Clinical Trials Register

Summary
EudraCT Number:	2015-000413-48
Sponsor's Protocol Code Number:	HOMAGE_2015.03.30
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:	2021-01-19
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

2015-000413-48

A.3

Full title of the trial

Bioprofiling response to mineralocorticoid receptor antagonists for the prevention of heart failure. A proof of concept clinical trial within the EU FP
7 "HOMAGE" programme ¿ Heart OMics in AGing

Risposta del profilo biologico agli antagonisti dei recettori dei mineralcorticoidi per la prevenzione dello scompenso cardiaco. Un programma di studio clinico di fattibilit¿ nei FP 7 UE ¿Heart OMics in
AGing¿ (HOMAGE)

A.3.1

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

HOMAGE Study. An European multicenter study in patients with heart failure risks under spironolactone

Studio HOMAGE. Studio multicentrico in Europa in pazienti con rischi di insufficenza cardiaca in trattamento con spironolattone

A.3.2

Name or abbreviated title of the trial where available

HOMAGE

A.4.1

Sponsor's protocol code number

HOMAGE_2015.03.30

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	ACS BIOMARKER
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ACS BIOMARKERS
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ACS Biomarker
B.5.2	Functional name of contact point	Sylvia Van Aren
B.5.3	Address:
B.5.3.1	Street Address	Oxfordlaan 70
B.5.3.2	Town/ city	Maastricht
B.5.3.3	Post code	6229
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 3949 7830
B.5.5	Fax number	+31 3949 7830
B.5.6	E-mail	sylvia.vanharen@acsbiomarker.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	SPIRONOLATTONE 1A PHARMA - 50 MG COMPRESSE 10 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	1A PHARMA S.R.L.
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	spironolattone
D.3.2	Product code	C03DA01
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	SPIRONOLATTONE
D.3.9.2	Current sponsor code	spironolattone
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	25
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

pazienti anziani con rischio cardiovascolare

Pazienti anziani con fattori di rischio clinici e biologici di sviluppo di scompenso cardiaco

E.1.1.1

Medical condition in easily understood language

pazienti anziani con rischio cardiovascolare

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	SOC
E.1.2	Classification code	10007541
E.1.2	Term	Cardiac disorders
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 investigate whether spironolactone can favourably alter extra-cellular
matrix remodelling, assessed by changes in the fibrosis biomarker
Procollagen Type III N-Terminal Peptide (PIIINP), in patients at
increased risk of developing heart failure and whether this effect is
greater in patients with increased plasma concentrations of Gal-3.
Italian Verificare se lo spironolattone pu¿ alterare favorevolmente il
rimodellamento della matrice extracellulare, valutato in base ai
cambiamenti del biomarcatore della fibrosi procollagene di tipo III Nterminale
del peptide (PIIINP), nei pazienti ad aumentato rischio di
sviluppare scompenso cardiaco e se questo effetto ¿ maggiore nei
pazienti con concentrazioni plasmatiche aumentate di Gal-3.

Verificare se lo spironolattone pu¿ alterare favorevolmente il rimodellamento della matrice extracellulare, valutato in base ai cambiamenti del biomarcatore della fibrosi procollagene di tipo III N-terminale del peptide (PIIINP), nei pazienti ad aumentato rischio di sviluppare scompenso cardiaco e se questo effetto ¿ maggiore nei pazienti con concentrazioni plasmatiche aumentate di Gal-3.

E.2.2

Secondary objectives of the trial

To investigate whether, over nine months. spironolactone can induce
favourable changes in: serum or plasma concentrations of other
biomarkers of extracellular matrix turnover, in cardiac remodelling, in
vascular function , in exercise capacity and To investigate whether
spironolactone alters the rate of the clinical composite of development of
heart failure or atrial fibrillation, non-fatal myocardial infarction or
stroke or CV death; or change pre-specified expected Adverse events

Studiare l'interazione tra spironolattone e concentrazione plasmatica di Gal-3: - sul rimodellamento cardiaco, valutato mediante ecocardiografia. Questo include il volume atriale sinistro, la massa ventricolare sinistra e misurazioni
Doppler della funzionalit¿ ventricolare sinistra e destra,
- Sulla performance cardiorespiratoria durante lo sforzo
- Sulla funzione vascolare valutata utilizzando tecnologie non invasive non
dolorose
- Sul peptide N-terminale tipo pro-B natriuretico (NT-proBNP), una
misurazione dello stress emodinamico.
- Su un insieme clinico di sviluppo di insufficienza cardiaca o fibrillazione
atriale, o infarto miocardico non fatale, o ictus, o morte cardiovascolare.
Descrivere l'interazione tra cambiamenti di PIIINP,di peptide procollagene di
tipo 1 C terminale (PICP), di telopeptide 1-collagene (ICTP) e dei livelli
basali di Gal-3, e di altri biomarcatori coinvolti nel processo di fibrosi
aldosterone correlati, tra cui:
- Cardiotrofina-1
- Siero solubile recettore d

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: Several assessments that were initially mandatory will be part of sub-studies, each patient will have the possibility to participate at the minimum core protocol or at the minimum core protocol and sub-studies. The objective is to reduce the number of patients refusing to participate at the study due to the high number of assessments during the follow up visits.
The site in Cortona will participate at the following sub-studies
- Sub-study A: screening blood tests for central laboratory evaluation
- Sub-study E: Blood and urine tests at one month follow-up

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Molte delle valutazioni che erano inizialmente obbligatorie, sono state spostate in specifi sottostudi, cos¿ che ciascun paziente avr¿ la possibilit¿ di partecipare ad uno studio minimo di base (¿core study¿) e agli eventuali sottostudi. L¿obiettivo ¿ di minimizzare il numero di pazienti che si rifiutano di partecipare allo studio a causa dell¿elevato numero di valutazioni previste nel corso delle visite di ¿follow up¿.
Il centro di Cortona parteciper¿ ai seguenti sottostudi:
- Sottostudio A: test ematici di screening da effttuare presso un laboratorio centrale;
- Sottostudio E: test ematici e urinari alla visita di ¿follow up¿ ad un mese.

E.3

Principal inclusion criteria

1.Written informed consent will be obtained prior to any study
procedure;
2. Age >60 years
3. Clinical risk factors for developing heart failure, either:
Coronary artery disease (h/o myocardial infarction, angioplasty or
coronary artery bypass)
Or
B. At least two of the following:
• Diabetes Mellitus requiring Hypoglycaemic Pharmacotherapy
• Receiving pharmacological treatment for Hypertension
• Microalbuminuria
• Abnormal ECG (left ventricular hypertrophy, QRS >120msec,
abnormal Q-waves)
4. Biological risk: NT-pro-BNP values between 125 and 1,000 ng/L or
BNP values between 35 and 280 pg/ml (consistent with ESC guidelines
indicating risk of HF but helping to rule out prevalent HF or atrial
fibrillation which are associated with marked increases in NTproBNP/
BNP and should be investigated)

1. Il consenso informato scritto deve essere ottenuto prima di ogni procedura dello studio;
2. Età >60 anni
3. Fattori di rischio clinici di sviluppo di insufficienza cardiaca, o: Malattia coronarica (storia di infarto miocardico, angioplastica o bypass coronarico)
O
B. Almeno due dei seguenti:
• Diabete Mellito che richiede una farmacoterapia ipoglicemizzante
• in trattamento farmacologico per ipertensione
• Microalbuminuria
• ECG anormale (ipertrofia ventricolare sinistra, QRS >120msec,
onde Q anormali)
4. rischio biologico: valori NT-pro-BNP tra 125 e 1,000 ng/L o valori BNP tra 35 e 280 pg/ml (coerenti con le linee guida ESC indicanti rischio di HF, ma che aiutano a escludere una HF prevalente o una fibrillazione atriale associate a spiccati aumenti di NT-proBNP / BNP e che dovrebbero essere studiate)

E.4

Principal exclusion criteria

1. Recent wound healing/inflammation:
• Surgical procedure, coronary, cerebral or peripheral vascular events
or infection in the prior 3 months
• Cancer
• Autoimmune disease
• Hepatic Disease
2. Pre-existing diagnosis of clinical HF
3. Moderate/severe LV systolic ventricular dysfunction, i.e. LVEF <45%
4. Moderate or severe valve disease (investigators opinion)
5. eGFR< 30ml/min
6. Serum potassium >5.0 mmol/L
7. Treatment with an MRA or a loop diuretic (furosemide, bumetanide,
ethacrynic acid or torasemide) in the previous three months
8. Potassium supplements or potassium-sparing diuretic at time of
enrolment.
9. Atrial fibrillation within one month prior to inclusion (AF lasting <60
seconds on ambulatory ECG monitoring is permitted)
10. History of hypersensitivity to spironolactone.
11. Patients unable to give written informed consent.
12. Participation in another interventional trial in the preceding month
13. Ability to walk is, in the investigators opinion, clearly limited by
joint disease or other locomotor problems rather than by
cardiorespiratory fitness

1. Recente guarigione di ferite / infiammazioni: • Interventi chirurgici, eventi vascolari coronarici, cerebrali o periferici o infezioni nei precedenti 3 mesi
• Cancro
• Malattia autoimmune
• Malattia epatica
2. Diagnosi pre-esistente di HF clinica
3. Disfunzione ventricolare sistolica LV moderata/severa LV, cioè LVEF <45%
4. Malattia valvolare moderata o grave (secondo l’opinione dello Sperimentatore)
5. eGFR< 30ml/min
6. Potassio sierico >5.0 mmol/L
7. in trattamento con MRA o un diuretico (furosemide, bumetanide, acido etacrinico o torasemide) nei tre mesi precedenti 8. Integratori di potassio o diuretici risparmiatori di potassio al momento dell'arruolamento. 9. fibrillazione atriale entro un mese prima dell'inclusione (è consentit auna durata AF <60 secondi nell’ECG ambulatoriale di controllo ) 10. Storia di ipersensibilità a spironolattone. 11. pazienti in grado di dare un consenso informato scritto. 12. partecipazione a un altro studio interventistico nel mese precedente 13. La capacità di camminare è, secondo gli sperimentatori, chiaramente limitata da malattia alle articolazioni o altri problemi locomotori piuttosto che capacità cardiorespiratoria

E.5 End points

E.5.1

Primary end point(s)

Changes in serum concentrations of PIIINP from baseline to nine
months.

Cambiamenti delle concentrazioni sieriche di PIIINP (RI test, laboratorio
centrale) dal basale a nove mesi. Si pensa che nove mesi possa essere un
periodo sufficiente per influenzare la fibrosi cardiaca per la quale il PIIINP è
un indicatore ampiamente accettato. La concentrazione sierica PIIINP è
ridotta dai MRA; una riduzione di PIIINP nel siero è associata a esiti clinici
più favorevoli.

E.5.1.1

Timepoint(s) of evaluation of this end point

at 9 months compared to baseline

a 9 mesi in confronto con il basale

E.5.2

Secondary end point(s)

1.Changes in levels of biomarkers of extracellular matrix turnover: PICP
(synthesis) and ICTP (degradation).
2.Cardiac remodelling, assessed by echocardiography
3.Distance walked on a shuttle walk-test with assessment of peak heart
and respiratory rate if data on shuttle test are available. .
4.Vascular function assessed by non-invasive technologies
5.Rate of the clinical composite of development of heart failure or atrial
fibrillation, non-fatal myocardial infarction or stroke or CV death
6.Safety endpoints: Investigator reported adverse events (AEs) will be
collected using the ad hoc reporting system. In addition, pre-specified
expected AEs will be monitored : Worsening renal function (decline in
eGFR >20%), Hyperkalemia (rise of serum potassium to >5.5 mmol/L),
Rate of gynaecomastia and/or breast pain, Changes in serum potassium
and eGFR, 4.5 Hypotension, falls and fractures

Cambiamenti nel siero o plasma dei livelli di biomarcatori di ricambio di
matrice extracellulare : PICP (sintesi) e ICTP (degrado), dal basale a 9 mesi
(RIA, laboratorio centrale).
Rimodellamento cardiaco, valutato mediante ecocardiografia, tra cui il
volume atriale sinistro, la massa ventricolare sinistra e misurazioni Doppler di
destra e funzione ventricolare sinistra e NT-proBNP (ELISA, Lab centrale),
dal basale a 9 mesi (centri certificati e letture centralizzate).
Distanza percorsa valutata con il shuttle walk-test con valutazione del picco
cardiaco e la frequenza respiratoria se sono disponibili dati del test shuttle.
Funzione vascolare valutata con tecnologie non invasive
Valutazione dell¿insieme clinico di sviluppo di insufficienza cardiaca o
fibrillazione atriale, infarto miocardico non fatale o ictus o morte
cardiovascolare dal basale a 9 mesi. Il comitato di valutazione degli eventi
clinici HOMAGE giudicher¿ tutti gli eventi avversi gravi in cieco.
Endpoint di sicurezza: gli eventi avversi riportati dallo Sperimentatore (AE)
saranno raccolti con il sistema di relazione ad hoc. Inoltre, saranno monitorati
AE attesi pre-specificati:
4.1. Peggioramento della funzione renale (calo di eGFR> 20%)
4.2. Iperpotassiemia (aumento del potassio sierico di> 5,5 mmol / L)
4.3. Tasso di ginecomastia e / o dolore al seno
4.4 Modifiche del potassio sierico e eGFR saranno valutate al giorno 7, Mese
1, 3, 6 e 9.
4.5 ipotensione, cadute e fratture

E.5.2.1

Timepoint(s) of evaluation of this end point

at 9 months compared to Baseline and more specifically for safety : at all
visits

a 9 mesi rispetto al basale e per la sicurezza ad ogni visita

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

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)

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

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

studio randomizzato in aperto con valutazione in cieco

open randomized clinical trial with blinded evaluation

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

solo trattamento di base - nessun trattamento addizionale

background treatment only - no additional treatment

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

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

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

All patients will have a final review (by telephone, letter, e-mail or
clinic as preferred by the patient) approximately 9 months after the
last patient has been enrolled.

Tutti i pazienti avranno un controllo finale (per telefono, lettera, email o in clinica a seconda di quanto preferito dal paziente) circa 9 mesi dopo l'arruolamento dell'ultimo paziente

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:

160

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

640

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

800

F.4.2.2

In the whole clinical trial

800

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)

Patients completing the randomized trial should generally stop
spironolactone unless a specific indication has developed or the patient
and their doctor agree that continuing spironolactone is their preferred
option.

I pazienti, a completamento del trial randomizzato, dovrebbero generalmente terminare lo spironolattone a meno che non si sia sviluppata per il paziente una indicazione specifica e il medico concordi che lo spironolattone sia l'opzione da preferire

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

2016-01-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-20

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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