Clinical Trials Register

Summary
EudraCT Number:	2022-002480-30
Sponsor's Protocol Code Number:	-
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:	2022-11-18
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

2022-002480-30

A.3

Full title of the trial

PeRinatal Outcomes with ACTive versus expectant management of women with Pre-labor Rupture Of Membranes: a phase III, open-label, randomized controlled multicentric trial

Esiti perinatali di un management attivo delle donne con rottura prematura delle membrane amniocoriali: uno studio multicentrico controllato randomizzato di fase III, in aperto

A.3.1

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

PeRinatal Outcomes with ACTive versus expectant management of women with Pre-labor Rupture Of Membranes: a phase III, open-label, randomized controlled multicentric trial

Esiti perinatali di un management attivo delle donne con rottura prematura delle membrane amniocoriali: uno studio multicentrico controllato randomizzato di fase III, in aperto

A.3.2

Name or abbreviated title of the trial where available

PROACT PROM

A.4.1

Sponsor's protocol code number

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 OSPEDALIERO-UNIVERSITARIA DI MODENA
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	Azienda Ospedaliero-Universitaria di Modena (Fondo Ricerca Aziendale)
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	Servizio Formazione, Ricerca e Innovazione
B.5.2	Functional name of contact point	Clinical Trial Quality Team
B.5.3	Address:
B.5.3.1	Street Address	via Del Pozzo
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.4	Telephone number	0594225868
B.5.5	Fax number	0594224369
B.5.6	E-mail	riceracainnovazione@aou.mo.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.2.1.2	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	DINOPROSTONE
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Vaginal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	-
D.3.9.3	Other descriptive name	dinoprostone
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2
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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	un agente ossitocico
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.2.1.2	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	dinoprostone
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Vaginal delivery system
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	-
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	10
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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Agente ossitocinico
D.IMP: 3
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.2.1.2	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	ossitocina
D.3.2	Product code	[-]
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.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	Yes
D.3.11.13.1	Other medicinal product type	nonapeptide ciclico
D.IMP: 4
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.2.1.2	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	misoprostolo
D.3.2	Product code	[-]
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.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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	Yes
D.3.11.13.1	Other medicinal product type	analogo sintetico della prostaglandina E1 (PGE1)

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

1400 Women with PROM at term and a GBS negative swab

La popolazione in studio consiste in 1400 pazienti gravide con diagnosi di rottura prematura delle membrane (PROM), con tampone vagino-rettale negativo per S. Agalactiae di gruppo B (GBS).

E.1.1.1

Medical condition in easily understood language

Pregnant patients diagnosed with premature rupture of membranes (PROM)

Pazienti gravide con diagnosi di rottura prematura delle membrane (PROM)

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

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	10073024
E.1.2	Term	Preterm premature rupture of membranes
E.1.2	System Organ Class	10036585 - Pregnancy, puerperium and perinatal conditions

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 first objective of this study is to evaluate whether active management of women with PROM (early induction) reduces the newborn need of respiratory support.

L'obiettivo primario di questo studio è valutare se la gestione attiva delle donne con PROM (induzione precoce) riduce la morbilità infettiva materna/ neonatale evitando il trattamento antibiotico durante il parto.

E.2.2

Secondary objectives of the trial

To evaluate the changes in the neonatal meconium microbiome and to assess the placental and umbilical cord histology in both the study arms.

Gli obiettivi secondari di questo studio sono legati alla sicurezza della gestione attiva valutata attraverso il tasso di nati morti, l'insorgenza di infezioni nella madre e nel feto e attraverso la durata del ricovero in ospedale sia della madre che del feto.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Neonatal meconium microbiome study
In this ancillary study, which will be carried out only in the Modena center, we aim to evaluate the meconium microbiome alteration in the first 24 hours of life, after a new strategy for managing fullterm pregnant women with PROM and negative GBS screening is implemented.

Placental/Umbilical cord histology
In this ancillary study, which will be carried out only in the Milano Buzzi center, we aim to evaluate the placental and umbilical cord samples to evaluate signs of histologic chorioamnionitis.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Studio neonatale del microbioma del meconio
In questo studio ancillare, che sarà effettuato solo nel centro di Modena, ci proponiamo di valutare l'alterazione del microbioma del meconio nelle prime 24 ore di vita, dopo che è stata implementata una nuova strategia per la gestione delle donne in gravidanza a termine con screening PROM e GBS negativo.

Istologia placentare/ombelicale
In questo studio ancillare, che sarà effettuato solo nel centro di Milano Buzzi, ci proponiamo di valutare i campioni di placenta e cordone ombelicale per valutare i segni di corioamnionite istologica.

E.3

Principal inclusion criteria

1. Gestational age = 37 weeks
2. Negative rectovaginal GBS swab
3. Absent/poor uterine contractile activity 6 h after PROM (0-2 contractions /10 min)
4. Cephalic presentation
5. Age =18 years of age at the time of randomization
6. Ability to provide an informed consent
7. Signed informed consent

1. Epoca gestazionale > 37 settimane
2. GBS negativo
3. Attività contrattile uterina (ACU) assente/scarsa a 6 ore dalla PROM (<1-2 contrazioni/10 minuti)
4. Presentazione cefalica
5. Età = 18 anni
6. Capacità di esprimere un consenso informato
7. Firma del consenso informato

E.4

Principal exclusion criteria

1. Prematurity (<37 weeks)
2. GBS positive vagino-rectal swab or with an unknown swab
3. Multiple pregnancies
4. Previous cesarean section (CS)
5. Breech presentation, transverse lie or other indication for elective CS
6. Suspected clinic for intra-amniotic infection
7. Stained amniotic fluid
8. Alterations of the FHR
9. Unknown exact ROM time

1. Prematurità (< 37 settimane)
2. Tampone vagino-rettale positivo per GBS o con tampone sconosciuto
3. Gravidanze multiple
4. Pregresso taglio cesareo (TC)
5. Presentazione podalica, situazione trasversa o altra indicazione a TC elettivo
6. Clinica sospetta per infezione intra-amniotica
7. Liquido amniotico macchiato
8. Alterazioni dell'FHR
9. Tempo ROM sconosciuto

E.5 End points

E.5.1

Primary end point(s)

The reduction of maternal/neonatal infectious morbidity through the active management of labor

La riduzione della morbilità infettiva materna/neonatale attraverso la gestione attiva del travaglio

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary end point will be evaluated through the measurement of the rate of chorioamnionitis diagnosis (according to the Triple I) during labor (visit 1), the need for antibiotic treatment for the mother and the neonate (visit 1, 2 and follow up at 48 hours post-partum), and the rate of ventilatory support measures carried out on the neonate after birth (visit 2).

L'end point primario sarà valutato attraverso la misurazione del tasso di diagnosi di corioamnionite (secondo la Tripla I) durante il travaglio (visita 1), la necessità di un trattamento antibiotico per la madre e il neonato (visita 1, 2 e follow up a 48 ore dopo il parto) e il tasso di misure di supporto ventilatorio effettuate sul neonato dopo la nascita (visita 2).

E.5.2

Secondary end point(s)

The secondary objectives of this study are related to the safety of the active management assessed through the rate of stillbirths, the onset of infections in the mother and fetus and through the length of hospitalization of both the mother and the fetus.

E.5.2.1

Timepoint(s) of evaluation of this end point

Labor, visits and follow up

Travaglio, visite e follow up

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

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

Yes

E.6.13.1

Other scope of the trial description

Reduction of maternal/neonatal infectious morbidity saving antibiotic treatment throughout labor

Riduzione della morbilità infettiva materna/neonatale risparmiando il trattamento antibiotico durante tutto il travaglio

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

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

tempo di travaglio Gestione in attesa

timing of labor Expectant Management

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:

1400

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

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

1400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1400

F.4.2.2

In the whole clinical trial

1400

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)

the best supportive therapy

la miglior terapia di supporto

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

2023-03-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-07-18

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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