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    Summary
    EudraCT Number:2017-000421-13
    Sponsor's Protocol Code Number:1913
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-07
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-000421-13
    A.3Full title of the trial
    Newborns with Congenital Diaphragmatic hernia: inhaled Nitric Oxide
    versus intravenous Sildenafil:
    an international randomized controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of high blood pressure in the lungs in newborns with a defect in
    the diaphragm; inhaled Nitric Oxide compared to intravenous Sildenafil.
    A.3.2Name or abbreviated title of the trial where available
    CoDiNOS trial
    A.4.1Sponsor's protocol code number1913
    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 SponsorErasmus MC
    B.1.3.4CountryNetherlands
    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 supportSSWO
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportCDH UK Sparks
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointresearch coordinator
    B.5.3 Address:
    B.5.3.1Street AddressWytemaweg 80
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015CN
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31107040704
    B.5.6E-mails.denotter@erasmusmc.nl
    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 revatio 0.8mg/ml solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/10/815
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection/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 INOmax 800ppm mol/mol inhalatiegas
    D.2.1.1.2Name of the Marketing Authorisation holderLinde
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation 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
    Congenital diaphragmatic hernia with pulmonary hypertension
    Hernia diafragmatica met pulmonale hypertensie
    E.1.1.1Medical condition in easily understood language
    Defect in diaphragm resulting in high blood pressure in the lungs
    Defect in het middenrif resulterend in hoge bloeddruk in de longen
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To compare the change in oxygenation index before and 12 hours after start of treatment between the patients treated with iNO and sildenafil
    E.2.2Secondary objectives of the trial
    The secondary objectives are:

    • To compare overall mortality
    • To compare the incidence of treatment failure (see paragraph 6.5)
    • To compare the time on intervention drug
    • To compare the need for ECMO
    • To compare the number of ventilator free days at day 28
    • To compare the vasoactive-inotropic support score before and after
    starting the intervention drug
    • To compare laboratory markers for pulmonary vascular endothelial
    damage and pulmonary hypertension (see paragraph 6.3)
    • To compare the use of other medication given for pulmonary
    hypertension
    • To compare the use of pulmonary and/or cardiac medication after
    discharge
    • To compare the incidence of long-term pulmonary hypertension at the
    age of 1 year
    • To compare the incidence of chronic lung disease
    - Compare the incidence of pulmonary hypertension in the absence of pulmonary
    vasodilator therapy on day 14 on echocardiography and/or death within
    the first 28 days of life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Diagnosis of CDH and pulmonary hypertension defined as 2 of the
    following 4 criteria:
    I. PAP> 2/3 systemic pressure estimated by echocardiography
    II. RV dilatation/septal displacement, RV dysfunction +/- LV
    dysfunction
    III. Pre-post ductal SpO2 difference > 10%
    IV. OI>20.
    • Parental informed consent
    • Children born at or after a gestational age of 34 weeks
    • Newborns who received a fetal intervention may be included
    E.4Principal exclusion criteria
    • Severe chromosomal anomaly, like trisomy 18 or trisomy 13, which
    may imply a decision to stop or not to start life-saving medical treatment
    • Severe cardiac anomaly, expected to need corrective surgery in the
    first 60 days of life (such as transposition of the great arteries, truncus
    arteriosus, coarctation aortae or double outlet right ventricle)
    • Renal anomalies associated with oligohydramnios
    • Severe orthopaedic and skeletal deformities, which are likely to
    influence thoracic, and / or lung development (such as chest wall
    deformities and spine anomalies)
    • Severe anomalies of the central nervous system
    E.5 End points
    E.5.1Primary end point(s)
    The main study endpoint is the difference in oxygenation index 12 hours after start of treatment between the patients treated with iNO and sildenafil
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 hours after start therapy
    E.5.2Secondary end point(s)
    - pulmonary hypertension in the absence of
    pulmonary vasodilator therapy on echocardiography on day 14 and/or
    death within the first 28 days of life
    • Overall mortality in the first year of life
    • Requirement of ECMO (only for ECMO centres)
    • Treatment failure (see paragraph 6.5, failure criteria)
    • Severity and presence of pulmonary hypertension on day 1 and/or
    just before starting the study drug, on day 14, on day 28 or at discharge
    (whatever comes first), at 6 months and 1 year according to the
    following echocardiographic parameters as described by the cardiologist:
    PAP < or > 2/3 systemic pressure, RV dilatation/septal displacement,
    RV dysfunction +/- LV dysfunction. (see Case Record Form)
    • Number ventilator free days on day 28 (deaths are counted as worst
    outcome)
    • Number of intervention drug free days on day 14
    • Fraction of days requiring medical treatment for pulmonary
    hypertension during the hospital admission, described as the use of iNO,
    sildenafil, prostanoids, endothelin 1 antagonists, and/or other
    medication for pulmonary hypertension
    • The level of specific laboratory markers and urine, up to day 28, to
    describe the severity and presence of pulmonary hypertension.
    • Vasoactive-inotropic support score before and 12 hours after starting
    study medication.
    • Requirement of PH medication, described as oral sildenafil, bosentan
    and/or a prostanoid at discharge and/or during the first year of life.
    • Severity of chronic lung disease using need for oxygen on day 28 and
    56.
    • Long-term pulmonary hypertension using echocardiography at the
    age of 6 and 12 months.
    • The development of neurological abnormalities evaluated with an
    ultrasound of the brain before start of intervention drug, after surgery
    and before discharge.
    E.5.2.1Timepoint(s) of evaluation of this end point
    day of surgery and day after surgery
    day of starting ECMO and day after ECMO
    day 14 and day 28 or at discharge (whichever comes first)
    day 56
    6 and 12 months
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Inhaled nitric oxide gas
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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 trial is ended when 90 have been included and the last patient is
    seen at the age of 12 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days6
    E.8.9.2In all countries concerned by the trial days6
    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: 90
    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: 15
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 75
    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
    Because the patients are newborns, parents will be asked for informed
    consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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)
    If pulmonary hypertension still exists on day 14, study therapy can be
    changed to other pulmonary hypertension treatment, for instance
    sildenafil orally. After day 14 treatment of pulmonary hypertension will
    be at the discretion of the local treatment team.
    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 CDH Euro Consortium
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-27
    P. End of Trial
    P.End of Trial StatusOngoing
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