Clinical Trials Register

Summary
EudraCT Number:	2015-001574-18
Sponsor's Protocol Code Number:	ESR-14-10076
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-27
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

2015-001574-18

A.3

Full title of the trial

TICAGRELOR IN PATIENTS WITH STABLE ISCHEMIC HEART DESEASE WITH ELEVATION OF TROPONIN

TICAGRELOR NELLA CARDIOPATIA ISCHEMICA STABILE IN PAZIENTI CON ELEVAZIONE DI TROPONINA - STUDIO TICIS

A.3.1

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

TICAGRELOR IN PATIENTS WITH STABLE ISCHEMIC HEART DESEASE WITH ELEVATION OF TROPONIN

TICAGRELOR NELLA CARDIOPATIA ISCHEMICA STABILE IN PAZIENTI CON ELEVAZIONE DI TROPONINA - STUDIO TICIS

A.3.2

Name or abbreviated title of the trial where available

TICIS

A.4.1

Sponsor's protocol code number

ESR-14-10076

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	AZIENDA UNITÀ SANITARIA LOCALE DELLA ROMAGNA
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	AUSL ROMAGNA - U.O. CARDIOLOGIA FORLI
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	AUSL ROMAGNA
B.5.2	Functional name of contact point	U.O CARDIOLOGIA FORLI
B.5.3	Address:
B.5.3.1	Street Address	VIA C. FORLANINI 34
B.5.3.2	Town/ city	FORLI
B.5.3.3	Post code	47121
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0543 735212
B.5.5	Fax number	+39 0543 738640
B.5.6	E-mail	marcello.galvani@auslromagna.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.2.1.1.1	Trade name	BRILIQUE - 90 MG - COMPRESSE RIVESTITE CON FILM - USO ORALE - BLISTER(PVC/PVDC/ALU) 60 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTRAZENECA AB
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.3.1	Product name	Ticagrelor
D.3.2	Product code	B01AC24
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	TICAGRELOR
D.3.9.1	CAS number	274693-27-5
D.3.9.2	Current sponsor code	AZD6140
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	90
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

patients with stable ischemic heart disease with elevation of troponin

PAZIENTI AFFETTI DA CARDIOPATIA ISCHEMICA CRONICA STABILECON AUMEN TO DEI VALORI DI TROPONINA

E.1.1.1

Medical condition in easily understood language

patients with stable ischemic heart disease with elevation of troponin

PAZIENTI AFFETTI DA CARDIOPATIA ISCHEMICA CRONICA STABILECON AUMEN TO DEI VALORI DI TROPONINA

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10055218
E.1.2	Term	Ischemic heart disease
E.1.2	System Organ Class	100000004849

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 reduction of the mean levels of hsTnT concentrations at the end of the study period in patient treated with Ticagrelor.

valutare se nei pazienti con cardiopatia ischemica stabile con danno miocardico il trattamento per 28 giorni con Ticagrelor in associazione a Cardioaspirin ¿ in grado di ridurre i livelli ematici di troponina T ad alta sensibilit¿ rispetto al trattamento con sola Cardioaspirin

E.2.2

Secondary objectives of the trial

- The reduction of the percentage of patients treated with Ticagrelor with hsTnT elevations
- The reduction of the percentage of patients treated with Ticagrelor with hsTnI elevations
- The reduction of the mean levels of hsTnI concentrations at the end of the study period.

- valutare se nei pazienti con cardiopatia ischemica stabile con danno miocardico il trattamento per 28 giorni con Ticagrelor ¿ in grado di ridurre i livelli ematici di troponina I ad alta sensibilit¿.
- valutare la percentuale di pazienti con cardiopatia ischemica stabile con danno miocardico trattati per 28 giorni con Ticagrelor in cui si ha una riduzione dei valori di troponina T ad alta sensibilit¿.
- valutare la percentuale di pazienti con cardiopatia ischemica stabile con danno miocardico trattati per 28 giorni con Ticagrelor in cui si ha una riduzione dei valori di troponina I ad alta sensibilit¿.

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

Other types of substudies
Specify title, date and version of each substudy with relative objectives: We shall explore whether the fall of hsTnT concentrations within the 99th percentile at the end of the study period, both in patients treated with ticagrelor or placebo, is associated with a distinctive plaque morphology at computed tomography (CT) angiography (only in those patients with this examination available at baseline).

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Nei pazienti trattati con Ticagrelor o placebo che eseguiranno la coronaroTc prima dell'arruolamento verr¿ valutato se la riduzione dei valori di Troponina T-hs entro il 99¿ percentile correla con una particolare morfologia della placca aterosclerotica documentata mediante coronaroTc.

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures
2. Female and male aged >18 years
3. Stable exertional angina (Class I or II according to the Canadian Cardiovascular Society classification) without significant variation in the preceding 2 months, associated with objective evidence of myocardial ischemia consisting of ischemia on a stress imaging test with nuclear myocardial perfusion, echo or cardiac
magnetic resonance wall motion, or cardiac magnetic resonance perfusion or with the finding of significant coronary obstructions (>50% reduction of luminal diameter of a major epicardial vessel) on coronary computed tomography angiography (CCTA) or,
4. At least moderate ischemia on a stress imaging test with nuclear myocardial perfusion (=10% myocardium), echo or cardiac magnetic resonance wall motion (=3/16 segments with stress-induced severe hypokinesis or akinesis), or cardiac
magnetic resonance perfusion (=12% myocardium), or the finding of severe
coronary obstructions (>70% reduction of luminal diameter of a major epicardial vessel on CCTA) in patients without symptoms attributable to myocardial ischemia
or,
5. Spontaneous myocardial infarction 1 to 3 years before enrollment, and one of the
following additional high-risk features: age =65 years, diabetes mellitus requiring
medication, a second prior spontaneous myocardial infarction, multivessel coronary
artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance of less than 60 ml per minute.
6. Biochemical evidence of myocardial injury (hsTnT= 14 ng/L in male, =10 ng/L in females).
7. Absence of contra-indications to ticagrelor .
8. Participant is willing to comply with all aspects of the protocol, including adherence to medical therapy and follow-up visits.
9. Treatment with ASA at a dose of 75 to 150 mg daily is mandatory in all patients

Firma del consenso informato
- Età=18 anni
- Angina stabile in assenza di variazioni dei sintomi nei due mesi antecedenti associata a evidenza strumentale di ischemia documentata mediante scintigrafia miocardica o ecostress o RMN cardiaca con stress alla dobutamina, o mediante studio RMN della perfusione miocardica da stress, o documentazione di stenosi del circolo coronarico superiori al 50% mediante coronaroTc; oppure
- Documentazione di ischemia moderata alla scintigrafia miocardica da sforzo (= 10%), all'ecostress/RMN cardiaca con stress farmacologico (=3/16 segmenti con ipocinesia o acinesia indotte da stress farmacologico), o studio RM della perfusione micoardica da stress (=12% del miocardio), o riscontro di stenosi emodinamicamente significative (>70%) alla coronaroTc.
- Evidenza di danno miocardico: valori di troponina T-hs superiori a 14 ng/L negli uomini e superiori a 10 ng/L nelle donne.
- Assenza di controindicazioni al Ticagrelor.
- Volontà del partecipante a rispettare tutti gli aspetti del protocollo, compresa l'adesione alla terapia medica e alle visite di follow-up.
- Terapia con Cardioaspirin alla posologia di 75-150 mg/die.

E.4

Principal exclusion criteria

1- Age >75 years.
2- Clinical heart failure.
2- LV ejection fraction <50% or regional wall motion abnormalities at echocardiography.
3- Severe chronic kidney disease (glomerular filtration rate < 30 ml/min/1.73 m2 measured with the Modification of Diet in Renal Disease (MDRD) Study Equation).
4- Unacceptable level of angina despite maximal medical therapy.
5- Very dissatisfied with medical management of angina.
6- History of noncompliance with medical therapy.
7- Acute coronary syndrome within the previous 6 months.
8- Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) within the previous 12 months.
9- Stroke within the previous 6 months or intracranial hemorrhage at any time.
10- History of ventricular tachycardia requiring therapy for termination, or symptomatic sustained ventricular tachycardia.
11- Planned major surgery necessitating interruption of dual antiplatelet therapy.
12- Need for oral anticoagulation therapy or dual antiplatelet therapy.
13- An increased risk of bradycardia.
14- Concomitant therapy with a strong cytochrome P-450 3A4 inhibitor or inducer.
14- Pregnancy.
15- Inability to comply with the protocol.

Età>75 anni
- Scompenso cardiaco
- Frazione d'eiezione del ventricolo sinistro<50% o presenza di anomalie della cinetica segmentaria all'ecocardiogramma
- IRC di grado severo (VFG<30 ml/min/1.73 mq misurata mediante MDRD, the Modification of Diet in Renal Disease Study Equation)
- Livelli di angina inaccettabili nonostante terapia medica ottimale.
- Persistenza di livelli di angina non soddisfacenti nonostante terapia medica
- Storia di scarsa compliance alla terapia medica.
- Sdr. coronarica acuta nei precedenti sei mesi.
- Angioplastica percutanea o intervento di bypass aortocoronarico nei precedenti 12 mesi.
- Stroke nei precedenti 6 mesi o emorragia intracranica pregressa
- Storia di tachicardia ventricolare interrotta farmacologicamente o mediante DC-shock o storia di tachicardia ventricolare sostenuta sintomatica.
- Intervento di chirurgia maggiore già programmato con necessità di interruzione della duplice terapia antiaggregante orale.
- Necessità di terapia anticoagulante orale o duplice terapia antiaggregante.
- Rischio aumentato di bradicardia.
- Terapia concomitante con inibitore o induttore del citocromo P-450 3A4
- Gravidanza
- Assenza di compliance al protocollo

E.5 End points

E.5.1

Primary end point(s)

It is expected that the mean hsTnT concentration at baseline will be 30 +/- 15 ng/L and that it will decrease to 15 +/- 10 ng/L at the end of the study. This 50% reduction in Tn levels is based on the biological variability of the hsTn assay in stable CAD patients and can be considered clinically meaningful given the long-term biological variability of hsTnT levels as assessed by the reference change value which is 32% for the hsTnT Roche assay as assessed in patients with stable CAD

Nei pazienti trattati con Ticagrelor e Cardioaspirin ci si attende una riduzione del 50% dei valori di medi troponina T-hs rispetto ai valori basali (da 30±15 ng/L a 15±10 ng/L).

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days

28 giorni

E.5.2

Secondary end point(s)

- The reduction of the percentage of patients with hsTnT elevations from 100% at baseline to 50% at the end of the study period.
-The reduction of the percentage of patients with hsTnI elevations from 100% at baseline to 50% at the end of the study period.
- The reduction of the mean levels of hsTnI concentrations at the end of the study period. It is expected that the mean hsTnI concentration at baseline will be 70 +/- 30 ng/L and that it will decrease to 40 +/- 30 ng/L at the end of the study. This 45% reduction can be considered clinically meaningful given the biological variability of Abbott hsTnI levels, as assessed by the reference change value, which is 49% at long term in patients with stable ischemic heart disease

al termine del periodo di studio si attende una riduzione del 50% del numero di pazienti con valori elevati di troponina T-hs;
- al termine del periodo di studio si attende una riduzione del 50% del numero di pazienti con valori elevati di troponina I-hs;
- nei pazienti trattati con Ticagrelor e Cardioaspirin ci si attende una riduzione del 45% dei valori medi di troponina I-hs rispetto ai valori basali (da 70¿30 ng/L a 40¿30 ng/L).

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days

28 giorni

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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)

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

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.8.5.1

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

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

400

F.4.2.2

In the whole clinical trial

400

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)

Usual care for ischemic heart disease

Trattamentl standard della cardiopatia ischemica cronica

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

2016-01-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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