensità di aggregazione piastrinica indotta da ADP(%AU/min)e PRI; Misura della correlazione tra intensità di aggregazione a Ts17e PRI;Misura della correlazione tra intensità di aggregazione aTs17 e AUC,logAUC,Cmax,Tmax del profarmaco e del metabolita attivo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects (aged 18 to 75 years) with non–ST-segment elevation ACS (NSTEACS) and GRACE risk score< 140. Patients included must have platelet count ≤450.000/mm3 at presentation

Pazienti: - di età compresa tra i 18 e i 75 anni - con diagnosi di NSTEACS e GRACE score <140 - conta piastrinica <450.000/ mm3

E.4

Principal exclusion criteria

-Cardiogenic shock at recruitment; - Refractory ventricular arhythmias;- Prior Transient Ischemic Attack or Stroke; -Active internal bleeding or history of bleeding diathesis;-Increased bleeding risk for:Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, active peptic ulcer disease, or severe hepatic impairment); arteriovenous malformation, or aneurysm;concomitant use of medications that increase the risk of bleeding as warfarin and fibrinolytic therapy; chronic use of non-steroidal anti-inflammatory drugs [NSAIDS] different from aspirin; CABG; platelet count <100.000/mm3 at presentation; anemia (hemoglobin <10 g/dL) at presentation. - Treatment with clopidogrel during the previous 30 days; -BMI > o = 33; -Intolerance or allergy to aspirin or clopidogrel;-Severe illness with life expectancy less than 1 year;-Test positive for pregnancy (based on a urine or serum pregnancy test) at presentation;-Women who have given birth within the previous 90 d;-Any condition associated with poor treatment compliance, including alcoholism, mental illness (or -Treatment with psychotropic drugs), or drug dependence.- Women of childbearing age not using contraception;- Women during lactation;- Patients in emergency situations;- Subjects incapable of giving legal consent.

-shock cardiogeno al momento del reclutamento -aritmia ventricolare refrattaria -storia positiva per TIA o stroke; diatesi emorragica o sanguinamento in atto; -rischio aumentato di emorragia per: - propensione al sanguinamento (trauma o interventi chirurgici recenti, sanguinamenti gastrointestinali, ulcera peptica o grave disfunzione epatica); -malformazioni arteriovenose o aneurismi noti; - CABG; - Terapia cronica con warfarin, farmaci fibrinolitici, farmaci antinfiammatori non steroidei diversi da aspirina. - Conta piastrinica <100.000/mm3 alla presentazione; - Anemia (Hb<10 g/dL) alla presentazione;- trattamento con clopidogrel nei 30 giorni precedenti-BMI > o = 33; - ipersensibilità o allergia ad aspirina o clopidogrel;- gravi comorbidità con aspettativa di vita <1 anno;- gravidanza (accertata con test su siero alla presentazione);- parto nei 90 giorni precedenti al reclutamento;- qualsiasi condizione associata a mancata compliance (alcolismo, disturbi mentali/psichici (incluso trattamento in atto o recente con psicofarmaci), dipendenza da droghe, altro; - Donne in età fertile che non fanno uso di contraccettivi; - Donne durante l'allattamento; - Pazienti in situazioni di emergenza;- Soggetti incapaci di dare validamente il proprio consenso.

E.5 End points

E.5.1

Primary end point(s)

PRI (%)

E.5.1.1

Timepoint(s) of evaluation of this end point

calculated at each time point (from TS1 to TS17)

calcolato ad ogni istante temporale (da TS1 a TS17)

E.5.2

Secondary end point(s)

1)Maximum intensity of platelet aggregation (%AU/min) induced by ADP and AA calculated from TS0 to TS17 for each test;2)Extent of platelet aggregation at Ts17;3)Cmax (ng/ml),Tmax,AUC of the prodrug,of the active and inactive metabolite;4)Frequency of polymorphic variants of CYP2C19,PON1,ABCB1 gene;5)Concentration (ng/ml) of serum TBX2 measured at TS0, TS6 TS9, TS12, TS15;6)Concentration (pg mg-1 creatinine) of urinary 11-dehydro TXB2 measured at Tu0, TU1, TU2, TU3, TU4

1)Massima intensità di aggregazione piastrinica (%AU/min) indotta da ADP e AA da TS0 a TS17 su ogni test;2)Intensità di aggregazione a Ts17;3)Cmax (ng/ml),Tmax, AUC, log AUC del profarmaco, del metabolita attivo e inattivo;4)Frequenza delle varianti polimorfiche del gene CYP2C19,PON1,ABCB1;5)Concentrazione (ng/ml) di TBX2 sierico misurato a Ts0, Ts6 Ts9, Ts12, Ts15;6) Concentrazione (pg mg-1 creatinina) di 11-deidro TXB2 urinario misurato a Tu0, Tu1, Tu2, Tu3, Tu4

E.5.2.1

Timepoint(s) of evaluation of this end point

1)From TS0 toTS17 for each test,2)Ts17;3)Cmax (ng/ml),Tmax,AUC of the prodrug,of the active and inactive metabolite;4)Frequency of polymorphic variants of CYP2C19,PON1,ABCB1 gene;5)Ts0, Ts6 Ts9, Ts12, Ts15;6)Tu0, Tu1, Tu2, Tu3, Tu4

1)da TS0 a TS17 su ogni test,2)Ts17;3)Cmax (ng/ml),Tmax, AUC, log AUC del profarmaco, del metabolita attivo e inattivo;4)Frequenza delle varianti polimorfiche del gene CYP2C19,PON1,ABCB1;5)Ts0, Ts6 Ts9, Ts12, Ts15;6)Tu0, Tu1, Tu2, Tu3, Tu4

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.7

Trial has a data monitoring committee

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

The study will be considered concluded when all samples have been be collected, laboratory tests performed and data analysed

Lo studio sarà considerato concluso quando tutti i campioni saranno stati raccolti, i test di laboratorio conclusi ed i dati analizzati.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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)

At the end of the study each patients will continue the dual antiplatelet therapy with clopidogrel and aspirin according to the international guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.

Alla fine dello studio i pazienti continueranno la terapia antiaggregante con clopidogrel e aspirina in accordo con le linee guida internazionali per il trattamento delle sindromi coronariche acute in pazienti che non hanno sopraslivellamento del tratto ST persistente.

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

2012-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-12

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

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