Clinical Trials Register

Summary
EudraCT Number:	2015-002189-21
Sponsor's Protocol Code Number:	838/15
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:	2021-05-27
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

2015-002189-21

A.3

Full title of the trial

"The combined effect of subcutaneous Granulocyte - Colony Stimulating Factor and Myocardial Contrast Echocardiography with intravenous infusion of sulphur hexafluoride on post-infarction left ventricular function¿

L¿effetto combinato del Fattore Stimolante le Colonie ¿ Granulocitarie somministrato per via sottocutanea e dell¿Ecocardiografia con infusione endovenosa di mezzo di contrasto contenente esafluoruro di zolfo sulla funzione ventricolare sinistra post-infarto

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

A.4.1

Sponsor's protocol code number

838/15

A.5.4

Other Identifiers

Name:

RIGENERA 2.0

Number:

RIGENERA 2.0

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	FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
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	PRIN
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	POLICLINICO GEMELLI
B.5.2	Functional name of contact point	DIPARTIMENTO SCIENZE CARDIOVASCOLAR
B.5.3	Address:
B.5.3.1	Street Address	LARGO GEMELLI 8
B.5.3.2	Town/ city	ROMA
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630154187
B.5.5	Fax number	063055535
B.5.6	E-mail	etico@rm.unicatt.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	SONOVUE - 8 MCG/ML POLVERE E SOLVENTE PER DISPERSIONE INIETTABILE 1 FLACONCINO (VETRO) +1 SIRINGA PRERIEMPITA (PLASTICA) 5 ML + 1 ADATTATORE MINI SPIKE USO EV
D.2.1.1.2	Name of the Marketing Authorisation holder	BRACCO INTERNATIONAL B.V.
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	sonovue
D.3.2	Product code	nd
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZOLFO ESAFLUORURO
D.3.9.2	Current sponsor code	nd
D.3.10	Strength
D.3.10.1	Concentration unit	µl/ml microlitre(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
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	MYELOSTIM - 13 5 FLAC LIOF 13.4 MIU+ 5 SIR SOLV 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	CHUGAI SANOFI AVENTIS
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	myelostim
D.3.2	Product code	nd
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENOGRASTIM
D.3.9.2	Current sponsor code	nd
D.3.10	Strength
D.3.10.1	Concentration unit	million IU million international units
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	13
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Comparator
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	SONOVUE - 8 MCG/ML POLVERE E SOLVENTE PER DISPERSIONE INIETTABILE 1 FLACONCINO (VETRO) +1 SIRINGA PRERIEMPITA (PLASTICA) 5 ML + 1 ADATTATORE MINI SPIKE USO EV
D.2.1.1.2	Name of the Marketing Authorisation holder	BRACCO INTERNATIONAL B.V.
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	sonovue
D.3.2	Product code	nd
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

acute myocardial infarction

infarto miocardico acuto

E.1.1.1

Medical condition in easily understood language

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	PT
E.1.2	Classification code	10000891
E.1.2	Term	Acute myocardial infarction
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 determine whether, in patients with large acute myocardial infarction undergoing primary or rescue angioplasty, the administration of subcutaneous Lenograstim [recombinant human Granulocyte-Colony Stimulating Factor (rhu G-CSF), Myelostim 34, Italfarmaco] associated with Myocardial Contrast Echocardiography and the intravenous infusion of sulphur hexafluoride (Sonovue, Bracco) determines an improvement:
- in regional and global contractile function, myocardial perfusion and infarct size assessed by cardiovascular magnetic resonance- Echocardiographic parameters of LV function - in the serum profile of inflammatory and mobilizing cytokines and of biomarkers of myocardial damage and wall stress

Determinare se, in pazienti con ampio infarto acuto del miocardio sottoposti ad angioplastica primaria o di salvataggio, la somministrazione di Fattore Stimolante le Colonie ¿ Granulocitarie associato a Ecocardiografia con Contrasto e infusione endovenosa di esafluoruro di zolfo (Sonovue, Bracco) determina un miglioramento:
- della funzione contrattile regionale e globale, perfusione miocardica e dimensione dell¿infarto valutati tramite risonanza magnetica cardiovascolare
- dei parametri Ecocardiografici di funzione ventricolare sinistra
- nel siero i livelli delle citochine di infiammazione e di mobilizzazione nonch¿ i biomarkers di danno miocardico e stress di parete

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated informed consent
2. Men and women of any ethnic origin aged = 18 years
3. Patients with acute ST-elevation myocardial infarction as defined by the universal definition of AMI.
4. Successful acute reperfusion therapy (residual stenosis visually <50% and TIMI flow =2) within 24 hours of symptom onset by successful percutaneous coronary intervention (PCI) or thrombolysis within 12 hours of symptom onset followed by successful PCI within 24 hours after thrombolysis
5. Left ventricular ejection fraction = 45% at 24 hours after revascularization, as documented by a two-dimensional echocardiogram.

1. Consenso informato firmato e datato
2. Uomini o donne di qualsiasi origine etnica = 18 anni
3. Pazienti con infarto del miocardio ed elevazione ST acuta come stabilito dalla definizione universale dell’AMI.
4. Terapia di riperfusione acuta di successo (stenosi residua visivamente < 50% e TIMI flow =2) entro 24 ore della comparsa dei sintomi dalla PCI o trombolisi entro 12 ore dalla comparsa dei sintomi seguita da PCI di successo entro 24 ore dopo la trombo lisi.
5. Frazione di eiezione del ventricolo sinistra = 45% a 24 ore dopo la rivascolarizzazione come documentato dall’ecocardiogramma bidimensionale.

E.4

Principal exclusion criteria

1. Participation in another clinical trial within 30 days prior to randomisation
2. Pregnant or nursing women or women in childbearing age not able to esclude the possibility of a pregnancy
3. Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study or to follow the protocol
4. Necessity to revascularise additional vessels, outside the target coronary artery after investigational therapy/placebo administration (additional revascularisations after primary PCI and before investigational therapy/placebo administration are allowed)
5. Persistent cardiogenic shock
6. Known hematologic and neoplastic diseases
7. Severe impaired renal function, i.e. GFR<30 ml/min
8. Persistent fever or diarrhoea not responsive to treatment within 4 weeks prior screening or severe infection
9. Uncontrolled hypertension (systolic >180 mmHg and diastolic >120 mmHg)
10. Life expectancy of less than 2 years from any non-cardiac cause or neoplastic disease

1. Partecipazione in un altro trial clinico entro 30 giorni dalla randomizzazione
2. Donne incinte o che allattano o in età fertile e che non possono escludere la possibilità di una gravidanza durante lo studio
3. Condizioni mentali che rendono il paziente incapace di capire la natura, lo scopo e le possibili conseguenze dello studio o del seguente protocollo
4. Necessità di rivascolarizzare vasi addizionali, oltre la coronaria target del trattamento sperimentale con terapia/placebo (rivascolarizzazioni supplementari dopo PCI primaria e prima della somministrazione della terapia sperimentale / placebo sono ammessi)
5. Shock cardiogeno persistente
6. Malattie neoplastiche ed ematologiche note
7. Disfunzione renale severa, i.e. GFR<30 ml/min
8. Febbre persistente o diarrea non responsiva al trattamento entro quattro settimane dallo screening o infezione grave
9. Ipertensione non controllata (sistolica >180 mmHg e diastolica >120 mmHg)
10. Aspettativa di vita inferiore a 2 anni per cause non cardiache o malattia neoplastica

E.5 End points

E.5.1

Primary end point(s)

Endpoint secondari di efficacia:
• Volume Telediastolico del ventricolo sinistro (LVEDV) documentato da Risonanza Magnetica Cardiaca a 6 mesi e rivalutata centralmente
• Volume Telesistolico del ventricolo sinistro (LVEDV) documentato da Risonanza Magnetica Cardiaca a 6 mesi e rivalutata centralmente
• Frazione di eiezione sinistra (LVEF) valutata tramite 2D Ecocardiografia a 6 mesi e rivalutata centralmente
• Volume Telediastolico del ventricolo sinistro (LVEDV) valutato tramite 2D Ecocardiografia a 6 mesi e rivalutata centralmente
• Volume Telesistolico del ventricolo sinistro (LVEDV) valutato tramite 2D Ecocardiografia a 6 mesi e rivalutata centralmente
• Eventi Clinici cardio-cerebrovascolari maggiori (morte, infarto del miocardio, ictus e riospedalizzazione per scompenso cardiac) a 1 anno

• Endpoint primario di efficacia: Frazione di eiezione ventricolare sinistra (LVEF) a 6 mesi documentata da Risonanza Magnetica Cardiaca e rivalutata centralmente.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

6 months/1years

Secondary efficacy endpoints:
¿ Left ventricular end-diastolic volume (LVEDV) assessed by Cardiac Magnetic Resonance at 6 months at 6 months and centrally reviewed
¿ Left ventricular end-systolic volume (LVEDV) assessed by Cardiac Magnetic Resonance at 6 months and centrally reviewed
¿ Left ventricular ejection fraction (LVEF) assessed by 2D Echocardiography at 6 months and centrally reviewed
¿ Left ventricular end-diastolic volume (LVEDV) assessed by 2D Echocardiography at 6 months and centrally reviewed
¿ Left ventricular end-systolic volume (LVEDV) assessed by 2D Echocardiography at 6 months and centrally reviewed
¿ Clinical Major adverse cardio-cerebrovascular events (death, myocardial infarction, stroke and rehospitalization due to heart failure) at 1 year

E.5.2.1

Timepoint(s) of evaluation of this end point

6 mesi/1 anno

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)

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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.8.5.1

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

"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

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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

120

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)

follow up according to standard of care

normale pratica clinica

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

2015-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-30

P. End of Trial
P.	End of Trial Status	Completed

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