Safety and Efficacy Study of Nitric Oxide for Inhalation on Chronic Lung Disease in Premature Babies

The Effects of Nitric Oxide for Inhalation on the Development of Chronic Lung Disease in Pre-term Infants

The purpose of this study is 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.

Study Overview

• Status: Completed
• Conditions: Lung Disease
• Intervention / Treatment: Drug: Nitric oxide; Drug: Placebo

Detailed Description

Although the effects of inhaled Nitric Oxide on pulmonary vascular tone are well-described and relevant to term infants with persistent pulmonary hypertension, the pathophysiology of respiratory failure in preterm infants may be quite different. Chronic lung disease (CLD) represents the final pathway of a heterogeneous group of pulmonary disorders of infancy that usually start in the neonatal period. CLD most commonly occurs in preterm (<30 weeks of gestational age (GA) infants with birth weights less than 1,500 grams (g), and especially in those very preterm (<26 weeks GA) with birth weights less than 1,000 g, and who have been treated for respiratory distress syndrome (RDS).

• Study Type: Interventional
• Enrollment (Actual): 800
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • UCL St. Luc
  • Charleroi, Belgium
    • Clinique Notre Dame
  • Edegem, Belgium
    • Universitair Ziekenhuis Antwerpen
  • Rocourt, Belgium
    • Clinique St. Vincent CHC
• Finland
  • Oulu, Finland, FI-90220
    • Oulun yliopsistollinen sairaala
• France
  • Creteil, France, 94000
    • Centre Hospitalier Intercommunal de Créteil
  • Nantes Cedex 1, France, 44093
    • Hospital Mere-Enfant
  • Paris, France, 75019
    • Hospital Robert Debre
• Germany
  • Berlin, Germany, 10117
    • Campus Charite Mitte
  • Heidelberg, Germany, 69115
    • Universitaetsklinikum Heidelberg
  • Mannheim, Germany, 68167
    • Universitaetsklinikum Mannheim
  • Marburg, Germany, 35033
    • Universitaetsklinikum Marburg
  • Muenchen, Germany, 81377
    • Universitaetsklinikum Muenchen
  • Tuebingen, Germany, 72076
    • Universitaeklinikum Tuebingen
  • Ulm, Germany, 89075
    • Univeritaetsklinik Ulm
• Italy
  • Ancona, Italy, 60123
    • Az. Osp. G. Salesi
  • Bergamo, Italy, 24128
    • Ospedali Riuniti
  • Bologna, Italy, 40138
    • Policlinico S. Orsola
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Careggi
  • Padova, Italy, 35128
    • University Padova
  • Roma, Italy, 00168
    • Policlinico Gemelli
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Beatrix Children's Hospital, University Medical Center Groningen
  • Rotterdam, Netherlands, 3000 CB
    • Sophia Kinderziekenhuis
• Spain
  • Barakaldo, Spain, 48903
    • Hospital de Cruces
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28007
    • Hospital Universitario Gregorio Mar
  • Madrid, Spain, 28046
    • Hosspital Univeritario La Paz
  • Santa Cruz de Tenerife, Spain, 38320
    • Hospital Universitario Canarias
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46009
    • Hospital Universitario La Fé
• Sweden
  • Stockholm, Sweden, SE-171 76
    • Astrid Lindgrens barnsjukjus, Karolinska Unviersritets sjukhuset-Solna
  • Uppsala, Sweden, SE-751 85
    • Akademiska sjukhuset
• United Kingdom
  • Gillingham, United Kingdom, ME7 5NY
    • Meedway Mariton Hospital
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • London, United Kingdom, SE5 9RS
    • Kings College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion 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 continuous positive airway pressure (CPAP) (fraction of inspired oxygen concentration (FiO2) ≥ 0.30 on a mean airway pressure ≥ 4cm water (H2O)) within 24 hours of birth in order to maintain an oxygen saturation (SpO2) ≥ 85%.
• Informed consent of the guardian.

Exclusion Criteria:

• Outborn infants.
• Infants ≥ 29 weeks gestational age.
• Infants requiring FiO2 >0.5 to maintain SpO2 >85%, on a sufficient mean airway pressure (e.g., > 8 cm H2O on controlled mechanical ventilation (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 severe bleeding or coagulation abnormalities at high-risk of diathesis, e.g., platelet <50,000 per millimeter cube (mm³), fibrinogen <0.5 gram per liter (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Inhaled Nitric Oxide (INO); INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for between 7 and 21 days	Drug: Nitric oxide; Nitric Oxide vapour (gas) for inhalation (400 ppm); Other Names: INO max®
Placebo Comparator: Placebo; Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days.	Drug: Placebo; Placebo gas for inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress	Survival without BPD is defined as the number of preterm infants of 36 weeks gestational age who survived the treatment period without the need for supplemental oxygen	21 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 7-year Follow-up	Number of participants who died between 2 years and the 7-year Follow-up Period	at 7-year Follow-up
Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up	The Strengths and Difficulties Questionnaire contained 25 questions that were used to create 5 scales (ranging from 10=most normal to 0=most abnormal) for emotional symptoms, conduct problems, hyperactivity, peer problems, and (10=most abnormal, 0=most normal) for prosocial.	At 7-year Follow-up

Collaborators and Investigators

• Sponsor: Mallinckrodt

Publications and helpful links

General Publications

• Laube M, Amann E, Uhlig U, Yang Y, Fuchs HW, Zemlin M, Mercier JC, Maier RF, Hummler HD, Uhlig S, Thome UH. Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide. PLoS One. 2017 Jan 3;12(1):e0169352. doi: 10.1371/journal.pone.0169352. eCollection 2017.
• Durrmeyer X, Hummler H, Sanchez-Luna M, Carnielli VP, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Mercier JC, Marlow N, Johnson S, Baldassarre J; European Union Nitric Oxide Study Group. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics. 2013 Sep;132(3):e695-703. doi: 10.1542/peds.2013-0007. Epub 2013 Aug 12.
• Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Baldassarre J; EUNO Study Group. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 Jul 31;376(9738):346-54. doi: 10.1016/S0140-6736(10)60664-2. Epub 2010 Jul 23.

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2005
• Primary Completion (Actual): March 16, 2008
• Study Completion (Actual): July 17, 2015

Study Registration Dates

• First Submitted: October 30, 2007
• First Submitted That Met QC Criteria: October 30, 2007
• First Posted (Estimate): October 31, 2007

Study Record Updates

• Last Update Posted (Actual): February 5, 2021
• Last Update Submitted That Met QC Criteria: February 4, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Preemie, Inhaled Nitric Oxide
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: INOT27; 2004-002312-29 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Discussion of statistical endpoints and analysis are included in manuscripts. Summary aggregate (basic) results (including adverse events information) and the study protocol are made available on clinicaltrials.gov (NCT00551642) when required by regulation. Individual de-identified patient data will not be disclosed. Requests for additional information should be directed to the company at medinfo@mnk.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No