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    Summary
    EudraCT Number:2019-004297-26
    Sponsor's Protocol Code Number:C19-29
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Not Authorised
    Date on which this record was first entered in the EudraCT database:2020-07-09
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-004297-26
    A.3Full title of the trial
    Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treocapa: Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen
    A.3.2Name or abbreviated title of the trial where available
    TREOCAPA
    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 SponsorINSERM The Institut national de la santé et de la recherche médicale
    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 supportThe Innovative Medicines Initiative (IMI),
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINSERM: Institut Santé Publique Biopark,
    B.5.2Functional name of contact pointClara Guyonneau
    B.5.3 Address:
    B.5.3.1Street AddressBiopark, bâtiment A, 8 rue de la Croix Jarry,
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75013
    B.5.3.4CountryFrance
    B.5.4Telephone number+33 (0)144236495
    B.5.6E-mailclara.guyonneau@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 AuthorisationUnited Kingdom
    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 nameParacetamol
    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 CodeAS1
    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
    Prophylactic treatment of the ductus arteriosus in preterm infants
    E.1.1.1Medical condition in easily understood language
    The ductus arteriosus blood vessel allows blood to go around the baby's lungs before birth. If the vessel doesn't close after birth it is referred to as Patent DA and leads to abnormal blood flow.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10034130
    E.1.2Term Patent ductus arteriosus
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10034130
    E.1.2Term Patent ductus arteriosus
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective

    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:
    a. Tolerance of acetaminophen at each dose
    b. 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).
    c. To evaluate the relationship between acetaminophen concentration and toxicity occurrence.

    Phase III:
    a. Early prophylactic treatment by acetaminophen decreases pain score and opiate consumption during the first 5 days of life.
    b. Early prophylactic treatment by acetaminophen reduces the number of back-up treatment of PDA (NSAIDs, surgery, trans-catheter procedure)
    c. Early prophylactic treatment by acetaminophen reduces catecholamines, opioid and parenteral nutrition requirements
    d. Pharmacokinetics of acetaminophen (in 50 preterms).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Study population

    ▪ The study population of the Phase II is constituted of 30 preterm infants of 23-26 weeks of gestational age (10 patients in 23-24 weeks of gestational age, 10 patients in 25 weeks of gestational age and 10 patients in 26 weeks of gestational age).
    ▪ The study population of the Phase III, is constituted of 396 preterm infants of 23-26 weeks of gestational age and of 398 preterm infants of 27-28 weeks of gestational age

    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 according to the local regulation)
    E.4Principal exclusion criteria
    Non-inclusion criteria
    ▪ Parental refusal
    ▪ 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 study endpoint/outcome

    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
    Phase II
    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.
    Phase III
    Survival without severe morbidity at 36 weeks of post menstrual age or at first discharge home, whichever comes first.
    E.5.2Secondary end point(s)
    Phase II Main secondary endpoints of phase II are tolerance of acetaminophen.
    We will investigate:
    (1) Acetaminophen plasma levels
    (2) Plasma ALAT & ASAT
    (3) Prospective clinical monitoring
    (4) Adverse effects and concomitant drug exposures

    Phase III
    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
    Phase II
    Monitoring of Adverse events will continue until discharge from the study at 36 weeks of post menstrual age or at first discharge home, whichever comes first, this is the maximum timepoint.

    Phase III
    Monitoring of Adverse events including pulmonary hemorrage will continue until discharge from the study at 36 weeks of post menstrual age or at first discharge home, whichever comes first, this is the maximum timepoint.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Phase II is dose finding and Phase II is randomized, double-blind, placebo-controlled
    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 concerned9
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Denmark
    Estonia
    Greece
    Hungary
    Ireland
    Italy
    Norway
    Portugal
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days1
    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: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    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.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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
    Neonates
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state139
    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)
    There are no arrangements being made for continued provision of the intervention for participants as it would not be of benefit or appropriate as the IMP is proposed as a Prophylactic treatment of the ductus arteriosus.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Foundation for the Care of Newborn Infants (EFCNI)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-06-02
    N.Ethics Committee Opinion of the trial applicationNot-Favourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-04
    P. End of Trial
    P.End of Trial StatusNot Authorised
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