Inhaled Nitric Oxide for Preventing Chronic Lung Disease in Premature Infants

Inhaled NO for the Prevention of Chronic Lung Disease

To determine whether or not inhaled nitric oxide (iNO) safely decreases the incidence of chronic lung disease (CLD) in premature infants.

Study Overview

• Status: Completed
• Conditions: Lung Diseases; Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: iNO; Other: Placebo

Detailed Description

BACKGROUND:

Despite advances in medical, nursing, and respiratory care, CLD affects up to 50 percent of premature infants. As a result, nearly 50,000 infants in the United States develop CLD. It is desirable to investigate therapies that decrease the incidence of CLD because it is associated with failure to thrive, developmental delay, increased risk of pulmonary infection, reactive airway disease, pulmonary hypertension, and death.

DESIGN NARRATIVE:

This is a randomized, double-blind, placebo-controlled, multi-center study. Three specific hypotheses will be tested: 1) iNO reduces the incidence of CLD; 2) iNO reduces serum and lung (tracheal aspirate) markers of inflammation; and 3) iNO does not increase the incidence of intraventricular hemorrhage in premature neonates. The primary endpoint is survival without CLD (defined as continued oxygen requirement) at 36 weeks post conceptional age.

A total of 793 premature newborns will be enrolled from 14 centers within 48 hours of birth. They will be randomly assigned to receive either placebo or iNO at 5 ppm until the breathing tube can be safely removed or after 21 days. The iNO will be delivered by an INOvent delivery system in such a way that physicians and nurses will not know which treatment each participant is receiving. Management strategies for aspects of patient care including mechanical ventilation, surfactant administration, fluid administration, and steroid use will be determined by physicians at each center. Serial cranial ultrasounds and methemoglobin levels will be monitored to determine adverse events. The first 200 patients will have serial blood samples and tracheal aspirates obtained for measurements of inflammatory mediators, including interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), endothelin-1, myeloperoxidase, neutrophil counts (tracheal aspirates), and endothelin-1 (blood). Participants will be seen at 12 and 24 months of age to monitor the long-term effects on the cardiopulmonary or neurologic systems. At these visits, a health questionnaire will be administered and Bayley II scales of infant development will be completed.

• Study Type: Interventional
• Enrollment (Anticipated): 793
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90033
      • Univeristy of Southern California/Good Samaritan Hospital
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Children's Hospital
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital & Clinics
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Children's Hospital of Oklahoma
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Women's Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Utah
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Weighing between 500 to 1250 grams at birth
• Gestational age of less than 34 weeks
• Less than 48 hours old
• Respiratory failure on mechanical ventilation
• Absence of structural heart disease (PDA, ASD less than 1 cm, or VSD less than 2 mm are permitted if known prior to study entry)
• Absence of lethal congenital anomaly

Exclusion Criteria:

• Concurrent participation in another experimental study (observational studies will be allowed with prior approval by the Steering Committee and Data and Safety Monitoring Board)
• Active pulmonary hemorrhage
• Unevaluated pneumothorax
• High frequency jet ventilation
• Expected short duration of ventilation (less than 48 hours from birth)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Inhaled Nitrogen
Experimental: Inhaled Nitric Oxide (iNO); Nitric Oxide study gas will be initiated at 5 ppm using the INOvent delivery system. The delivery system provides for masked delivery of the treatment gas. This dose will be used for a 21-day period or until extubation.	Drug: iNO; Inhaled Nitric Oxide for Preventing Chronic Lung Disease in Premature Infants; Other Names: Inhaled nitric oxide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Participant's survival without CLD	(measured at 36 weeks after birth)

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Chair: John P. Kinsella, MD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, Sekar KC, Auten RL, Bhutani VK, Gerdes JS, George TN, Southgate WM, Carriedo H, Couser RJ, Mammel MC, Hall DC, Pappagallo M, Sardesai S, Strain JD, Baier M, Abman SH. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006 Jul 27;355(4):354-64. doi: 10.1056/NEJMoa060442.
• Mourani PM, Kinsella JP, Clermont G, Kong L, Perkins AM, Weissfeld L, Cutter G, Linde-Zwirble WT, Abman SH, Angus DC, Watson RS; Prolonged Outcomes after Nitric Oxide (PrONOx) Investigators. Intensive care unit readmission during childhood after preterm birth with respiratory failure. J Pediatr. 2014 Apr;164(4):749-755.e3. doi: 10.1016/j.jpeds.2013.11.062. Epub 2013 Dec 31.
• Watson RS, Clermont G, Kinsella JP, Kong L, Arendt RE, Cutter G, Linde-Zwirble WT, Abman SH, Angus DC; Prolonged Outcomes After Nitric Oxide Investigators. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009 Nov;124(5):1333-43. doi: 10.1542/peds.2009-0114. Epub 2009 Oct 19.

Study record dates

Study Major Dates

• Study Start: September 1, 2000
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: October 12, 2000
• First Submitted That Met QC Criteria: October 12, 2000
• First Posted (Estimate): October 13, 2000

Study Record Updates

• Last Update Posted (Estimate): October 6, 2015
• Last Update Submitted That Met QC Criteria: October 5, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Lung Diseases; Bronchopulmonary Dysplasia; 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: 99-233; U01HL064857 (U.S. NIH Grant/Contract)