Clinical Trials Register

Summary
EudraCT Number:	2019-003699-38
Sponsor's Protocol Code Number:	CEDM-MRI
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:	2021-05-24
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

2019-003699-38

A.3

Full title of the trial

DETECTION RATE AND CLASSIFICATION OF BREAST LESIONS WITH DIGITAL MAMMOGRAPHY WITH CONTRAST MEDIUM (CEDM) ALONE AND IN COMBINATION WITH TOMOSYNTHESIS COMPARED TO MR IMAGING WITH GADOLINIUM IN DYNAMICS (DCE-MRI)

DETECTION RATE E CLASSIFICAZIONE DELLE LESIONI MAMMARIE CON LA MAMMOGRAFIA DIGITALE CON MEZZO DI CONTRASTO (CEDM) DA SOLA E IN COMBINAZIONE ALLA TOMOSINTESI RISPETTO ALL’IMAGING DI RM CON GADOLINIO IN DINAMICA (DCE-MRI)

A.3.1

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

CLASSIFICATION OF BREAST LESIONS WITH DIGITAL MAMMOGRAPHY WITH CONTRAST MEDIUM (CEDM)

CLASSIFICAZIONE DELLE LESIONI MAMMARIE CON LA MAMMOGRAFIA DIGITALE CON MEZZO DI CONTRASTO (CEDM)

A.3.2

Name or abbreviated title of the trial where available

CEDM-MRI

A.4.1

Sponsor's protocol code number

CEDM-MRI

A.5.4

Other Identifiers

Name:

CEDM-MRI

Number:

CEDM-MRI

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	ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE
B.5.2	Functional name of contact point	SC RADIODIAGNOSTICA
B.5.3	Address:
B.5.3.1	Street Address	Via Mariano Semmola, snc
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	0815903738
B.5.5	Fax number	0815903825
B.5.6	E-mail	a.petrillo@istitutotumori.na.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	VISIPAQUE
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	VISIPAQUE
D.3.2	Product code	[VISIPAQUE]
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IODIXANOLO
D.3.9.2	Current sponsor code	CEDM-MRI
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	320
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

Breast souspicious lesions

Lesioni mammarie sospette

E.1.1.1

Medical condition in easily understood language

Breast souspicious lesions

Lesioni mammarie sospette

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066275
E.1.2	Term	Comedocarcinoma of breast
E.1.2	System Organ Class	100000004864

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 study aims to evaluate the detection rate and the diagnostic accuracy, the evaluation of breast pathology in terms of multifocality, multicentricity, bilaterality of the CEDM alone and in combination with the Tomosynthesis with respect to the magnetic resonance considered both CE-MRI that as DCE-MRI.

Lo studio mira a valutare su base casistica il tasso di rilevazione e l'accuratezza diagnostica, la valutazione della patologia mammaria in termini di multifocalità, multicentricità, bilateralità della CEDM da sola e in combinazione con i Tomosintesi rispetto alla risonanza magnetica considerata sia CE -MRI che come DCE-MRI.

E.2.2

Secondary objectives of the trial

Secondary objective is the evaluation of a radiomic signature of morphological and textile characteristics extracted from the three imaging techniques (CEDM, DBT and MRI) in the classification of breast diseases in terms of benignity, malignancy, grade and tumor phenotype. For magnetic resonance imaging, the dynamic characteristics that can be extracted from the DCE-MRI and the perfusion and diffusion characteristics that can be extracted from the Diffusion Weighted Imaging and Diffusion Kurtosis Imaging methods will also be considered according to the Magnetic Resonance imaging protocol for the valuable functional information content described.

Obiettivo secondario è la valutazione di una firma radiomica di caratteristiche morfologiche e tessili estratte dalle tre tecniche di imaging (CEDM, DBT e MRI) nella classificazione delle malattie mammarie in termini di benignità, malignità, grado e fenotipo tumorale. Per la risonanza magnetica saranno considerate anche le caratteristiche dinamiche estraibili dalla DCE-MRI e le caratteristiche di perfusione e diffusione estraibili dalle modalità Diffusion Weighted Imaging and Diffusion Kurtosis Imaging Secondo il protocollo di imaging di Risonanza Magnetica per il prezioso contenuto informativo funzionale descritto.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a) age> 18 years
b) patients with suspected mammary pathology or patients in pre-surgical staging due to already ascertained breast pathology (conventional ultrasound and / or traditional 2D mammography) or with a cito / pathological examination
c) full information on the study and signature of the informed consent to participate in the study
d) execution of examinations at any time of the menstrual cycle
e) estimated glomerular filtrate rate (eGFR)> 60mL / min / 1.73m2, derived from serum creatinine dosage within two weeks prior to study enrollment

a) età > 18 anni
b) pazienti con sospetta patologia mammaria o pazienti in stadiazione pre-chirurgica per patologia mammaria già accertata all’imaging convenzionale (Ecografia e/o Mammografia tradizionale 2D) o con l’esame cito/isto-patologico
c) piena informazione sullo studio e firma del consenso informato alla partecipazione allo studio
d) esecuzione degli esami in qualsiasi momento del ciclo mestruale
e) tasso stimato di filtrato glomerulare (eGFR) > 60mL/min/1.73m2, derivato dal dosaggio di creatinina nel siero entro due settimane precedenti l'arruolamento nello studio

E.4

Principal exclusion criteria

Absolute exclusion criteria
a) presence of pacemakers or other devices in the chest wall
b) inability to maintain an immobile position during the examination
c) inflammatory dermatological diseases (psoriasis, eczema, etc.)
d) presence of tattoos on the affected area
e) presence of nipple piercings that cannot be removed
f) internal / external devices that prevent correct patient positioning
g) metal / electronic systems, metal splinters
h) particular conformation of the breast which prevents the examination from being carried out (in particular breast too large)
i) metal allergies
j) allergies to iodine and / or gadolinium contrast medium
k) claustrophobia
l) acute renal failure of any severity due to hepatorenal syndrome and / or established in the pre-operative period after liver transplantation
m) acute or chronic, moderate or severe renal failure (glomerular filtration rate <60mL / min / 1.73m2)
n) hypersensitivity to the active ingredient of the contrast medium or to any of the excipients (see brochure Visipaque 320)
o) Full-blown thyrotoxicosis
p) participation in a clinical study in which an experimental drug was administered within 30 days or 5 half-lives of the study drug
q) any clinical condition that in the investigator's judgment would make the patient unsuitable for the study
r) presence of breast implants
s) pregnancy or breastfeeding **
t) presence of severe heart disease and pulmonary hypertension
u) presence of acute brain pathologies, history of epilepsy
v) presence of paraproteinemia (myelomatosis and Waldenström macroglobulinemia)
w) presence of pheochromocytoma
x) presence of hyperthyroidism.
** The state of pregnancy was first ascertained from enrollment by means of the dosage of Beta-hCG on the urine (pregnancy test or urinary beta-HCG) or on the blood (plasma beta-hCG).

Relative exclusion criteria
a) targeted micro-biopsy in the ipsilateral breast within three months from the date of enrollment in the study
b) needle drawn into the ipsilateral breast within one month of the study enrollment date
c) presence of surgical clips or open wounds

Criteri di esclusione assoluti
a) presenza di pacemakers o altri devices nella parete toracica
b) incapacità a mantenere una posizione immobile durante l'esame
c) malattie dermatologiche infiammatorie (psoriasi, eczema, ecc.)
d) presenza di tatuaggi sulla zona interessata
e) presenza di piercing al capezzolo che non possono essere rimossi
f) dispositivi interni/esterni che impediscono il corretto posizionamento della paziente
g) impianti metallici/elettronici, schegge metalliche
h) particolare conformazione della mammella che impedisce l'esecuzione dell'esame (in particolare mammella troppo grandi)
i) allergie ai metalli
j) allergie al mezzo di contrasto iodato e/o gadolinio
k) claustrofobia
l) insufficienza renale acuta di qualsiasi gravità dovuta a sindrome epatorenale e/o stabilitasi nel periodo pre-operatorio al trapianto di fegato
m) insufficienza renale acuta o cronica, moderata o grave (tasso di filtrazione glomerulare <60mL/min/1.73m2)
n) ipersensibilità al principio attivo del mdc o ad uno qualsiasi degli eccipienti (vedere brochure Visipaque 320)
o) Tireotossicosi conclamata
p) partecipazione ad uno studio clinico in cui è stato somministrato un farmaco sperimentale entro 30 giorni o 5 emivite del farmaco in studio
q) qualsiasi condizione clinica che a giudizio dello sperimentatore renderebbe il paziente non idoneo per lo studio
r) presenza di protesi mammarie
s) stato di gravidanza o allattamento**
t) presenza di gravi cardiopatie e da ipertensione polmonare
u) presenza di patologie cerebrali acute, anamnesi di epilessia
v) presenza di paraproteinemia (mielomatosi e macroglobulinemia di Waldenström)
w) presenza di feocromocitoma
x) presenza di ipertiroidismo.
**Lo stato di gravidanza è stato accertato prima dall’arruolamento mediante il dosaggio della Beta-hCG sulle urine (Test di gravidanza o beta-HCG urinaria) o sul sangue (beta-hCG plasmatica).

Criteri di esclusione relativi
a) micro-biopsia mirata nella mammella ipsilaterale entro tre mesi dalla data di arruolamento nello studio
b) ago aspirato nella mammella ipsilaterale entro un mese dalla data di arruolamento nello studio
c) presenza di clips chirurgiche o ferite aperte

E.5 End points

E.5.1

Primary end point(s)

Equivalence / Comparability of CEDM alone and in combination of DBT compared to Magnetic Resonance with contrast medium (CE-MRI) in terms of detection rate and diagnostic accuracy. The ability to assess the extent of mammary pathology in terms of multifocality, multicentricity and bilaterality will also be compared. Standard of truth is the outcome of the cyto-histo-pathological examination.
Detection time after the outcome of the biotic collection or after the outcome of the histology on the surgically removed sample.

Equivalenza/Comparabilità della CEDM da sola e in combinazione della DBT rispetto alla Risonanza Magnetica con mdc (CE-MRI) in termini di detection rate e accuratezza diagnostica. La capacità nella valutazione dell’estensione della patologia mammaria in termini di multifocalità, multicentricità e bilateralità sarà anche confrontata. Standard of truth è l’esito dell’esame cito/isto-patologico.
Tempo di rilevazione dopo esito del prelievo biotico o dopo esito dell’istologia sul campione asportato chirurgicamente.

E.5.1.1

Timepoint(s) of evaluation of this end point

Following biopsy or surgical treatment

A seguito di prelievi bioptico o di trattamento chirurgico

E.5.2

Secondary end point(s)

Evaluation of the diagnostic accuracy of a radiomatic signature of morphological and textural features extracted from the three modalities (CEDM, DBT and MRI) in the classification of mammary lesions in terms of benignity, malignancy, grade and tumor phenotype (luminal A, luminal B, HER2 +, triple negative). For MRI, the dynamic features that can be extracted from the DCE-MRI and the perfusion and diffusion features that can be extracted from the Diffusion Weighted Imaging and Diffusion Kurtosis Imaging modes foreseen in the Resonance imaging protocol for the valuable functional information content it contains will also be considered.
Standard of truth is the outcome of the cyto-histo-pathological examination.
Detection time after the outcome of the biotic collection or after the outcome of the histology on the surgically removed sample.

Valutazione dell’accuratezza diagnostica di una firma radiomica di features morfologiche e tessiturali estratte dalle tre modalità (CEDM, DBT e MRI) nella classificazione delle lesioni mammarie in termini di benignità, malignità, grado e fenotipo tumorale (luminal A, luminal B, HER2+, triple negative). Per la MRI saranno considerate anche le features dinamiche estraibili dalla DCE-MRI e le features di perfusione e diffusione estraibili dalle modalità Diffusion Weighted Imaging e Diffusion Kurtosis Imaging prevista nel protocollo di imaging di Risonanza per il prezioso contenuto informativo funzionale che contiene.
Standard of truth è l’esito dell’esame cito/isto-patologico.
Tempo di rilevazione dopo esito del prelievo biotico o dopo esito dell’istologia sul campione asportato chirurgicamente.

E.5.2.1

Timepoint(s) of evaluation of this end point

Following biopsy or surgical treatment

A seguito di prelievi bioptico o di trattamento chirurgico

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

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)

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

a singolo braccio

single arm

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

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

36 MONTHS and in any case until reaching at least 358 cases of breast lesions

36 MESI e comunque fino al raggiungimento di almeno 358 casi di lesioni mammarie

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:

358

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

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

358

F.4.2

For a multinational trial

F.4.2.1

In the EEA

358

F.4.2.2

In the whole clinical trial

358

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)

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

2021-04-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-11

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

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