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    Summary
    EudraCT Number:2017-004684-12
    Sponsor's Protocol Code Number:iNO_Protocol_V1.1_16.07.17
    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:2019-02-25
    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 number2017-004684-12
    A.3Full title of the trial
    Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A Randomised Controlled Trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nitric oxide administration in the heart-lung machine during surgery for heart defects
    Toediening van stikstofmonoxide in de hartlongmachine bij kinderen met congenitale hartafwijkingen
    A.3.2Name or abbreviated title of the trial where available
    Nitric Oxide during Cardio Pulmonary Bypass in CHD
    A.4.1Sponsor's protocol code numberiNO_Protocol_V1.1_16.07.17
    A.5.4Other Identifiers
    Name:ANZCTRNumber:ACTRN12617000821392
    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 SponsorLady Cilento Children's Hospital
    B.1.3.4CountryAustralia
    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 supportStichting Hart4Onderzoek
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Utrecht
    B.5.2Functional name of contact pointWKZ
    B.5.3 Address:
    B.5.3.1Street AddressLundlaan 8
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031887554704
    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 INOmax
    D.2.1.1.2Name of the Marketing Authorisation holderLinde Healthcare AB
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameNitric oxide
    D.3.4Pharmaceutical form Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOther use (Noncurrent)
    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 heart disease ranks still within the top causes of infant mortality in industrialized countries. Despite considerable advances over the past decade, the exposure to cardiopulmonary bypass (CPB), which is needed for most heart surgeries, remains responsible for major side effects: The exposure of patient blood to large artificial surfaces in the CPB circuit triggers a very strong systemic inflammatory syndrome, which leads in a third of patients to low cardiac output syndrome (LCOS).
    E.1.1.1Medical condition in easily understood language
    Cardiac surgery often requires cardiopulmonary bypass. Children often develop an inflammatory response to bypass and this contributes to complications after surgery and delayed recovery.
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    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
    To investigate in a double blind randomized controlled trial in children undergoing open heart surgery if NO exposure during CPB reduces the postoperative duration of invasive mechanical ventilation (defined as ventilator free days within 28 days post randomisation) compared to control.
    E.2.2Secondary objectives of the trial
    1. To investigate if NO reduces the incidence of low cardiac output syndrome (LCOS), requirement for extracorporeal life support (ECLS), and 90-day mortality.
    2. To investigate if NO reduces the length of PICU stay and health care costs
    3. To investigate if NO reduces the inflammatory response following CPB.
    4. To investigate if NO reduces the ischaemic cerebral damage following congenital heart surgery with CPB.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Platelet function during cardiopulmonary bypass during surgery for congenital heart defects. To investigate if NO reduces the negative effects of CPB on platelet activation and platelet function. (This question is answered within the subgroup of children included at the Utrecht study side)

    E.3Principal inclusion criteria
    - All infants and children < 2 years of age undergoing open heart surgery on CPB
    - Elective cardiac surgery and consent of parents/guardian.
    E.4Principal exclusion criteria
    - Signs of persistently elevated pulmonary vascular resistance preoperatively requiring iNO or preoperative use of intravenous drugs involved in the NO pathway such as GTN, within 48 hours prior to CPB.
    - Patient is on ECLS prior to surgery
    - Concurrent known confirmed bacterial sepsis/septic shock, diagnosed within <48 hours prior to surgery and being actively treated with antibiotics at time of surgery (suspected sepsis treated with antibiotics is not an exclusion criteria unless inotropes are required for
    treatment of septic shock at time of surgery)
    - Preoperative acute respiratory distress syndrome requiring HFOV ventilation <48 hours of surgery
    - Patient requires high doses of vasoactive drugs prior to surgery with an inotrope score ≥15 met within 24 hours prior to surgery: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS) (2): VIS = dopamine dose (mcg/kg/min) + dobutamine
    dose (mcg/kg/min) + 100 x adrenaline dose (mcg/kg/min) + 100 x noradrenaline dose (mcg/kg/min) + 10 x milrinone dose (mcg/kg/min) + 10,000 x vasopressin dose (U/kg/min).
    - Cardiac arrest within one week (7d) prior to surgery
    - Emergency cardiac surgery which may preclude obtaining informed consent (defined as acutely required life-saving procedure in a patient unlikely to survive the next hours without the surgery)
    - Pre-existing methaemoglobinemia (MetHb>3%)
    E.5 End points
    E.5.1Primary end point(s)
    Length of mechanical ventilation as defined as the duration of respiratory support for all episodes with an endotracheal tube in situ for the first 28 days post randomisation. The outcome will be reported using ventilator free days (VFD). A systematically zero value will be assigned for patient who die to allow important weight to death as the most pejorative outcome.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days postsurgical intervention
    E.5.2Secondary end point(s)
    1- Incidence of LCOS, need for ECLS, and Mortality
    2- The length of stay in PICU, hospital length of stay and health care costs
    3- Levels of systemic inflammatory markers and levels of markers of myocardial injury
    4- Platelet function and levels of markers for platelet activation prior, during, and after CPB
    5- Extent of new and worsened ischemic white matter changes on cerebral MRI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- 28 days
    2- 1 year postsurgical intervention
    3- at 0,12, and 24 hours post surgery
    4- day of surgery
    5- during hospitalisation
    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 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
    routine care, standard respiratory gases (oxygen-air mix) during bypass at a flow rate of 3L/min
    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 No
    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
    Australia
    New Zealand
    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
    1 year after completion of the last patient included/operated or when the DSMB may recommend ceasing the trial

    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 200
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 50
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 150
    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
    subjects under age (neonates, infants and toddlers) incapable of giving informed consent personally.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 1470
    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)
    not different from the expected normal treatment of that condition
    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 Paediatric Study Group ANZICS
    G.4.3.4Network Country Australia
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-06
    P. End of Trial
    P.End of Trial StatusOngoing
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