Clinical Trials Register

Summary
EudraCT Number:	2008-003529-17
Sponsor's Protocol Code Number:	ARCADIA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-10-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-003529-17

A.3

Full title of the trial

A PROSPECTIVE, RANDOMIZED, OPEN LABEL, BLINDED END-POINT (PROBE) TRIAL TO EVALUATE WHETHER, AT COMPARABLE BLOOD PRESSURE CONTROL, ACE INHIBITOR THERAPY MORE EFFECTIVELY THAN NON RAS INHIBITOR THERAPY REDUCES CARDIOVASCULAR MORBIDITY AND MORTALITY IN CHRONIC DIALYSIS PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY AND/OR ARTERIAL HYPERTENSION (ARCADIA Study)

Studio prospettico, randomizzato in aperto per valutare se, a livelli paragonabili di controllo pressorio, la terapia con ACE inibitore possa ridurre in maniera piu` efficace rispetto a farmaci non inibitori del sistema renina-angiotensina la mortalita` e la morbidita` cardiovascolare in pazienti in trattamento emodialitico cronico, affetti da ipertrofia ventricolare e/o ipertensione arteriosa

A.3.1

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

Study to assess efficacy of angiotensin converting enzyme inhibitors on mortality and cardiovascular morbidity in patients on chronic hemodialysis, with ventricular hypertrophy and / or hypertension

Studio per valutare l`efficacia dei farmaci inibitori dell`enzima di conversione dell`angiotensina sulla mortalita` e morbidita` cardiovascolare in pazienti in trattamento emodialitico cronico, affetti da ipertrofia ventricolare e/o ipertensione arteriosa

A.3.2

Name or abbreviated title of the trial where available

ARCADIA

A.4.1

Sponsor's protocol code number

ARCADIA

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00985322

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	IST. DI RICERCHE FARMACOLOG. M. NEGRI
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	AIFA (bandi per la ricerca indipendente)
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 di Ricerche Farmacologiche Mario Negri
B.5.2	Functional name of contact point	Lab. att. regolatorie studi clinici
B.5.3	Address:
B.5.3.1	Street Address	via G. Camozzi, 3
B.5.3.2	Town/ city	Ranica
B.5.3.3	Post code	24020
B.5.3.4	Country	Italy
B.5.4	Telephone number	035 45351
B.5.5	Fax number	035 4535371
B.5.6	E-mail	paola.boccardo@marionegri.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	TRIATEC
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS 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	Ramipril
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	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.2.1.1.1	Trade name	TRIATEC
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS 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	Ramipril
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	No
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	TRIATEC
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS 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	Ramipril
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	10
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

End stage renal disease

Insufficienza renale terminale

E.1.1.1

Medical condition in easily understood language

End stage renal disease

Insufficienza renale terminale

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

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	10029151
E.1.2	Term	Nephropathy
E.1.2	System Organ Class	10038359 - Renal and urinary 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 assess whether, at comparable BP control, ACE inhibitor as compared to non-RAS inhibitor therapy reduces the incidence of a combined end-point of CV death (including sudden cardiac death and cardiac arrest resuscitation) and myocardial infarction or non-fatal stroke.

- Valutare se, a livelli paragonabili di controllo pressorio, la terapia con ACE inibitori riduce in modo piu` significativo rispetto alla terapia con farmaci che non agiscono sul Sistema Renina-Angiotensina l`incidenza di end point compositi di morte per eventi cardiovascolari (inclusa la morte improvvisa e ripresa dopo arresto cardiaco) e infarto del miocardio o ictus non fatale.

E.2.2

Secondary objectives of the trial

- To compare the incidence of the single components of the combined end-point, of myocardial or peripheral revascularizations, new onset of atrial fibrillation in one of its three forms (paroxysmal, persistent and permanent) or recurrence of the arrhythmia in patients who experienced paroxysmal or persistent atrial fibrillation previously, hospitalizations for chronic heart failure and thrombosis of the artero-venous fistula. - To evaluate whether ACE inhibitors limit progression or achieve regression of LVH and ameliorate some of the components of the metabolic syndrome and whether these effects correlates with CV outcomes. - To compare the cost/effectiveness of the two treatments.

Obiettivi secondari- Paragonare l`incidenza delle singole componenti degli end point combinati,della rivascolarizzazione del miocardio o periferica,fibrillazione atriale parossistica di nuova insorgenza o persistente,ospedalizzazioni per malattia cardiaca cronica e trombosi della fistola artero-venosa.- Valutare se la terapia con ACE inibitori limita la progressione o permette la regressione di LVH e migliora alcuni dei componenti della sindrome metabolica e se questi effetti correlano con gli outcome cardiovascolari.- Paragonare il rapporto costo/efficacia dei due trattamenti.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Men and women >18 years of age who are on chronic renal replacement treatment since at least 6 months with two or three haemodialysis sessions per week - Hypertension (pre-dialysis systolic and/or diastolic BP >140/90 mmHg or post-dialysis systolic and/or diastolic BP >130/80 mmHg or ongoing antihypertensive therapy) and/or - LVH defined by a cardiac mass index >130 g/m2 for men and 100 g/m2 for women (17) within three months of enrolment. - Written informed consent.

- Uomini e donne di eta` superiore ai 18 anni, che siano sottoposti a emodialisi ( due o tre sedute alla settimana) da almeno sei mesi - Ipertensione (pressione sistolica/diastolica >140/90 mmHg o pressione sistolica/diastolica post-dialisi >130/80 mmHg o terapia antiipertensiva in corso) e/o - Ipertrofia ventricolare sinistra definita come indice di massa cardiaca >130 g/m2 per gli uomini e > 100 g/m2 per le donne nei tre mesi precedenti l`arruolamento nello studio - Consenso informato scritto

E.4

Principal exclusion criteria

- Specific indication (such as heart failure) or contraindication (such as hypersensitivity) to ACE inhibitor therapy. - Any concomitant medication with ACE inhibitors and angiotensin II receptor antagonists - Hyperkalemia (serum potassium >6 mEq/L) despite optimal control of metabolic acidosis and blood glucose (in diabetics) in patient with less then three dialysis sessions per week. - Symptomatic chronic or intradialytic hypotension. - Arrhythmias that in the Investigator judgement might be worsened by hyperkalemia (such as sinus bradycardia, delayed atrio-ventricular conduction, atrio-ventricular blocks). - CV events (stroke, acute myocardial infarction or other acute coronary syndromes) over the last three months. - Uncontrolled hyper- or hypo-thyroidism. - Active systemic disease, malignancies and any clinical condition associated with a life-expectancy of less than 2 years - Drug or alcohol abuse, psychiatric disorders and inability to understand the potential risks or benefits of the study - Pregnancy, lactation or child bearing potential and ineffective contraception

- Specifiche indicazioni (come l`insufficienza cardiaca) o controindicazioni (come l`ipersensibilita`) alla terapia con ACE inibitori - Terapia concomitante con ACE inibitori e antagonisti recettorilai dell`angiotensina II - Iperpotassemia (potassio sierico >6mEq/L) nonostante un controllo ottimale dell`acidosi metabolica e della glicemia (nei diabetici) in pazienti che fanno meno di tre sedute dialitiche alla settimana. - Ipotensione sintomatica cronica o intradialitica - Aritmia che a giudizio del medico potrebbe essere peggiorata dall`iperpotassemia (come bradicardia sinusale, conduzione atrio-ventriculare ritardata, blocco atrio-ventriculare) - Eventi cardiovascolari (ictus, infarto acuto del miocardio o altre sindromi coronariche) negli ultimi tre mesi - Iper- o ipo-tiroidismo non controllati - Patologia sistemica attiva, tumori e qualunque altra condizione clinica che si associ ad un`aspettativa di vita inferiore ai due anni - Uso di droghe o abuso di alcool , malattie psichiatriche e incapacita` a comprendere i potenziali rischi e i benefici derivati dalla partecipazione allo studio; - Gravidanza, allattamento o donne potenzialmente fertili che non facciano uso di un sistema di contraccezione ritenuto scientificamente valido.

E.5 End points

E.5.1

Primary end point(s)

The main outcome variable will be a combined end-point of cardiovascular death (including sudden death and cardiac arrest resuscitation) and myocardial infarction or non-fatal stroke.

L'end point principale sara' un end point combinato di morte cardiovascolare (comprendente la morte improvvisa e la ripresa dopo arresto cardiaco)e l'infarto o l'ictus non fatale.

E.5.1.1

Timepoint(s) of evaluation of this end point

At randomization and then every three months.

Alla randomizzazione e poi ogni 3 mesi.

E.5.2

Secondary end point(s)

- Incidence of the single components of the combined end-point, of myocardial or peripheral revascularizations, new onset of atrial fibrillation2 in one of its three forms (paroxysmal, persistent and permanent) or recurrence of the arrhythmia in patients who experienced paroxysmal or persistent atrial fibrillation previously, hospitalizations for chronic heart failure3 and thrombosis of the artero-venous fistula.

Incidenza delle singole componenti degli end point combinati, della rivascolarizzazione del miocardio o periferica, fibrillazione atriale parossistica di nuova insorgenza o persistente, ospedalizzazioni per malattia cardiaca cronica e trombosi della fistola artero-venosa.

E.5.2.1

Timepoint(s) of evaluation of this end point

At randomization, 12 and 24 months.

Alla randomizzazione, a 12 mesi e a 24 mesi.

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

Yes

E.8.1.7.1

Other trial design description

disegno PROBE

PROBE design

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

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

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:

130

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

136

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

266

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, on the basis of the results, the phisician will evaluate the possibility of treating the patient with an ACE inhibitor.

Al termine dello studio, sulla base dei risultati ottenuti,il medico valutera` la possibilita` di prescrivere al paziente un farmaco ACE inibitore.

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

2008-11-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-10-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-27

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