E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of chronic lung disease in pre-term infants ( gestational age < 29 weeks) with respiratory distress. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054933 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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.
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E.3 | Principal 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 |
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
2 Sub-studies (INOT27-M & INOT27-TA) |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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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” |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 0 |