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    Summary
    EudraCT Number:2019-004297-26
    Sponsor's Protocol Code Number:C19-29
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-07-20
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNorway - NOMA
    A.2EudraCT number2019-004297-26
    A.3Full title of the trial
    Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen
    Profylaktisk behandling mot persisterende åpenstående ductus arteriosus hos svært premature barn
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prophylactic treatment of the ductus arteriosus in preterm infants by paracetamol
    Forebyggende behandling mot vedvarende åpenstående ductus arteriosus hos svært premature barn
    A.3.2Name or abbreviated title of the trial where available
    TREOCAPA
    Paracetamolstudien
    A.4.1Sponsor's protocol code numberC19-29
    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 SponsorInstitut National de la Santé et de la Recherche Médicale (INSERM)
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInnovative Medicines Initiative 2 (H2020 programme)
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInserm
    B.5.2Functional name of contact pointSandrine COUFFIN-CADIERGUES
    B.5.3 Address:
    B.5.3.1Street Address8 rue de la Croix jarry
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75013
    B.5.3.4CountryFrance
    B.5.4Telephone number33144 23 64 16
    B.5.6E-mailrqrc.siege@inserm.fr
    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 Paracetamol
    D.2.1.1.2Name of the Marketing Authorisation holderB. BRAUN MELSUNGEN AG CARL-BRAUN-STRASSE 1 34212 MELSUNGEN ALLEMAGNE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNacetaminophen
    D.3.9.3Other descriptive namePARACETAMOL
    D.3.9.4EV Substance CodeSUB09611MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number0.75 ml/kg
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patent ductus arteriosus
    E.1.1.1Medical condition in easily understood language
    In many extremely preterm infants, the ductus arteriosus does not constrict itself. The ductus arteriosus is open.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objectives :
    Phase II: The objective of Phase II is to define the minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7 in preterm infants of 23-26 weeks of gestation

    Phase III: The primary objective is an increase in surviving without severe morbidity at 36 weeks of post menstrual age (or at discharge if it occurs before) from 50% (placebo group) to 60% in group receiving a prophylactic treatment by acetaminophen during the first 5 days of life.
    E.2.2Secondary objectives of the trial
    Secondary objectives :
    Phase II:
     Tolerance of acetaminophen at each dose
     Pharmacokinetics of acetaminophen and evaluation of the concentration-response curve (i.e., acetaminophen exposure vs. time to close the ductus arteriosus or decrease the size of ductus).
     To evaluate the relationship between acetaminophen concentration and toxicity occurrence.

    Phase III:
     Early prophylactic treatment by acetaminophen decreases pain score and opiate consumption during the first 5 days of life.
     Early prophylactic treatment by acetaminophen reduces the number of back-up treatment of PDA (NSAIDs, surgery, trans-catheter procedure)
     Early prophylactic treatment by acetaminophen reduces catecholamines, opioid and parenteral nutrition requirements
     Pharmacokinetics of acetaminophen (in 50 preterms).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ▪ Birth between 23-26 W for Phase II, between 23-28 W for Phase III
    ▪ Post natal age < 12 hours
    ▪ Parental or Legal Authority Consent
    ▪ Parents with a social security or health insurance (if applicable)
    E.4Principal exclusion criteria
    ▪ Birth defect / Congenital anomaly
    ▪ Twin-to-twin transfusion syndrome
    ▪ Suspicion of pulmonary hypoplasia
    ▪ Suspicion of hepatic impairment (hemorrhagic syndrome and/or severe hypoglycemia)
    ▪ Clinical instability that can lead to rapid death
    ▪ Impossibility to start treatment before 12 hours of life
    ▪ Parents placed under judicial protection
    ▪ Participation in other clinical trial using acetaminophen during the first 5 days of life, indomethacin or ibuprofen during the first 3 days of life or using rescue treatment of PDA not recommended in the TREOCAPA trial
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint of phase II is the closure of Ductus Arteriosus (DA) assessed by echocardiography during the first 7 days of life, defined as DA closed at two consecutive echocardiographies or if the DA is closed at echocardiography of Day 7
    Primary endpoint of phase III is the survival without severe morbidity at 36 weeks of post menstrual age or at first discharge home, whichever comes first. The severe morbidities include bronchopulmonary dysplasia (BPD Grade 3 according to NIH consensus), necrotizing enterocolitis (NEC) of Bell's stage II or III, intraventricular hemorrhage (IVH) grade III-IV or cystic leukomalacia observed at any time up to 36 weeks of post menstrual age.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint of phase II will be evaluate at day 7.

    Primary endpoint of phase III is evaluate at 36 weeks of post menstrual age or at first discharge home.
    E.5.2Secondary end point(s)
    Main secondary endpoints of phase II are tolerance of acetaminophen. We will investigate:
    (1) Acetaminophen serum levels
    (2) Serum ALAT & ASAT
    (3) Prospective clinical monitoring
    (4) Adverse effects and concomitant drug exposures


    Main secondary endpoints of phase III are:
    (1) Number of rescue treatment to close ductus by non steroid antiinflamatory drugs (NSAIDs) or by surgery or by transcatheter.
    (2) Diastolic systemic arterial pressure during the first week
    (3) Early and all Pulmonary hemorrhage
    (4) Cathecholamines, and opiate consumption during the first week of life
    (5) Volume of enteral nutrition during the first week of life
    (6) Interaction between parent involvement during the first week of life and medical care
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 36 weeks of post menstrual age or at first discharge home
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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) No
    E.8.2.2Placebo Yes
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    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 Yes
    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
    The end of the study is defined as the date of completion of the last visit or procedure of the last participant.
    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 months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 824
    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: 824
    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
    Patients included in this trial are extremely preterm infants (24-28 weeks of gestation)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 824
    F.4.2.2In the whole clinical trial 824
    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)
    A follow-up study will be done next year in 2020.
    The main objective will be to examine whether early prophylactic treatment by acetaminophen in very preterm infants is associated with a better outcome at 18 months of corrected age from a neurodevelopmental point of view.
    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 Decision2020-07-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-21
    P. End of Trial
    P.End of Trial StatusCompleted
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