Clinical Trials Register

Summary
EudraCT Number:	2023-000082-13
Sponsor's Protocol Code Number:	GR-2021-12374243
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:	2023-02-06
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

2023-000082-13

A.3

Full title of the trial

Surgical versus Medical Treatment in Microprolactinomas (SUMET PRO)

A.3.1

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

Surgical versus Medical Treatment in Microprolactinomas (SUMET PRO)

A.3.2

Name or abbreviated title of the trial where available

SUMET PRO

A.4.1

Sponsor's protocol code number

GR-2021-12374243

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 USL DI BOLOGNA
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	Ministero della Salute
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 USL di Bologna - IRCCS ISNB
B.5.2	Functional name of contact point	Programma Neurochirurgia Ipofisi
B.5.3	Address:
B.5.3.1	Street Address	Via Altura, 3
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40139
B.5.3.4	Country	Italy
B.5.6	E-mail	federica.guaraldi@ausl.bologna.it

D. IMP Identification
D.IMP: 1
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	DOSTINEX - 0.5MG COMPRESSE 8 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA 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	CABERGOLINA
D.3.9.2	Current sponsor code	G02CB03
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	0.5
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

Microprolactinomas

Diagnosi clinica e biochimica di iperprolattinemia

E.1.1.1

Medical condition in easily understood language

Microprolactinomas

Diagnosi clinica e biochimica di iperprolattinemia

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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10036831
E.1.2	Term	Prolactin-producing pituitary tumour
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the non-inferiority of EES with respect to CAB (standard care) for the rate of biochemical remission (defined as prolactin normalization in the absence of treatment) at 6- and 12-month follow-up, in newly diagnosed, treatment naïve patients with m-PRL.

Determinare la non inferiorità della EES (trattamento sperimentale) rispetto a CAB (cura standard) in termini di tasso di remissione biochimica a 6 e 12 mesi di follow-up, in pazienti con m-PRL di nuova diagnosi, mai trattati

E.2.2

Secondary objectives of the trial

- To determine m-PRL remnant at MRI with g.c.m. performed at 6 and 12 months after EES or starting CAB.
- To determine the rate of drug resistance (defined as failure to achieve normal prolactin levels and a reduction of adenoma size <50% on maximally tolerated doses after at least 6 months of treatment), and of AEs, in patients treated with CAB. Potential predictors of drug resistance may be also investigated.
- To determine the type and rate of surgical complications. Potential predictors of surgical complications may be also investigated.

- Definire la capacità di EES vs. CAB nel ridurre la massa del m-PRL a 6 e 12 mesi tramite valutazione con RMN
- Determinare il tasso di resistenza alla terapia ed EA nei pazienti trattati con CAB, ed identificarne i potenziali predittori
- Determinare l’incidenza e la tipologia di complicanze nei pazienti trattati con EES, ed identificarne i potenziali predittori

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- age > 18 years old
- male or female gender
- clinical manifestations suggestive for hyperprolactinemia
- prolactin levels above upper lower limits confirmed at >2 single determinations, and at serial
determinations (prolactin curve)
- exclusion of macroprolactin
- exclusion of other endogenous or iatrogenic causes of hyperprolactinemia, according to the
Endocrine Society Guidelines
- evidence of a pituitary adenoma with maximum diameter = 10 mm (m-PRL) at the MRI with g.c.m.
- patient able to understand the study purpose, to give informed written consent, and to respond to
self-administered questionnaires
- no previous medical, surgical or radiation treatment for hyperprolactinemia
- signed informed consent

età >18 anni; sesso maschile o femminile; diagnosi clinica e biochimica di iperprolattinemia; esclusione di macroprolattina, di cause endogene o iatrogene di iperprolattinemia; evidenza alla RMN di un adenoma ipofisario con diametro massimo <10 mm (m-PRL); nessun precedente trattamento per l'iperprolattinemia; paziente in grado di comprendere lo scopo dello studio, di dare il consenso informato scritto e di rispondere ai questionari autosomministrati

E.4

Principal exclusion criteria

- contraindications to general anesthesia or surgery
- contraindications to CAB
- pregnancy at the time of randomization
- clinical and/or biochemical evidence of concomitant secretion of other pituitary hormones (i.e., GH,
TSH, FSH/LH and/or ACTH) by the microadenoma
- prior surgery or radiotherapy to the skull base and/or hypothalamic-pituitary area
- prior CAB treatment
- concomitant treatment with other dopamine agonists
- patient unable to understand the study purpose and/or to give informed written consent and/or to
respond to self-administered questionnaires
- other medical conditions that to the opinion of physicians are not compatible with inclusion in a trial.

controindicazioni all'anestesia generale o all'EES; controindicazioni a CAB; concomitante trattamento con altri dopamino agonisti; gravidanza al momento della randomizzazione; concomitante secrezione di altri ormoni ipofisari da parte dell’adenoma; precedente chirurgica/radioterapia del basicranio o CAB; paziente incapace di comprendere lo scopo dello studio e/o di dare il consenso informato scritto e/o di rispondere ai questionari autosomministrati

E.5 End points

E.5.1

Primary end point(s)

Prolactin levels will be measured on single fasting venous sampling at 6- and 12-month follow up to determine the rate of biochemical remission in patients treated with EES or CAB.

I livelli di prolattina saranno misurati su un singolo prelievo venoso a digiuno a 6 e 12 mesi di follow-up per determinare il tasso di remissione biochimica nei pazienti trattati con EES o CAB.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 and 12 month

6 e 12 mesi

E.5.2

Secondary end point(s)

MRI with g.c.m will be performed at study enrollment (baseline) and at 6- and 12- month follow-up to evaluate m-PRL diameter, so the ability of EES and CAB to reduce tumor mass.
Patient QoL, depression and anxiety scores (DAS) and ICD-RB will be assessed at baseline and at 6- and 12-month follow-up through self-administered validated questionnaires in patients randomized to CAB. Intra- and inter-patient variations will be recorded. Descriptive analysis will be performed to determine the overall impact of CAB on QoL, as well as the type and incidence of physical and psychological AEs.
Prolactin levels at baseline and at 6- and 12-month follow-up will be assessed to determine the rate of drug resistance. Predictive analysis will be then performed to identify pre-treatment patient and m-PRL factors associated with increased risk of AEs and of CAB resistance.
Patient QoL and DAS will be assessed at baseline and at 6- and 12-month follow-up through self-administered validated questionnaires (same as per patients treated with CAB) in patients randomized to EES arm. Intra- and inter-patient variations will be recorded. Descriptive analysis will be performed to determine the overall impact of EES on QoL, as well as the type and incidence of surgical complications. Predictive analysis will be then performed to identify pre-treatment patient and m-PRL factors associated with increased risk of developing surgical complications.

Verrà eseguita un'analisi comparativa della riduzione dei livelli di prolattina e delle dimensioni dell'adenoma alla risonanza magnetica nei pazienti trattati con EES e cabergolina a 6 e 12 mesi di follow-up per determinare l'efficacia del trattamento a inizio e fine follow-up.
La QoL dei pazienti, i punteggi di depressione e ansia e l'ICD saranno valutati al basale e 6 e 12 mesi mediante questionari autosomministrati e validati nei pazienti randomizzati a CAB. Verranno registrate le variazioni intra- e inter-paziente. Verrà eseguita un'analisi descrittiva per determinare l'impatto complessivo della CAB sulla QoL, nonché il tipo e l'incidenza degli EA fisici e psicologici. I livelli di prolattina al basale e ai suddetti follow-up saranno valutati per determinare il tasso di resistenza al farmaco. Verrà quindi eseguita un'analisi predittiva per identificare i fattori associati ad aumento del rischio di EA e resistenza alla DA.
La QoL dei pazienti sarà valutata al basale e 6 e 12 mesi dall’EES mediante questionari autosomministrati e validati nei pazienti trattati con chirurgia. Saranno registrate le variazioni intra- e inter-paziente. Verrà eseguita un'analisi descrittiva per determinare l'impatto complessivo della EES sulla QoL, nonché il tipo e l'incidenza delle complicanze chirurgiche. Verrà quindi eseguita un'analisi predittiva per identificare i fattori associati ad un aumento del rischio di complicanze.

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 6 and 12 month

3,6 e 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

E.6.5

Efficacy

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

Chirurgia

Surgery

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 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 2023-02-06.

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)

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

2023-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-16

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

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