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    Summary
    EudraCT Number:2018-004482-14
    Sponsor's Protocol Code Number:P160917
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-07-03
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-004482-14
    A.3Full title of the trial
    Tocolysis in the management of preterm premature rupture of membranes before 34 weeks of gestation:
    a double-blinded randomized controlled trial
    Tocolyse en cas de rupture prématurée des membranes avant 34 semaines d’aménorrhée :
    un essai contrôlé randomisé en double-aveugle
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This research aims to improve the future of mothers and children facing the opening of the water pouch (or rupture of membranes) occurred prematurely before the 8th month of pregnancy. Premature rupture of the membranes before the 8th month of pregnancy exposes to a high risk of premature delivery. A drug called tocolysis will be prescribed to reduce uterine contractions and delay the risk of preterm birth
    Cette recherche vise à améliorer le devenir des mères et des enfants confrontés à l’ouverture de la poche des eaux (ou rupture des membranes) survenue prématurément avant le 8eme mois de grossesse. La rupture prématurée des membranes avant le 8eme mois de grossesse expose à un risque élevé d’accouchement prématuré. Un médicament que l’on appelle tocolyse va être prescrit pour diminuer les contractions utérines et retarder le risque d’accouchement prématuré
    A.3.2Name or abbreviated title of the trial where available
    TOCOPROM
    TOCOPROM
    A.4.1Sponsor's protocol code numberP160917
    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 SponsorASSISTANCE PUBLIQUE-HOPITAUX DE PARIS (AP-HP)
    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 supportMinistry of Health,
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE-HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital Saint Louis
    B.5.3 Address:
    B.5.3.1Street Address1 av Claude VELLEFAUX
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number330144 84 17 79
    B.5.5Fax number330144 84 17 01
    B.5.6E-mailshohreh.azimi@aphp.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 NIFEDIPINE
    D.2.1.1.2Name of the Marketing Authorisation holderMYLAN
    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 Prolonged-release tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pregnant women with PPROM at 22 to 33 weeks gestation
    E.1.1.1Medical condition in easily understood language
    -Preterm premature rupture of membranes (PPROM) between 220/7 - 336/7 weeks of gestation, as diagnosed by obstetric
    E.1.1.2Therapeutic area Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]
    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
    The purpose of this study is to prospectively assess whether short-term (48 hours) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22 to 33 completed weeks’ gestation.
    E.2.2Secondary objectives of the trial
    To assess the impact of 48 hours tocolysis in cases of PPROM at 22 to 33 weeks’ gestation on prolongation of gestation, maternal morbidity and neonatal minor morbidity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Preterm premature rupture of membranes (PPROM) between 22 0/7 - 33 6/7 weeks of gestation, as diagnosed by obstetric teams: the diagnosis is usually based on 2 positive criteria from maternal history, sterile speculum examination to confirm fluid leakage from the cervical canal and performance of a diagnostic test.
    - Singleton gestation
    - Fetus alive at the time of randomization
    - 18 years of age or older
    - French speaking
    - Affiliated to social security or an equivalent system
    - Informed consent and signed
    E.4Principal exclusion criteria
    - PPROM ≥ 24 hrs before diagnosis
    - Ongoing tocolytic treatment at the time of PPROM
    - Any tocolytic treatment between PPROM diagnosis and randomization
    - Fetal condition contraindicating expectant management including chorioamnionitis, intrauterine fetal demise, non-reassuring fetal heart rate at the time of randomization
    - Cervical dilation > 5 cm
    - Iatrogenic rupture following amniocentesis (<5 weeks after amniocentesis)
    - Major fetal anomaly
    - Maternal allergy or contra-indication to Nifedipine or placebo drug components:
    - Myocardial infarction
    -Unstable angina pectoris
    - Hepatic insufficiency
    -Cardiovascular shock- beta blockers
    - Coadministration of diltiazem or rifampicine
    - Hypotension (systolic blood pressure < 90 mmHg)
    -Participation to another interventional study
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint
    The primary composite outcome is based on the most recent published results concerning the prognosis of preterm infants (21,38). It is defined by:
    - fetal death (in utero fetal death occurring from randomization to birth),
    - neonatal death up to discharge from hospital (death from birth to discharge, in delivery room or in neonatal intensive care unit [NICU]),
    - and/or neonatal severe morbidity.

    Neonatal severe morbidity is defined as any of the following:
    o mechanical ventilation ≥ 48 hrs, defined as high frequency or conventional mechanical ventilation during at least 48 consecutive hours during the hospitalization (61)
    o severe bronchopulmonary dysplasia (BPD), defined as requiring oxygen for at least 28 days plus the need for 30% or more oxygen and/or mechanical ventilator support or continuous positive airway pressure at 56 days postnatal age or 36 weeks’ postmenstrual age or discharge, whichever comes first (62)
    o severe intraventricular hemorrhage (IVH), defined as IVH associated with ventricular dilatation (grade III IVH) and intraparenchymal hemorrhage (i.e., large unilateral parenchymal hyperdensity or large unilateral porencephalic cyst, grade IV IVH); diagnosed by ultrasound (63)
    o cystic periventricular leucomalacia, periventricular white matter echolucencies at ultrasonography (64)
    o neonatal early-onset sepsis, diagnosed from positive bacteriology findings in blood or cerebrospinal fluid (confirmed infection) beginning during the first three days of life (65)
    o necrotizing enterocolitis, stages II and III necrotizing enterocolitis according to Bell’s staging (66)
    o retinopathy of prematurity: stage 3 or greater retinopathy of prematurity according to the international classification (67) and/or laser treatment

    These data will be collected from obstetric and neonatal medical files, including diagnosis, after mothers and infants respective discharge from hospital.
    E.5.2Secondary end point(s)
    Secondary endpoints
    Maternal and antenatal data will be collected from obstetric files, after women’s discharge from hospital.

    Prolongation of gestation will be evaluated through different criteria:
    - Latency duration, defined as the duration from PPROM to delivery
    - Pregnancy prolongation beyond 48 hours after randomization,
    - Pregnancy prolongation beyond 1 week after randomization,
    - Gestational age at delivery,
    - Delivery after 37 weeks of gestation.

    Concerning maternal morbidity, we will assess the rates of endometritis in each arm, based on clinical diagnosis associating fever (temperature ≥ 38.0°C) with uterine tenderness, purulent or foul-smelling lochia, and in the absence of any other cause, during the first 10 days postpartum (68).
    Neonatal data will be collected from neonatal files, after infant’s discharge from hospital.

    Neonatal morbidity:
    We will isolate each criteria included in the composite primary outcome and assess its association with tocolysis treatment.
    We will also study:
    - Severe fetal acidemia, defined as cord umbilical artery pH less than 7.00 or base deficit greater than 16 mEq/L (16 mmol/L), or both (69)
    - Respiratory distress syndrome, defined from clinical diagnosis as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with a requirement for supplemental oxygen with a fraction of inspired oxygen of more than 0.21 and a chest radiograph showing hypoaeration and reticulogranular infiltrates
    - Mild or moderate BPD, defined as requiring oxygen for at least 28 days plus the need for 21% (mild) - 30% (moderate) oxygen at 56 days postnatal age or 36 weeks’ postmenstrual age or discharge, whichever comes first (62)
    - Grades I-II IVH, defined according to Papile’s classification: subependymal hemorrhage (grade I IVH) or intraventricular hemorrhage without ventricular dilatation (grade II IVH) as diagnosed by ultrasound (63)
    - Late-onset sepsis, diagnosed from positive bacteriology findings in blood or cerebrospinal fluid (confirmed infection) beginning in the 4th day of life or afterwards (70).
    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 No
    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) No
    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 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) 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 concerned25
    E.8.5The trial involves multiple Member States No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    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) Yes
    F.1.2.1Number of subjects for this age range: 850
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state850
    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 Decision2019-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-11
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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