Clinical Trials Register

Summary
EudraCT Number:	2019-002008-41
Sponsor's Protocol Code Number:	GR-MET-19
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:	2020-12-16
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

2019-002008-41

A.3

Full title of the trial

Effect of metyrapone on cardiovascular risk factors in patients with adrenal incidentalomas and subclinical/mild Cushing's syndrome

Effetto della terapia con Metirapone sul rischio cardiovascolare in pazienti con incidentalomi surrenalici e sindrome di Cushing subclinica

A.3.1

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

Effect of metyrapone on cardiovascular risk factors in patients with adrenal incidentalomas and subclinical/mild Cushing's syndrome

Effetto della terapia con Metirapone sul rischio cardiovascolare in pazienti con incidentalomi surrenalici e sindrome di Cushing subclinica

A.3.2

Name or abbreviated title of the trial where available

GR-MET-19

A.4.1

Sponsor's protocol code number

GR-MET-19

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 DI BOLOGNA POLICLINICO S.ORSOLA-MALPIGHI
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	AIFA - Italian Medicines Agency
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	AOU di Bologna
B.5.2	Functional name of contact point	U.O. Endocrinologia
B.5.3	Address:
B.5.3.1	Street Address	via Albertoni 15
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	0512143009
B.5.5	Fax number	0512143080
B.5.6	E-mail	guido.didalmazi@unibo.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	CORMETO - "250 MG CAPSULE MOLLI" 50 CAPSULE IN FLACONE HDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATOIRE HRA PHARMA
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	CORMETO
D.3.2	Product code	[CORMETO]
D.3.4	Pharmaceutical form	Capsule, soft
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	metirapone
D.3.9.2	Current sponsor code	metirapone
D.3.9.3	Other descriptive name	metirapone
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	250 to 750
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

patients with adrenal incidentalomas and subclinical/mild Cushing’s syndrome

incidentalomi surrenalici e sindrome di Cushing subclinica

E.1.1.1

Medical condition in easily understood language

patients with adrenal incidentalomas and subclinical/mild Cushing’s syndrome

incidentalomi surrenalici e sindrome di Cushing subclinica

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	10011652
E.1.2	Term	Cushing's syndrome
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

The main aim of the study is to investigate the efficacy of adding Metyrapone to the standard antihypertensive treatment in improving blood pressure control of hypertensive patients with SCS and bilateral adrenal tumors

Valutare l’efficacia del trattamento con Metirapone associato a terapia antipertensiva (prescritta nell’ambito del normale percorso assistenziale) vs osservazione (sola terapia antipertensiva prescritta nel normale percorso assistenziale) nel migliorare il controllo pressorio in pazienti con ipertensione arteriosa ed incidentalomi surrenalici bilaterali associati a SCS

E.2.2

Secondary objectives of the trial

- to identify biomarkers of treatment efficacy and monitoring
- to evaluate the adrenal morphology after treatment with Metyrapone

1) Identificare nuovi bio-marcatori di efficacia e di monitoraggio della terapia con Metirapone;
2) Valutare i cambiamenti morfologici delle ghiandole surrenaliche dopo trattamento con Metirapone.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Run-in
Inclusion criteria for run-in phase:
- age >18 years and <75 years
- monolateral/bilateral nodules with benign radiological characteristics associated with enlarged adrenal limb width >5 mm at CT scan
- SCS (absence of catabolic signs of Cushing’s syndrome) associated with at least one of the following conditions:
o Cortisol after 1 mg dexamethasone suppression test >50 nmol/L and baseline ACTH <10 pg/mL
o Cortisol after 1 mg dexamethasone suppression test >50 nmol/L and high salivary cortisol at 11 p.m.
o Cortisol after 1 mg dexamethasone suppression test >138 nmol/L
- Arterial hypertension (blood pressure =140/90 mmHg and/or current treatment with antihypertensive drugs)
- Patients who are not candidate for adrenalectomy
- Written informed consent.

Criteri di inclusione – run-in (fase 1)
- età >18 anni e <75 anni
- noduli surrenalici monolaterali o bilaterali con caratteristiche di benignità associati ad ispessimento dei bracci dei surreni >5 mm alla TC addome
- SCS (rilevata 2 volte nei 6 mesi precedenti il run-in) definita dall’assenza di segni catabolici di sindrome di Cushing in associazione a una di queste 3 condizioni:
o Livelli di cortisolo dopo test al desametasone 1 mg >50 nmol/L associato ad ACTH basale <10 pg/mL
o Livelli di cortisolo dopo test al desametasone 1 mg >50 nmol/L associato a cortisolo salivare notturno (ore 23:00) aumentato
o Livelli di cortisolo dopo test al desametasone 1 mg >138 nmol/L
- Ipertensione arteriosa (PA =140/90 mmHg e/o trattamento antipertensivo in atto)
- Pazienti che non possono essere sottoposti ad intervento chirurgico
- Acquisizione del consenso informato.

Criteri di inclusione – randomizzazione (fase 2)
- PA >100/60 mmHg e <130/85 mmHg in corso di terapia antipertensiva (minima dose efficace) entro 6-10 mesi dall’arruolamento.

E.4

Principal exclusion criteria

Exclusion criteria:
- Body mass index =40 kg/m2
- Pregnancy or breastfeeding
- Women in childbearing age who do not use barrier contraceptives. Barrier contraceptives are:
o male or female condom with or without spermicide
o cap, diaphragm or sponge with spermicide
o a combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods)
- Glucocorticoid treatment during the last year before enrollment
- Drugs known to have interactions with Metyrapone
- Drug allergy to Metyrapone or drugs belonging to the same class
- Patients with severe illness
- Patients with primary adrenal insufficiency and severe hypopituitarism
- Patients with reduced liver function
- Patients with untreated hypothyroidism or taking drugs acting on the hypothalamus-pituitary-adrenal axis
- Patients with drug hypersensitivity to Metyrapone or to one of the excipients listed in paragraph 6.1 of the summary of product characteristics (SPCs) – Metyrapone.

Criteri di esclusione
- Indice di massa corporea =40 kg/m2
- Donne in gravidanza o allattamento; la diagnosi di gravidanza verrà eseguita mediante dosaggio di ß-HCG sierica
- Donne in età fertile che utilizzino misure contraccettive diverse da quelle di barriera. Le misure contraccettive di barriera sono:
o Preservativo maschile o femminile con o senza spermicida
o Coppetta cervicale, diaframma o spugne con spermicida
o Combinazione di preservativo maschile e coppetta cervicale, diaframma o spugne con spermicida (metodi di barriera doppi)
- Trattamento con steroidi nell’ultimo anno prima dell’arruolamento
- Assunzione di farmaci noti per interferire con il Metirapone
- Nota o sospetta ipersensibilità al farmaco o alla classe farmacologica in studio
- Pazienti con gravi condizioni cliniche che, a giudizio dello Sperimentatore, controindicano la partecipazione del paziente allo studio
- Pazienti con insufficienza corticosurrenale primaria, con ridotta secrezione surrenale e ipopituitarismo grave
- Pazienti con ridotta funzionalità epatica
- Pazienti con ipotiroidismo non trattato o in trattamento con farmaci che svolgono un’azione sull’asse ipotalamo-ipofisi-surrene
- Pazienti con ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti elencati al paragrafo 6.1 del RCP - Metirapone.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the reduction of the number and/or the dose of antihypertensive drugs after 12 months of treatment with Metyrapone, while keeping blood pressure within pre-fixed target range (>100/60 mmHg e <130/85 mmHg)

Endpoint primario: riduzione del numero e/o del dosaggio dei farmaci antipertensivi a 12 mesi dall’inizio del trattamento con Metirapone, mantenendo il target pressorio prefissato (PA >100/60 mmHg e <130/85 mmHg)

E.5.1.1

Timepoint(s) of evaluation of this end point

12 moths

12 mesi

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

(sola terapia antipertensiva prescritta nel normale percorso assistenziale e del tutto indipendentem

standard antihypertensive treatment in improving blood pressure control of hypertensive (treatment p

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-12-16.

Yes

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)

normal patient 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

2019-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-19

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

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