Clinical Trials Register

Summary
EudraCT Number:	2016-004580-39
Sponsor's Protocol Code Number:	TOSCA_GHDDP
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:	2021-06-01
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

2016-004580-39

A.3

Full title of the trial

Treatment of Growth Hormone Deficiency associated with Chronic Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Study

TRATTAMENTO DEL DEFICIT DI GH ASSOCIATO AD INSUFFICIENZA CARDIACA CRONICA: STUDIO CLINICO MULTICENTRICO, RANDOMIZZATO, DOPPIO CIECO, PLACEBO

A.3.1

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

Treatment of Growth Hormone Deficiency in patient with Chronic Heart Failure

TRATTAMENTO DEL DEFICIT DI GH IN PAZIENTI CON INSUFFICIENZA CARDIACA CRONICA.

A.3.2

Name or abbreviated title of the trial where available

Treatment of Growth Hormone Deficiency associated with Chronic Heart Failure: A Randomized, Double-B

TRATTAMENTO DEL DEFICIT DI GH ASSOCIATO AD INSUFFICIENZA CARDIACA CRONICA: STUDIO CLINICO MULTICENTR

A.4.1

Sponsor's protocol code number

TOSCA_GHDDP

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	AOU FEDERICO II
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	A.O.U Federico II
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	A.O.U FEDERICO II
B.5.2	Functional name of contact point	DIPARTIMENTO DI SCIENZE MEDICHE TR
B.5.3	Address:
B.5.3.1	Street Address	VIA S. PANSINI
B.5.3.2	Town/ city	NAPOLI
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390817464375
B.5.5	Fax number	+390817464375
B.5.6	E-mail	cittadin@unina.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	SAIZEN - 1 FLACONCINO POLV. 8 MG + 1 CARTUCCIA. SOLV. INSERITI IN UN DISPOSITIVO PER LA RICOSTITUZIONE
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SERONO S.P.A.
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	somatropina
D.3.2	Product code	[026863100]
D.3.4	Pharmaceutical form	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	SOMATROPINA
D.3.9.2	Current sponsor code	H01AC01
D.3.9.3	Other descriptive name	somatropin
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	100
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)	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	Yes
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

Growth Hormone Deficiency associated with Chronic Heart Failure

DEFICIT DI GH NELL'INSUFFICIENZA CARDIACA CRONICA

E.1.1.1

Medical condition in easily understood language

Growth Hormone Deficiency in patients with Chronic Heart Failure

DEFICIT DI GH IN PAZIENTI CON INSUFFICIENZA CARDIACA CRONICA

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

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	10056438
E.1.2	Term	Growth hormone deficiency
E.1.2	System Organ Class	10014698 - Endocrine 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

Aim of the current study is to assess the cardiovascular effects of GH replacement therapy in patients with coexisting GHD and CHF

Indagare gli effetti cardiovascolari della terapia sostitutiva con GH nei pazienti con GHD ed ICC.

E.2.2

Secondary objectives of the trial

1. Hospitalizations for any cause requiring a ward stay longer than one night
2. End-systolic LV volumes
3. NT-proBNP levels
4. QoL scores
5. Endothelial function (flow-mediated vasodilation)
6. Muscle strength (handgrip)
7. Levels of Endothelial Progenitor Cells (EPCs)
8. Levels of lymphocyte G protein-coupled receptor kinase (GRK)-2

• Ospedalizzazione per tutte le cause: definito come degenza in un reparto per più di una notte consecutiva
• volume telediastolico del VS
• livelli di NT-pro BNP
• qualità di vita mediante score QoL
• funzione endoteliale (mediante vasodilatazione flusso mediata)
• forza muscolare (handgrip)
• livelli delle cellule progenitrici endoteliali (EPCs)
• livelli linfocitari dei recettori chinasi 2 G protein-coupled (GRK-2)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) patients of either sex affected by CHF NYHA class I-III, secondary to ischemic or idiopathic di-lated cardiomyopathy;
2) age range 18-85 years;
3) stable and optimal medical therapy for at least three months prior to randomization, including ACE inhibitors or AT1 antagonists and beta-blockers (unless untolerated);
4) LV ejection fraction 40% or less and LV end-diastolic dimension 55 mm or more;
5) GH deficiency diagnosed with GHRH + arginine provocative test;
6) signed informed consent.

- Pazienti di entrambi i sessi con diagnosi di ICC secondaria a cardiopatia dilatativa post-ischemica o idiopatica, secondo le attuali linee guida, in classe NYHA I-III.
- Età 18-85 anni
- Frazione di eiezione del ventricolo sinistro minore o uguale a 40% e diametro del ventricolo sinistro maggiore o uguale a 55 mm.

E.4

Principal exclusion criteria

1) inability to perform a bicycle exercise test;
2) poorly controlled diabetes mellitus (HbA1c >8.5) and/or active proliferative or severe non-proliferative diabetic retinopathy;
3) active and/or history of malignancy: there is no evidence that GH replacement in adults increases the risk of de novo or recurrent malignancy. GH will not be initiated in patients with active neoplasm, either newly diagnosed or recurrent as well as in subjects with a history of cancer shorter than one year. Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors will be ruled out prior to initiation of treatment. GH therapy will not be used in patients with any evidence of progression or recurrence of an underlying intracranial space-occupying lesion.
4) unstable angina or recent myocardial infarction (less than six months);
5) severe liver or kidney disease (serum creatinine levels >2.5 mg/dl)
6) patients with acute critical illnesses caused by complications of open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure.
7) active infection or sepsis.
8) any allergies to growth hormone, or other ingredients such as benzyl alcohol, sucrose, phosphoric acid, sodium hydroxide, or metacresol

- Incapacità di effettuare un test da sforzo al cicloergometro
- Diabete mellito in scarso controllo glicometabolico (HbA1c > 8,5%) e/o retinopatia proliferativa o retinopatia non proliferativa di grado severo
- Insufficienza renale severa (livelli di creatinina > 2,5 mg/dl)
- Cirrosi epatica avanzata
- Malattia neoplastica attiva o storia di malignità: non ci sono prove che la sostituzione di GH negli adulti aumenti il rischio di neoplasia de novo o tumore maligno recidivante. La terapia con GH non sarà iniziata in pazienti con neoplasia attiva, sia di nuova diagnosi che ricorrente, nonché in soggetti con una storia di cancro inferiore a un anno. Poiché deficit di ormone della crescita può essere un segno precoce della presenza di un tumore ipofisario (o, raramente, altri tumori cerebrali), la presenza di tali tumori sarà esclusa prima dell'inizio del trattamento. La terapia con GH non sarà utilizzato in pazienti con qualsiasi evidenza di progressione o la reiterazione di lesione intracranica occupante spazio
- Pazienti con gravi malattie acute causate da complicazioni per interventi chirurgici a cuore aperto o addominali, traumi accidentali multipli, o insufficienza respiratoria acuta
- Infezione attiva o sepsi.
- Eventuali allergie a ormone della crescita, o altri eccipienti quali alcool benzilico, saccarosio, acido fosforico, idrossido di sodio, o metacresolo.

- Sindrome Coronarica Acuta nei 6 mesi precedenti

E.5 End points

E.5.1

Primary end point(s)

The objective of the study is to determine whether treatment of GHD improves peak oxygen con-sumption (peak VO2), a recognized surrogate end-point of CHF progression. According to previous observations, we set a target increase of peak VO2 in the treated arm at 3 ml/kg/min at the end of the study

L’obiettivo dello studio è determinare se il trattamento con GHD migliora il picco di consumo di ossigeno (peak VO2), un importante e riconosciuto end-point surrogato di progressione di ICC. In accordo con le precedenti osservazioni, abbiamo settato come obiettivo peak VO2 di almeno 3 ml/kg/min alla conclusione dello studio

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

Secondary end-points include:
1. Hospitalizations
2. End-systolic LV volumes
3. NT-proBNP levels
4. QoL scores
5. Endothelial function (flow-mediated vasodilation)
6. Muscle strength (handgrip)
7. Levels of Endothelial Progenitor Cells (EPCs)
8. Levels of lymphocyte G protein-coupled receptor kinase (GRK)-2

• ospedalizzazione
• volume telediastolico del VS
• livelli di NT-pro BNP
• qualità di vita mediante score QoL
• funzione endoteliale (mediante vasodilatazione flusso mediata)
• forza muscolare (handgrip)
• livelli delle cellule progenitrici endoteliali (EPCs)
• livelli linfocitari dei recettori chinasi 2 G protein-coupled (GRK-2)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 Months

12 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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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.8.6 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

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

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)

patients may continue the treatment after the end of study if needed

i pazienti potranno continuare il trattamento dopo il termine dello 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

2018-07-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-18

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

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