Clinical Trials Register

Summary
EudraCT Number:	2013-004955-19
Sponsor's Protocol Code Number:	PARIDA-01/2013
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:	2014-05-22
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

2013-004955-19

A.3

Full title of the trial

PARACETAMOL VERSUS IBUPROFEN FOR PATENT DUCTUS ARTERIOSUS TREATMENT IN PRETERM INFANTS.

PARACETAMOLO VERSUS IBUPROFENE PER IL TRATTAMENTO DEL DOTTO DI BOTALLO PERVIO NEL NEONATO PRETERMINE: Studio clinico multicentrico randomizzato, controllato, doppio cieco

A.3.1

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

Paracetamol versus ibuprofen, (a drug that represents the standard treatment in this condition) to treat preterm infants with Perstent Ductus Arteriosus unclosure that is without sponatanous clousure at the

Uso del paracetamolo in confronto ad ibuprofene, che rappresenta il farmaco già in uso in questa condizione di malattia, di bambini nati prematuri che presentano il foro di Botallo pervio, cioè non spontaneamente saldato alla nascita che, se non trattata, può comportare serie conseguenze a livello cardio circolatorio

A.3.2

Name or abbreviated title of the trial where available

PARIDA

A.4.1

Sponsor's protocol code number

PARIDA-01/2013

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 Ospedaliera di Padova
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 Ospedaliera di Padova
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 Ospedaliera di Padova
B.5.2	Functional name of contact point	Dipartimento per la salute della Do
B.5.3	Address:
B.5.3.1	Street Address	Via Giustiniani, 1
B.5.3.2	Town/ city	Padova
B.5.3.3	Post code	35.128
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390498213545
B.5.5	Fax number	+390498211407
B.5.6	E-mail	lago@pediatria.unipd.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	No
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	paracetamol
D.3.4	Pharmaceutical form	Solution for infusion
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	PARACETAMOL
D.3.9.3	Other descriptive name	(N- acetyl-para-amino-phenol) , Acetaminophen
D.3.9.4	EV Substance Code	SUB09611MIG
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	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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	medicinal substance of chemical origin
D.IMP: 2
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	Pedea 5 mg/mL solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Orphan Europe SARL
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	Solution for infusion
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	IBUPROFEN
D.3.9.1	CAS number	15687-27-1
D.3.9.4	EV Substance Code	SUB08098MIG
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	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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	medicinal product of chemical synthesis

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 infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patent ductus arteriosus hemodynamically important

dotto arterioso pervio emodinamicamente rilevante

E.1.1.1

Medical condition in easily understood language

a neonate ductus arteriosus that lails to close soon after birth

dotto arterioso nel neonato che non si chiude spontaneamente subito dopo la nascita

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10034190
E.1.2	Term	PDA Repair patent ductus arteriosus
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the efficacy and safety of 2 therapeutic regimens for PDA treatment ( paracetamolo vs ibuprofen) in a population of preterm newborns of GA <31+6 weeks with respiratory distress syndrome (RDS) and HsPDA:

Cnfrontare l’efficacia e la sicurezza del trattamento standard del PDA con ibuprofene vs trattamento sperimentale con paracetamolo per la chiusura farmacologica di un PDA emodinamicamente significativo (HsPDA) in neonati pretermine con distress respiratorio

E.2.2

Secondary objectives of the trial

To evaluate the safety of the 2 therapeutic regimens of paracetamol or ibuprofen.

Valutare la sicurezza dei 2 regimi terapeutici a confronto costituiti da paracetamolo e ibuprofene.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• inborn neonates
• preterm neonates ≤ 31+ 6 days weeks gestation
• < 72 hours of life
• newborns with HsPDA
• parental written informed consent for participation in the study must be obtained

• neonati INBORN (nati in sede)
• neonati pretermine < 31 +6 settimane gestazionali
• < 72 ore di vita
• neonati con HsPDA
• ottenimento del consenso informato scritto dei genitori per la partecipazione allo studio

E.4

Principal exclusion criteria

• Serum creatinine concentration greater than 1,5 mg/dl (132 Mole/L)
• Urine output less than 1 ml/Kg/h with adeguate fluid intake (70-90 ml/kg/die)
• Severe IVH (> grade II according to Volpe classification)
• Clinical bleeding tendency (as revealed by hematuria, blood in the gastric aspirate or in the stools, blood in the endotracheal tube aspirate)
• Necrotizing enterocolitis or marked abdominal distention with gastric bile residuals
• Thrombocyte count of less than 50.000/mm3
• Proved Sepsis
• Severe coagulopathy or liver failure
• Evidence of severe birth asphyxia, that is an APGAR score below 5 at 5 minutes of age and/or umbilical arterial pH < 7.0
• Known genetic or chromosomal disorders
• Participation in another clinical trial of any placebo, drug, biological, or device conducted under the provisions of a protocol.

• evidenza di asfissia severa alla nascita, definita da un APGAR score minore di 4 a 5 minuti di vita e/o pH dell’arteria ombelicali < 7.0
• disordini genetici o cromosomici conosciuti
• concentrazione di creatinina nel siero maggiore di 1,5 mg/dl (132 µM/l)
• escrezione urinaria minore di 1 ml/Kg/h con adeguato introito di fluidi (70-90 ml/Kg/die)
• IVH severa (> grado II secondo la classificazione Volpe)
• tendenza al sanguinamento clinico (rilevato attraverso ematuria, sangue nell’aspirato gastrico o nelle feci, sangue nell’aspirato del tubo endotracheale)
• enterocolite necrotizzante o marcata distensione addominale con residui gastrici biliari
• conta delle piastrine minore di 50.000/mm3
• sepsi confermata
• coagulopatia severa o insufficienza epatica
• partecipazione in un altro trial clinico con placebo o farmaci, biologico, o dispositivo condotto sotto la disposizione di un protocollo.

E.5 End points

E.5.1

Primary end point(s)

The rate of ductal closure after the first and second course of pharmacological treatment. (PDA diagnosed by ECHO criteria)

Percentuale della chiusura del PDA dopo il primo ciclo di tre dosi e dopo un ulteriore secondo ciclo “rescue”, valutati mediante Ecocardiografia.

E.5.1.1

Timepoint(s) of evaluation of this end point

The percentage of patients with ductal closure obtained during the study period by echocardiographic evaluation performed after the first three doses, the second three doses, by one week from the end of pharmacological treatment and at discharge. The need of rescue therapy (third course), the rate of reopening and surgical legation will be also considered.

Percentuale della chiusura del PDA dopo il primo ciclo di tre dosi e dopo un ulteriore secondo ciclo “rescue”, valutati mediante Ecocardiografia.

E.5.2

Secondary end point(s)

• Rate of reduced urine output, increase of serum creatinine values and weight
• Rate of reduced in creatinine clearance in mL/min/1.73 m2
• Incidence of IVH/PVL or death within 28 days of life
• Rate of bleeding (pulmonary, renal and gastrointestinal)
• Rate of NEC (all stages according to the modified Bell’s criteria)
• Rate of isolated bowel perforation
• Rate of pulmonary hypertension
• Rate of need for mechanical ventilation at one week of age
• Rate of broncopulmonary dysplasia (BPD)
• Rate of proved sepsis
• Rate of retinopathy of prematurity (ROP)
• Time to start minimal enteral feeding
• Time to full enteral feeding (days)
• Time to regain birth weight (days)
• Survival without major morbidities (BPD, severe IVH, NEC, PVL, ROP, pneumothorax, any late infection).
• Rate of toxic plasma levels of drugs and metabolites.
Moreover, the evaluation of the drug’s safety will be achieved by monitoring and registering adverse events (AEs), serious adverse events, routine laboratory exams and measuring vital signs.

• incidenza di insufficienza renale definita attraverso riduzione dell’escrezione di urina, aumento del valore della creatinina sierica, anomale aumento di peso ed edema.
• incidenza di emorragie intraventricolari (IVH), leucomalacia periventricolare (PVL) o morte entro 28 giorni di vita (outcome composito)
• incidenza di tendenza al sanguinamento valutata attraverso emorragie significative polmonari, renali e gastriche.
• incidenza di enterocolite necrotizzante e perforazione intestinale isolata (senza segni di NEC)
• incidenza di ventilazione meccanica nei neonati ad una settimana di vita
• tolleranza della nutrizione enterale (età alla quale i neonati raggiungono la nutrizione enterale totale)
• incidenza di tossicità epatica
• incidenza di sopravvivenza senza comorbidità maggiori (BPD, IVH severa, NEC, PLV, ROP, pneumotorace, infezione tardiva)
• incidenza di livelli tossici nel sangue dei principi attivi/metaboliti.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Incidence of IVH/PVL or death within 28 days of life7
• Rate of mechanically ventilated newborns at one week of age.
The other end-points, will be registered when they happen.

-IVH e PVL o morte a 28 giorni di vita
- N° neonati ventilati a 7 giorni di vita
Gli altri end-point saranno registrati al tempo in cui accadono.

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

double-dummy

double-dummy to ensure the double-blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

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

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"

Ultima visita dell'ultimo paziente

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

116

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Yes

F.1.1.2.1

Number of subjects for this age range:

116

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)

F.1.3

Elderly (>=65 years)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

preterm newborn infants

neonati

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

116

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)

NONE

NESSUNO

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

2014-09-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-10

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

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