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    Summary
    EudraCT Number:2004-002312-29
    Sponsor's Protocol Code Number:INOT -27
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-02-23
    Trial results View 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 number2004-002312-29
    A.3Full title of the trial
    The Effects of Nitric Oxide for Inhalation on the development of chronic lung disease in pre-term infants.
    A.3.2Name or abbreviated title of the trial where available
    INOT-27
    A.4.1Sponsor's protocol code numberINOT -27
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberEUNO Preemie
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorINO Therapeutics
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 INO max® (Nitric Oxide for Inhalation, 400 ppm)
    D.2.1.1.2Name of the Marketing Authorisation holderINO Therapeutics AB, Sweden
    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 nameINO max® (Nitric Oxide) for inhalation (400 ppm)
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Inhalation gas
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnitric oxide
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.04
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeNitric Oxide for inhalation
    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 placeboInhalation gas
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prevention of chronic lung disease in pre-term infants ( gestational age < 29 weeks) with respiratory distress.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 7.0
    E.1.2Level LLT
    E.1.2Classification code 10054933
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and efficacy of inhaled nitric oxide to reduce the risk of chronic lung disease in pre-term infants with respiratory distress and to assess the long term effects of the therapy on the development of these children over 7 years of clinical follow up.
    E.2.2Secondary objectives of the trial
    To assess:
    -number of days of assisted ventilation.
    -length of hospitalisation.
    -Survival without severe IVH, and PVL.
    - total number of days in-hospital from 36 weeks GA to one year and two years corrected age.
    - average number of days in-hospital for respiratory illness from 36 weeks GA to one year and two years corrected age.

    GA- gestational age
    IVH - intraventricular hemorrhage
    PVL - periventricular leukomalacia
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1) MRI Sub-Study INOT-27M (at selected centres only)
    The use of 40-week MRI scans to determine the effects of inhaled NO on the brain of premature infants:

    Title:
    MRI brain imaging in preterm infants randomized to clinical study INOT-27 (The
    prevention of chronic lung disease in preterm infants (gestational age < 29 weeks) with respiratory distress)

    Objective:
    The primary objective is to determine the extent of brain abnormality using quantitative MRI measures in preterm infants (< 29 weeks GA) randomized into clinical study INOT-27, and to compare the extent of abnormality between infants treated with inhaled NO and those treated with placebo.

    The secondary objective will be to correlate the extent of MRI-defined brain abnormality with neurodevelopmental status at 2 years of age.


    2) Tracheal Aspirate Sub-Study INOT27-TA (at selected centres only)
    Inflammatory Mediators In Tracheal Aspirates Of Preterm Infants Participating In The Euno (INOT27) Study:

    Tracheal Aspirate Samples are collected on Days 2, 4, 7, 14 & 21 of the main Euno study. These are analysed in the INOT27TA Substudy.


    E.3Principal inclusion criteria
    The patient must meet the following criteria:

    • Inborn preterm infants 24+0 weeks–28+6 days weeks gestational age (defined by first trimester ultrasound or if not available based on the last menstrual period) who
    requires the use of surfactant within 24 hours of birth, (either prophylactically or for
    signs of developing respiratory distress), or who requires the use of CPAP (FiO2 ≥
    0.30 and mean airway pressure ≥ 4cm H2O) within 24 hours of birth in order to
    maintain an SpO2 ≥ 85%.

    • Informed consent of the parent or legal guardian.

    CPAP = Continuous Positive Airway Pressure
    SpO2 = Oxygen saturation by pulse oximeter
    E.4Principal exclusion criteria
    The patient will be excluded from enrollment if any of the following are true:

    • Outborn infants.
    • Infants ≥ 29 weeks gestational age.
    • Infants with birth weight <500 grams.
    • Infants requiring FiO2 >0.5 to maintain SpO2 >85%, on a sufficient mean airway
    pressure (e.g., > 8 cm H2O on CMV) in order to achieve adequate chest inflation (8-9
    ribs on Chest X-ray) two hours after the proper administration of exogenous
    surfactant.
    • Any suspected congenital heart disease other than patent ductus arteriosus or atrial septal defect.
    • Any infant with suspected lung hypoplasia associated with congenital diaphragmatic hernia
    • Any infant with severe bleeding and/or coagulation abnormalities at high-risk of
    diathesis, e.g., platelet <50,000/mm3, fibrinogen <0.5 g/L, other clotting factors <10%.
    • Any infant in whom a decision has been made not to provide full treatment, e.g.,
    chromosomal abnormalities, severe multiple abnormalities, severe birth asphyxia, etc.
    • Use of another investigational drug or device before or during the active study period.

    CMV = Controlled Mechanical Ventillation.
    FiO2 = Fraction of inspired oxygen concentration
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Variable

    The primary efficacy variable for this study will be a binary endpoint determined by
    assessment at 36 week post-menstrual age (PMA). An infant who is alive without CLD at 36 PMA will be counted as a ‘success’. An infant who has died, or who has CLD at 36 weeks PMA will be counted as a ‘failure’.

    CLD is defined as the need for supplemental oxygen at 36 weeks post-menstrual age
    (based on a physiologic assessment).
    PMA = Post-menstrual age
    CLD = chronic lung disease
    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 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 Yes
    E.6.13.1Other scope of the trial description
    2 Sub-studies (INOT27-M & INOT27-TA)
    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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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 Information not present in EudraCT
    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
    Study to include 7 years of clinical follow up in order to assess the long term effects on the development of the infant i.e.
    "2 years of recruitment and intervention, followed by 7 years of clinical follow-up”
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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
    Pre-term infants (gestational age < 29 weeks) with respiratory distress.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state108
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 800
    F.4.2.2In the whole clinical trial 800
    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)
    Follow up assessments made by study doctor to monitor progress of child at 1 and 2 years of age and again at 6-7 years of age.
    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 Decision2005-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-06-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-23
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