Clinical Trials Register

Summary
EudraCT Number:	2021-005394-66
Sponsor's Protocol Code Number:	ESR-20-21070
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:	2021-11-23
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

2021-005394-66

A.3

Full title of the trial

Effects of Dapagliflozin on cardiac deformation and clinical outcomes in heart failure with reduced and mildly reduced ejection fraction

Effetti del Dapagliflozin sulla deformazione cardiaca e sugli esiti clinici nello scompenso cardiaco con frazione di eiezione ridotta e moderatamente ridotta

A.3.1

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

Effects of Dapagliflozin on cardiac deformation and clinical outcomes in heart failure with reduced and mildly reduced ejection fraction

Effetti del Dapagliflozin sulla deformazione cardiaca e sugli esiti clinici nello scompenso cardiaco con frazione di eiezione ridotta e lievemente ridotta

A.3.2

Name or abbreviated title of the trial where available

ESR-20-21070

A.4.1

Sponsor's protocol code number

ESR-20-21070

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 OSPEDALIERA UNIVERSITARIA SENESE
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	ASTRAZENECA
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	AZIENDA OSPEDALIERO UNIVERSITARIA SENESE
B.5.2	Functional name of contact point	U.O.C. Diagnostica Cardiovascolare
B.5.3	Address:
B.5.3.1	Street Address	Viale Bracci, 1
B.5.3.2	Town/ city	SIENA
B.5.3.3	Post code	53100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0577585377
B.5.5	Fax number	0577585377
B.5.6	E-mail	matteo.cameli@unisi.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	FORXIGA - 10 MG - COMPRESSE RIVESTITE CON FILM- USO ORALE - BLISTER CALENDARIZZATO (ALU/ALU) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL- MYERS SQUIBB/ASTRAZENECA EEIG
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	Dapagliflozin
D.3.2	Product code	[Dapagliflozin]
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	DAPAGLIFLOZIN
D.3.9.1	CAS number	461432-26-8
D.3.9.2	Current sponsor code	461432-26-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
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.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

heart failure with left ventricular ejection fraction <50%

insufficienza cardiaca con frazione di eiezione ventricolare sinistra < 50%

E.1.1.1

Medical condition in easily understood language

heart failure with reduced or mildly reduced left ventricular ejection fraction

insufficienza cardiaca con frazione di eiezione ventricolare sinistra ridotta o moderatamente ridotta

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	10024102
E.1.2	Term	Left cardiac failure
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

determine the changes over time in left ventricular myocardial performance in non-diabetic patients with HFrEF and HFmrEF treated with Dapagliflozin at 3 and 6 months of follow up, compared to the standard of care of optimal medical therapy according to the ESC guidelines for heart failure.

determinare le variazioni nel tempo della performance del miocardio ventricolare sinistro in pazienti non diabetici con HFrEF e HFmrEF trattati con Dapagliflozin a 3 e 6 mesi di follow up, rispetto allo standard di cura consistente nella terapia medica ottimale secondo le linee guida ESC dello scompenso cardiaco

E.2.2

Secondary objectives of the trial

Evaluate the effect of Dapagliflozin in addition to optimal medical therapy after 3 and 6 months of treatment against the standard of care regarding:
- reverse remodeling of the left ventricle
- left ventricular diastolic function and congestion.
- structure and function of the right ventricle
- cardiovascular clinical events (hospitalization for heart failure, cardiovascular death and death from all causes).
Exploratory Objectives: To evaluate the effects of Dapagliflozin in addition to optimal medical therapy on the burden of heart failure symptoms relative to standard of care.

Valutare l'effetto del Dapagliflozin in aggiunta alla terapia medica ottimale dopo 3 e 6 mesi di trattamento rispetto allo standard di cura riguardo a:
- rimodellamento inverso del ventricolo sinistro
- funzione diastolica ventricolare sinistra e congestione.
- struttura e funzione del ventricolo destro
- eventi clinici cardiovascolari (ospedalizzazione per scompenso cardiaco, morte cardiovascolare e morte per tutte le cause).
Obiettivi esplorativi: Valutare gli effetti del Dapagliflozin in aggiunta alla terapia medica ottimale sul carico dei sintomi di insufficienza cardiaca rispetto allo standard di cura.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients can be included in the study only if they meet the following criteria:
1. Providing informed consent prior to any specific study procedure
2. Female or male non-diabetic outpatients> 18 years
3. Have heart failure with left ventricular ejection fraction <50%, according to the ESC definition [1], such as patients with signs (pulmonary crepitus, peripheral edema, elevated jugular venous pressure) and / or symptoms (dyspnoea, fatigue, ankle swelling) of heart failure, left ventricular ejection fraction <40% or 40-49%.
4. Already on OMT according to ESC HF guidelines [1] (for HFrEF this mainly includes an angiotensin converting enzyme (ACE) inhibitor or sacubitril / valsartan, a beta blocker and a mineralocorticoid receptor antagonist (MRA)).
5. Subjects without severe chronic kidney disease (eGFR with CKD-EPI formula must be = 30 mL / min)
6. Negative pregnancy test (urine or serum) for female subjects of childbearing age.
7. Female subjects must be 1 year postmenopausal, surgically sterile, or use an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in combination with a spermicide) for the duration of the study (from sign the consent) and for 3 months after the last dose of Drug A / placebo to prevent pregnancy. Also, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; Additional barrier methods should be used in combination with the spermicide.
8. Male subjects must be surgically sterile or use an acceptable method of contraception (defined as barrier methods in combination with spermicides) for the duration of the study (from the time they sign the consent) and for 3 months after the last drug dose A / placebo matching to prevent pregnancy in a partner.
9. Subjects who are blood donors should not donate blood during the study and for 3 months after their last dose of Drug A.

I Pazienti potranno essere inclusi nello studio solo se rispondono ai criteri di seguito riportati:
1. Fornitura del consenso informato prima di qualsiasi procedura specifica dello studio
2. Pazienti ambulatoriali non diabetici di sesso femminile o maschile > 18 anni
3. Essere affetti da insufficienza cardiaca con frazione di eiezione ventricolare sinistra < 50%, secondo la definizione ESC [1], come pazienti con segni (crepitii polmonari, edema periferico, elevata pressione venosa giugulare) e/o sintomi (dispnea, affaticamento, gonfiore alla caviglia) di insufficienza cardiaca, frazione di eiezione ventricolare sinistra < 40%, o compresa tra 40-49%.
4. Essere già in OMT secondo le linee guida ESC HF [1] (per HFrEF questo comprende principalmente un inibitore dell'enzima di conversione dell'angiotensina (ACE) o sacubitril/valsartan, un beta-bloccante e un antagonista del recettore dei mineralcorticoidi (MRA)).
5. Soggetti senza malattia renale cronica grave (eGFR con formula CKD-EPI deve essere = 30 ml/min)
6. Test di gravidanza negativo (urina o siero) per soggetti di sesso femminile in età fertile.
7. I soggetti di sesso femminile devono essere in post-menopausa da 1 anno, sterili chirurgicamente o utilizzare un metodo contraccettivo accettabile (un metodo contraccettivo accettabile è definito come un metodo di barriera in combinazione con uno spermicida) per la durata dello studio (dal momento firmano il consenso) e per 3 mesi dopo l'ultima dose di Farmaco A/placebo corrispondente per prevenire la gravidanza. Inoltre, sono consentiti contraccettivi orali, impianto contraccettivo approvato, contraccezione iniettabile a lungo termine, dispositivo intrauterino o legatura delle tube. La sola contraccezione orale non è accettabile; devono essere utilizzati ulteriori metodi di barriera in combinazione con lo spermicida.
8. I soggetti di sesso maschile devono essere chirurgicamente sterili o utilizzare un metodo contraccettivo accettabile (definito come metodi di barriera in combinazione con spermicidi) per la durata dello studio (dal momento in cui firmano il consenso) e per 3 mesi dopo l'ultima dose del farmaco A /matching placebo per prevenire la gravidanza in un partner.
9. I soggetti che sono donatori di sangue non devono donare sangue durante lo studio e per 3 mesi dopo la loro ultima dose di Farmaco A.

E.4

Principal exclusion criteria

Patients cannot be included in the study if only one of the following exclusion criteria is present:
1. Involvement in study planning and / or conducting (applies to both investigator staff and study site staff)
2. Previous enrollment or randomization in the present study
3. Participation in another clinical study with an investigational product within the past 6 months
4. Previous treatment with any SGLT2 inhibitor
5. Type II diabetes mellitus
6. Atrial fibrillation at the time of enrollment
7. Chronic kidney damage with creatinine clearance <30 ml / min (calculated from the CKD-EPI formula)
8. <18 years
9. For women only - ongoing pregnancy (confirmed with positive pregnancy test)
10. For women only - breastfeeding
11. Poor quality of echocardiographic images that compromises a correct speckle tracking analysis
12. Failure to sign informed consent
13. Persistent toxicities (> CTCAE grade 2) caused by previous anticancer therapies, excluding alopecia
14. Patients on dialysis
15. Patients with known hypersensitivity to Dapagliflozin or to any of the excipients of the product
16. Any concomitant drug known to be associated with Torsades de pointes or potent inducers of cytochrome P450 3A4 (CYP3A4)
17. History of QT prolongation associated with other drugs that required discontinuation of that drug
18. Congenital long QT syndrome
19. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia

I Pazienti non potranno essere inclusi nello studio se sarà presente anche solamente uno solo dei criteri di esclusione di seguito riportati:
1. Coinvolgimento nella pianificazione e/o conduzione dello studio (si applica sia al personale dello sperimentatore che al personale del sito di studio)
2. Precedente arruolamento o randomizzazione nel presente studio
3. Partecipazione ad un altro studio clinico con un prodotto sperimentale negli ultimi 6 mesi
4. Trattamento precedente con qualsiasi inibitore SGLT2
5. Diabete mellito di tipo II
6. Fibrillazione atriale al momento dell’arruolamento
7. Danno renale cronico con clearance della creatinina < 30 ml/min (calcolato dalla formula CKD-EPI)
8. <18 anni
9. Solo per donne - gravidanza in corso (confermata con test di gravidanza positivo)
10. Solo per donne - allattamento al seno
11. Scarsa qualità delle immagini ecocardiografiche che comprometta una corretta analisi speckle tracking
12. Mancata firma di consenso informato
13. Tossicità persistenti (>grado CTCAE 2) causate da precedenti terapie antitumorali, esclusa l'alopecia
14. Pazienti in dialisi
15. Pazienti con nota ipersensibilità a Dapagliflozin o ad uno qualsiasi degli eccipienti del prodotto
16. Qualsiasi farmaco concomitante noto per essere associato a Torsioni di punta o potenti induttori del citocromo P450 3A4 (CYP3A4)
17. Storia di prolungamento dell'intervallo QT associato ad altri farmaci che hanno richiesto l'interruzione di quel farmaco
18. Sindrome congenita del QT lungo
19. Storia di aritmia (contrazioni ventricolari premature multifocali, bigeminismo, trigeminismo, tachicardia ventricolare), che è sintomatica o richiede trattamento (grado 3 CTCAE) o tachicardia ventricolare sostenuta asintomatica

E.5 End points

E.5.1

Primary end point(s)

Determine changes over time (at 3 and 6 months) in left ventricular myocardial performance by basal and speckle tracking echocardiography in non-diabetic patients with HFrEF and HFmrEF treated with Dapagliflozin in addition to optimal medical therapy, compared to standard of care according to ESC guidelines for heart failure .

Determinare le variazioni nel tempo (a 3 e 6 mesi) della performance del miocardio ventricolare sinistro mediante ecocardiografia base e speckle tracking in pazienti non diabetici con HFrEF e HFmrEF trattati con Dapagliflozin in aggiunta alla terapia medica ottimale, rispetto allo standard di cura secondo le linee guida ESC per lo scompenso cardiaco.

E.5.1.1

Timepoint(s) of evaluation of this end point

at 3 and 6 months

a 3 e 6 mesi

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

after 3 and 6 months

dopo 3 e 6 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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

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

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)

At the end of the observation of the patient as defined in § 5.4, the Investigator will have to fill in the appropriate "End of study" form.

Al termine dell’osservazione del paziente così come definita nel § 5.4, lo Sperimentatore dovrà compilare l’apposita scheda di “Fine studio”.

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

2022-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-02-21

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

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