Clinical Trials Register

Summary
EudraCT Number:	2012-002248-26
Sponsor's Protocol Code Number:	IEOS701/412
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:	2012-09-13
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

2012-002248-26

A.3

Full title of the trial

Prevention of anthracycline-induced cardiotoxicity: a multicentre randomizedtrial comparing two therapeutic strategies.

Prevenzione della cardiotossicita' da antracicline: uno studio multicentrico randomizzato che mette a confronto due strategie terapeutiche.

A.3.1

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

Prevention of anthracycline-induced cardiotoxicity: a multicentre randomizedtrial comparing two therapeutic strategies.

Prevenzione della cardiotossicita' da antracicline: uno studio multicentrico randomizzato che mette a confronto due strategie terapeutiche.

A.3.2

Name or abbreviated title of the trial where available

ICOS_ONE

A.4.1

Sponsor's protocol code number

IEOS701/412

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	ISTITUTO EUROPEO DI ONCOLOGIA
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	Ricerca finalizzata Ministero della Salute
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Fondazione Umberto Veronesi
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	ISTITUTO EUROPEO DI ONCOLOGIA
B.5.2	Functional name of contact point	Ufficio studi clinici
B.5.3	Address:
B.5.3.1	Street Address	via Ramusio 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20141
B.5.3.4	Country	Italy
B.5.4	Telephone number	02 57 48 98 48
B.5.5	Fax number	02 57 48 97 81
B.5.6	E-mail	ufficio.studiclinici@ieo.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	NAPRILENE*28CPR 5MG
D.2.1.1.2	Name of the Marketing Authorisation holder	SIGMATAU IND.FARM.RIUNITE SpA
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	ENALAPRIL MALEATE
D.3.9.1	CAS number	76095-16-4
D.3.9.4	EV Substance Code	SUB01884MIG
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	5
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	Yes
D.3.11.13.1	Other medicinal product type	prodotto di sintesi
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.2.1.1.1	Trade name	CARDICOR*28CPR RIV 2,5MG
D.2.1.1.2	Name of the Marketing Authorisation holder	RECORDATI SpA
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	BISOPROLOL HEMIFUMARATE
D.3.9.1	CAS number	66722-45-0
D.3.9.4	EV Substance Code	SUB31068
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	2.5
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	Yes
D.3.11.13.1	Other medicinal product type	prodotto di sintesi
D.IMP: 3
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	TAREG*14CPR RIV 40MG PVC/PE/PV
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
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	VALSARTAN
D.3.9.1	CAS number	137862-53-4
D.3.9.4	EV Substance Code	SUB00017MIG
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	40
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	Yes
D.3.11.13.1	Other medicinal product type	prodotto di sintesi

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

Anthracycline-‐induced cardiotoxicity

Cardiotossicità da antracicline

E.1.1.1

Medical condition in easily understood language

Possible cardiac damage caused by anthracyclines (a class of drugs used in cancer chemotherapy)

Possibili danni cardiaci causati dal trattamento antitumorale con farmaci della famiglia delle antracicline.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10008444
E.1.2	Term	Chemotherapy cardiotoxicity attenuation
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 primary objective of the study is to assess whether enalapril started concomitantly to anthracycline therapy can prevent cardiac toxicity more effectively than when enalapril is prescribed to selected patients showing laboratory evidences of cardiac injury after chemotherapy.

Valutare se un trattamento con enalapril somministrato dall’inizio della terapia con antracicline è più efficace nel prevenire la tossicità̀ cardiaca rispetto ad un trattamento cominciato in conseguenza all'innalzamento della troponina cardiaca.

E.2.2

Secondary objectives of the trial

Secondary objectives will be the reduction of admissions to hospital for cardiovascular causes; deaths for cardiovascular causes. Differences between the two study groups in the following continuous variables will be also assessed: (1) cardiac structural and functional variables by echocardiography (in all patients), by Magnetic Resonance Imaging (in a subgroup); (2)biomarkers such as NT-‐pro BNP, PTX- ‐3. Quality of life of patients will be also assessed.

Obiettivi secondari dello studio sono la riduzione dei ricoveri ospedalieri e le morti per cause cardiovascolari. Verranno inoltre valutate variabili strutturali e funzionali cardiache tramite ecocardiografia (in tutti i pazienti), tramite risonanza magnetica (in un sottogruppo); verranno valutati biomarcatori come la NT-‐pro BNP e PTX3, e la qualità di vita dei pazienti oncologici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age equal to or greater than 18years; 2. Patients with any of the following diagnosis of cancer: acute leukemia, Non-‐Hodgkin lymphoma, Hodgkin’s lymphoma, breast cancer, sarcoma; 3. Indication for first-‐and second-‐line therapy with anthracyclines; 4. Serum creatinine<177μmol/L (2mg/100mL); 5. Systolic blood pressure>100mmHg and <170mmHg; 6. LVEF>50%; 7. Written informed consent;

1. Età maggiore o uguale di 18 anni all’arruolamento; 2. Presenza di una delle seguenti neoplasie: leucemia mieloide acuta dell'anziano, linfoma aggressivo, neoplasia della mammella o sarcoma; 3. Indicazione al trattamento con antracicline; 4. Creatinina plasmatica <177μmol/L (2mg/100mL); 5. Pressione arteriosa sistolica (PAS)>100mmHg e <170mmHg; 6. Frazione di eiezione del ventricolo sinistro (LVEF)> 50%; 7. Il paziente ha firmato il modello di consenso informato;

E.4

Principal exclusion criteria

1. History or clinical/instrumental evidences of heart failure and/or ischemic heart disease; 2. Plasma supranormal concentrations of cardiac troponin (i.e. higher than the cut-‐off recommended by the manufacturer); 3. Systolic blood pressure<100mmHg; 4. Heart rate<50 bpm; 5. Prior malignancy requiring chemotherapy; 6. Uncontrolled hypertension defined as systolic blood pressure>170mmHg; 7. Treatment with ACEi or BB within 4 weeks prior to study start; 8. Known intolerance to enalapril, except for cough; 9. Planned treatment with dexaroxane; 10. Participation in another experimental drug trial within 4 weeks prior to study start; 11. Non-‐co-‐operative behaviour or suspected poor compliance; 12. Pregnancy or breast feeding; 13. Scheduled mediastinal radiotherapy

1. Storia evidenze clinico-strumentali di insufficienza cardiaca e/o cardiopatia ischemica; 2. Livelli plasmatici sovranormali di troponina cardiaca (cioè superiori ai valori massimi di normalità forniti dal produttore); 3. Pressione arteriosa sistolica<100 mmHg; 4. Frequenza cardiaca < 50 bpm; 5. Pregresso trattamento antitumorale chemioterapico; 6. Ipertensione incontrollata (PAS >170mmHg); 7. Trattamento con ACEi e BB nelle 4 settimane antecedenti alla randomizzazione; 8. Intolleranza verso Enalapril; 9. Trattamento prestabilito con Dexaroxane; 10. Partecipazione ad un altro studio sperimentale nelle 4 settimane antecedenti alla randomizzazione; 11. Evidenti segni di potenziale bassa compliance; 12. Gravidanza o alattamento; 13. Programmato trattamento radioterapico in sede mediastinica

E.5 End points

E.5.1

Primary end point(s)

Time to first elevation of cTn concentration above the cut-‐off recommended by the manufacturer, over a follow up of 1 year from the end of CT.

Prima occorrenza di innalzamento della cTn oltre il valore soglia raccomandato dal produttore nell'arco di un anno dopo la fine della chemioterapia

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year, starting from the end of the last cycle of chemotherapy.

1 anno a partire dall'ultimo ciclo chemioterapico

E.5.2

Secondary end point(s)

Changes over time in a. left ventricular function; b. NT-‐proBNP, cTn; c. PTX3.

Variazioni nel tempo di a. funzione del ventricolo sinistro; b. NT-‐proBNP, cTn; c. PTX3.

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year, starting from the end of the last cycle of chemotherapy.

1 anno a partire dall'ultimo ciclo chemioterapico

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

STESSO FARMACO INIZIATO DOPO L'AUMENTO DI Tn

SAME DRUG ADMINISTERED AFTER Tn ELEVATION

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

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

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

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:

128

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

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

Yes

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

268

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)

ROUTINE CARE

NORMALI PROGRAMMI DI ASSISTENZA

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

2012-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-11

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

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