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    Summary
    EudraCT Number:2013-003883-30
    Sponsor's Protocol Code Number:044CF13273
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-12
    Trial results View 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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-003883-30
    A.3Full title of the trial
    Efficacy and safety of paracetamol in comparison to ibuprofen for patent ductus arteriosus treatment in preterm infants. A randomized, open label, comparator-controlled, prospective study.
    Efficacia e sicurezza di paracetamolo in confronto a ibuprofene nel trattamento del dotto arterioso pervio nei neonati pretermine. Studio randomizzato, in aperto, controllato verso farmaco di confronto, prospettico.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of paracetamol in the treatment of patent ductus arteriosus in preterm infants.
    Efficacia e sicurezza di paracetamolo nel trattamento del dotto arterioso pervio nei
    neonati pretermine.
    A.3.2Name or abbreviated title of the trial where available
    Paracetamol in Patent Ductus Arteriosus
    Paracetamolo nel trattamento del dotto arterioso pervio
    A.4.1Sponsor's protocol code number044CF13273
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAziende Chimiche Riunite Angelini Francesco ACRAF S.p.A
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportACRAF S.p.A
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationACRAF S.p.A
    B.5.2Functional name of contact pointClinical Trial Application Unit
    B.5.3 Address:
    B.5.3.1Street AddressPiazzale della Stazione s.n.c
    B.5.3.2Town/ cityS.Palomba-Pomezia (RM)
    B.5.3.3Post code00040
    B.5.3.4CountryItaly
    B.5.4Telephone number+390691945335
    B.5.5Fax number+39069194333
    B.5.6E-mailg.orticelli@angelini.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TACHIPIRINA 10 mg/ml soluzione per infusione
    D.2.1.1.2Name of the Marketing Authorisation holderAziende Chimiche Riunite Angelini Francesco ACRAF S.p.A
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTACHIPIRINA 10 mg/ml soluzione per infusione
    D.3.2Product code 044
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name PEDEA 5 mg/ml soluzione iniettabile
    D.2.1.1.2Name of the Marketing Authorisation holderOrphan Europe SARL
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/01/20 on 14 February 2001
    D.3 Description of the IMP
    D.3.1Product namePEDEA 5 mg/ml soluzione iniettabile
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Patent ductus arteriosus
    Dotto arterioso pervio
    E.1.1.1Medical condition in easily understood language
    Missing closure of Botallo ductus in preterm infants
    Mancata chiusura del dotto di Botallo nei neonati pretermine
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10034190
    E.1.2Term PDA Repair patent ductus arteriosus
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study objective is to assess the efficacy and safety of paracetamol in comparison to ibuprofen in the treatment of patent ductus arteriosus in preterm infants.
    L'obiettivo dello studio è valutare l’efficacia e la sicurezza di paracetamolo in confronto a ibuprofene nel trattamento del dotto arterioso pervio nei neonati pretermine.
    E.2.2Secondary objectives of the trial
    Not applicable
    Non applicabile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Male or female preterm infants with no limitation of race.
    Gestational age 25+0-31+6 weeks.
    Age 24-72 hours.
    Echocardiographic evidence of hemodynamically significant patent ductus arteriosus at the first 24-72 hours of life.
    The diagnosis of hemodynamically significant PDA requiring treatment will be made by echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium-to-aortic root ratio >1.3 or a ductal size >1.5 mm and excluding the cases in which the closing flow pattern suggests a restrictive PDA [Varvarigou 1996, Su 2008].
    Willingness of the parents/legally authorized representative/child to sign the Informed Consent Form.
    Neonati pretermine maschi e femmine con nessuna limitazione etnica.
    Età gestazionale 25+0-31+6 settimane.
    Età 24-72 ore.
    Evidenza ecocardiografica di dotto arterioso pervio ed emodinamicamente
    significativo tra le prime 24-72 ore di vita.
    La diagnosi di dotto arterioso pervio ed emodinamicamente significativo, che
    richiede trattamento, sarà effettuata tramite evidenza ecocardiografica di shunt
    duttale sinistro-destro, con rapporto tra atrio sinistro e radice aortica >1,3 o una
    dimensione del dotto >1,5 mm ed escludendo i casi in cui il pattern del flusso
    suggerisce un PDA restrittivo [Varvarigou 1996, Su 2008].
    Volontà dei genitori, o del rappresentante legalmente riconosciuto, del bambino a
    firmare il modulo di consenso informato.
    E.4Principal exclusion criteria
    Outborn patients.
    Major congenital anomalies, including but not limited to congenital heart defects, Down syndrome newborn and/or newborn suffering from congenital anomalies diagnosed during the fetal period.
    Known positive HIV and/or known positive HCV newborn’s mother.
    Life threatening infection, complicated or not by multiple organ dysfunction and failure syndrome.
    Hydrops fetalis.
    Pulmonary hypertension diagnosed in the first 24-48 hours of life by means of heart ultrasound when the presence of a right-to-left shunt through the foramen ovale or ductus arteriosus is demonstrated, or when the estimated pulmonary pressure, in terms of the tricuspid regurgitation jet, is greater than two-thirds of the systemic arterial pressure.
    Grade 3 or 4 intraventricular haemorrhage (IVH).
    Urine output <1 ml/kg of body weight/h during a 24 h collection period or urine output <0.5 ml/kg of body weight/h in case it is measured at 24 hours of life of newborn.
    Serum creatinine concentration > 1.5 mg/dl (132 µmol/l).
    Platelet count < 50,000/mm3.
    Major bleeding, as revealed by haematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or consistent oozing of blood from puncture sites.
    Severe liver failure, defined as elevated liver enzymes (ALT/GPT and AST/GOT) > 2 times the upper boundary of the normal range. For this kind of population the following normal ranges will be considered [Rosenthal, 1997]:
    - ALT/GPT: 6-50 U/L
    - AST/GOT: 35-140 U/L
    Medical need of administering other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) different from ibubrofen.
    Participation to another trial involving any investigational drug.
    Outborn neonati
    Anomalie congenite maggiori, incluse ma non limitate a difetti cardiaci congeniti,
    nati con sindrome di Down e/o nati che soffrono di anomalie congenite
    diagnosticate durante il periodo fetale.
    Positività nota per HIV e/o HCV della madre.
    Infezione con pericolo di vita, complicate o no da disfunzione o sindrome da
    insufficienza multi-organo.
    - Idrope fetale.
    - Ipertensione polmonare diagnosticata nelle prime 24-48 ore di vita tramite
    ecografia cardiaca che dimostri presenza di uno shunt destro-sinistro attraverso il
    forame ovale o il dotto arterioso, o quando la pressione polmonare stimata, in
    termini di rigurgito tricuspidale è maggiore di due terzi rispetto la pressione
    arteriosa sistemica.
    Emorragia interventricolare (IVH) di grado 3 o 4.
    Diuresi <1 ml/kg di peso /h durante un periodo di 24 ore o <0,5 ml/kg di peso/h
    nel caso venga misurato alle prime 24 ore di vita del neonato.
    Concentrazione sierica di creatinina > 1,5 mg/dl (132 μmol/l).
    Conta piastrinica < 50.000/mm3.
    Sanguinamenti maggiori, rivelati da ematuria, o sangue nell’aspirato
    endotracheale, o sangue nell’aspirato gastrico, o sangue nelle feci, o sangue
    consistente dai siti di iniezione.
    - Insufficienza epatica severa, definite da valori degli enzimi epatici (ALT/GPT e
    AST/GOT) > 2 volte il limite normale superiore dei valori di riferimento. Per il tipo
    di popolazione coinvolto nello studio i seguenti valori di riferimento verranno
    considerati [Rosenthal, 1997]:
    - ALT/GPT: 6-50 U/L
    - AST/GOT: 35-140 U/L
    necessità medica di somministrazione di altri Farmaci antiinfiammatori non
    steroidei (FANS) differenti da ibuprofene.
    Partecipazione ad un altro studio clinico che coinvolge qualsiasi farmaco
    sperimentale.
    E.5 End points
    E.5.1Primary end point(s)
    Primary end-point:
    success rate in closing PDA using paracetamol in comparison to ibuprofen after the first 3 days of treatment.
    End-point primario:
    Successo nella chiusura del PDA utilizzando paracetamolo in confronto a
    ibuprofene dopo i primi 3 giorni di trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 3 (visit 3)
    Giorno 3 (visita 3)
    E.5.2Secondary end point(s)
    Secondary endpoints:
    • number of re-openings at 30 days;
    • success rate in closing PDA after the second treatment course of ibuprofen as rescue medication;
    • success rate of closing PDA after the first day and the second day of the first treatment course;
    • incidence of surgical ligation at 30 days;
    • incidence of renal failure, liver failure, gastrointestinal complications (including isolated intestinal perforation) at 30 days;
    • incidence of death at 30 days and at 40 weeks post-conception;
    • incidence of sepsis at 30 days;
    • hospital-stay duration in Neonatal Intensive Care Unit;
    • occurrence of adverse events at 30 days.
    End-points secondari:
    • il numero di riaperture a 30 giorni;
    • il successo di chiusura del PDA dopo il secondo ciclo di trattamento con
    ibuprofene come farmaco “rescue”;
    • il successo di chiusura del PDA dopo il primo giorno e il dopo il secondo giorno di
    trattamento con il primo ciclo di farmaco;
    • l’incidenza di intervento chirurgico a 30 giorni;
    • l’incidenza di insufficienza renale, insufficienza epatica, complicazioni
    gastrointestinali (incluse le perforazioni intestinali isolate) a 30 giorni;
    • l’incidenza di morte a 30 giorni e a 40 settimane post-concezionali;
    • l’incidenza di sepsi a 30 giorni;
    • la durata di permanenza in Terapia Intensiva Neonatale;
    • l’incidenza di eventi avversi a 30 giorni.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 30 (followup 3) or 40 weeks post-conception (follow-up 4)
    Giorno 30 (follow-up 3) o 40 settimane post-concezionali (follow-up 4)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 110
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 110
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Preterm neonates
    Neonati pretermine
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    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)
    At the end of the trial the subjects will be follow according to the common clinical practice
    I soggetti al termine della loro partecipazione allo studio verranno seguiti secondo la 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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-01-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-10
    P. End of Trial
    P.End of Trial StatusCompleted
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