Clinical Trials Register

Summary
EudraCT Number:	2022-003314-37
Sponsor's Protocol Code Number:	CCM1862
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:	2023-01-10
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

2022-003314-37

A.3

Full title of the trial

Effects of combined diuretic therapy on exercise capacity, alveolus-capillary diffusion, and maintenance of euvolemia in chronic congestive heart failure, diuretic therapy compared between loop diuretics and potassium sparing diuretics

Effetti della terapia diuretica combinata sulla capacità d’esercizio, la diffusione alveolo-capillare e il mantenimento dell’euvolemia nello scompenso cardiaco congestizio cronico, terapia diuretica a confronto con diuretici dell’ansa e risparmiatori di potassio

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

CCM 1862

A.4.1

Sponsor's protocol code number

CCM1862

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	CENTRO CARDIOLOGICO SPA FONDAZIONE MONZINO
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CENTRO CARDIOLOGICO MONZINO
B.5.2	Functional name of contact point	UFFICIO STUDI CLINICI
B.5.3	Address:
B.5.3.1	Street Address	VIA RIPAMONTI 426
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	02574898478
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	DIAMOX - 250 MG COMPRESSE 12 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA 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	DIAMOX
D.3.2	Product code	[DIAMOX]
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	ACETAZOLAMIDE
D.3.9.1	CAS number	59-66-5
D.3.9.2	Current sponsor code	NA
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	250
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.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	ZAROXOLYN - 10 MG COMPRESSE 50 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA 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.3.4	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	METOLAZONE
D.3.9.1	CAS number	17560-51-9
D.3.9.2	Current sponsor code	NA
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	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	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.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	ZAROXOLYN - 5 MG COMPRESSE 50 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA S.R.L.
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	METOLAZONE
D.3.9.1	CAS number	17560-51-9
D.3.9.2	Current sponsor code	NA
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	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

congestive heart failure

scompenso cardiaco congestizio

E.1.1.1

Medical condition in easily understood language

congestive heart failure

scompenso cardiaco congestizio

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 compare two different treatment strategies (control arm treated with loop diuretic and potassium sparing and experimental arm that will combine such therapy with acetazolamide and free-dose metolazone) in patients with chronic heart failure. Specifically, the following will be assessed: trend of short- to medium-term re-hospitalizations, degree of congestion and volemia by body weight assessment and vector impedance measurement (BIVA), functional capacity by cardiopulmonary exercise testing (CPET), subjective perception of health status assessed by questionnaires, and neurohormonal response.

Confrontare due diverse strategie terapeutiche (braccio di controllo trattato con diuretico dell’ansa e risparmiatore di potassio e braccio sperimentale che assocerà a tale terapia acetazolamide e metolazone a dose libera) in pazienti affetti da scompenso cardiaco cronico. In particolare verranno valutati: andamento di riospedalizzazioni a breve-medio termine, grado di congestione e volemia tramite valutazione del peso corporeo e misurazione dell’impedenzometria vettoriale (BIVA), capacità funzionale tramite test da sforzo cardiopolmonare (CPET), percezione soggettiva dello stato di salute valutato con questionari e risposta neuroormonale.

E.2.2

Secondary objectives of the trial

• Assess the degree of congestion and volemia through the course of body weight and measurement of vector impedance (BIVA) between patients with chronic heart failure treated with standard diuretic therapy and combined diuretic therapy
• To evaluate differences in the effects on functional capacity through CPET with VO2 max measurement and on alveolar-capillary diffusion between patients with chronic heart failure treated with standard diuretic therapy and combined diuretic therapy
• Assess differences in the trend of subjective perception of health through Kansas City Cardiomiopathy Questioning between patients with chronic heart failure treated with standard diuretic therapy and combined diuretic therapy
• Assess differences in neurohormonal response by measuring NT-proBNP between patients with chronic heart failure treated with standard diuretic therapy and combined diuretic therapy

• Valutare il grado di congestione e volemia tramite l’andamento del peso corporeo e la misurazione dell’impedenzometria vettoriale (BIVA) tra pazienti affetti da scompenso cardiaco cronico trattati con terapia diuretica standard e terapia diuretica combinata
• Valutare differenze degli effetti sulla capacità funzionale tramite CPET con misurazione del VO2 max e sulla diffusione alveolo-capillare tra pazienti affetti da scompenso cardiaco cronico trattati con terapia diuretica standard e terapia diuretica combinata
• Valutare differenze nell’andamento della percezione soggettiva di salute tramite Kansas City Cardiomiopathy Questionaire tra pazienti affetti da scompenso cardiaco cronico trattati con terapia diuretica standard e terapia diuretica combinata
• Valutare differenze nell’andamento della risposta neuroormonale tramite misurazione di NT-proBNP tra pazienti affetti da scompenso cardiaco cronico trattati con terapia diuretica standard e terapia diuretica combinata

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) written informed consent signed
2) Age: 18-80
3) Patients with chronic heart failure (at reduced or preserved ejection fraction)
4) Patients discharged after hospitalization for acute heart failure (at least second episode of decompensation in the past 12 months)
5) Patients being treated with loop diuretics at the same or higher dosage of furosemide 40 mg (or equivalent) at the time of admission

1) Firma del consenso informato
2) Età: 18-80 anni
3) Pazienti affetti da scompenso cardiaco cronico (a ridotta o conservata frazione di eiezione)
4) Pazienti dimessi dopo ricovero per scompenso cardiaco acuto (almeno secondo episodio di scompenso negli ultimi 12 mesi)
5) Pazienti in trattamento con diuretici dell’ansa a dosaggio uguale o superiore di furosemide 40 mg (o equivalente) al momento del ricovero

E.4

Principal exclusion criteria

1) age <18 years or >85 years
2) patients with severe aortic stenosis
3) patients with severe renal failure (eGFR<20 ml/min/1.73m2 according to Cockroft-Gault)
4) patients with severe hyponatremia
5) Medical therapy for heart failure optimized during hospitalization
6) Documented current pregnancy and lactating status in women of childbearing potential

1) età <18 anni o >85 anni
2) pazienti affetti da stenosi aortica severa
3) pazienti affetti da insufficienza renale grave (eGFR<20 ml/min/1.73m2 secondo Cockroft-Gault)
4) pazienti affetti da iponatriemia severa
5) Terapia medica per lo scompenso cardiaco ottimizzata durante il ricovero
6) Donne in età fertile in stato di gravidanza o di allattamento accert

E.5 End points

E.5.1

Primary end point(s)

Evaluate differences in the trend of short- to medium-term re-hospitalizations between chronic heart failure patients treated with standard diuretic therapy (control arm) and combination diuretic therapy (experimental arm)

Valutare differenze nell’andamento di riospedalizzazioni a breve-medio termine tra pazienti affetti da scompenso cardiaco cronico trattati con terapia diuretica standard (braccio di controllo) e terapia diuretica combinata (braccio sperimentale)

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months

3 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

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

Cure standard

Standart of care

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

Information not present in EudraCT

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

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

standard of care

percorso di cura standard

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

2023-03-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-04-19

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

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