Early Inhaled Nitric Oxide for Respiratory Failure in Newborns (Early iNO)

This study has been terminated.
(Halted after 3 years because of a persistent decline in enrollment)
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
INO Therapeutics
Information provided by:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00005773
First received: June 1, 2000
Last updated: May 12, 2011
Last verified: April 2011
  Purpose

This prospective, randomized controlled trial tested whether initiating iNO therapy earlier would reduce death and reduce the use of extracorporeal membrane oxygenation (ECMO) -- temporary lung bypass -- therapy compared with the standard recommendation threshold. Infants who were born at >34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) >15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to receive either early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. The neurodevelopment of the subjects were evaluated at 18-22 months corrected age.


Condition Intervention Phase
Infant, Newborn
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Pneumonia, Aspiration
Respiratory Distress Syndrome, Newborn
Respiratory Insufficiency
Drug: Inhaled Nitric Oxide
Drug: Standard iNO therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Death or use of extracorporeal membrane oxygenation (ECMO) [ Time Frame: Hospital discharge or 120 days of life ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Use of iNO therapy based on the standard recommended threshold [ Time Frame: Hospital Discharge or 120 days of life ] [ Designated as safety issue: Yes ]
  • Progression to severe respiratory failure (OI>40) [ Time Frame: Hospital discharge or 120 days of life ] [ Designated as safety issue: Yes ]
    Severe respiratory failure, defined as OI >40

  • Neurodevelopmental impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]

Enrollment: 302
Study Start Date: August 1998
Study Completion Date: August 2003
Primary Completion Date: May 2001 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Early iNO Management
Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25.
Drug: Inhaled Nitric Oxide
Study gas was initiated at a concentration of 5 ppm, and the dose was increased to 20 ppm when the infant had <=20 mm Hg increase in PaO2 (less than full response).
Active Comparator: Standard iNO management
Begin a sham initiation of iNO in term and near-term infants in respiratory failure with an oxygenation index (OI) between 15-25; initiated actual iNO therapy based on standard threshold (OI >=25).
Drug: Standard iNO therapy
Begin a sham initiation of iNO in term and near-term infants in respiratory failure with an oxygenation index (OI) between 15-25; initiated actual iNO therapy based on standard threshold (OI >=25).

Detailed Description:

Respiratory failure occurs in near term and term infants as a complication of perinatal aspiration syndromes, pneumonia, sepsis, respiratory distress syndrome and primary pulmonary hypertension. Recently a collaborative trial of the NICHD Neonatal Research Network and the Canadian Inhaled Nitric Oxide Study Group (the NINOS trial) demonstrated that inhaled nitric oxide (iNO) reduced the number of deaths and the need for extracorporeal membrane oxygenation (ECMO) therapy -- a lung bypass mechanism -- from 64 percent to 46 percent. The standard recommended threshold for initiation of iNO therapy, based on this trial, was an oxygenation index (OI) >=25.

The purpose of this study is to determine if administration of inhaled nitric oxide earlier in the course of respiratory failure and to infants with less severe respiratory failure, decreases the incidence of ECMO or death, as suggested by the sub-group analysis of the original NINOS trial. This prospective, randomized controlled trial tested whether initiating iNO therapy earlier would reduce death and reduce the use of ECMO therapy compared with the standard recommendation threshold.

Infants who were born at >34 weeks' gestation (near- or full-term) were enrolled when they required assisted ventilation and had an oxygenation index (OI) >15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to receive either early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. The neurodevelopment of the subjects were evaluated at 18-22 months corrected age.

The study compared the outcome of infants received iNO at OI >15 and <25, with a control group that received a simulated early procedure with iNO actually given based on the standard recommendation. iNO was delivered at 20 ppm during the initial dose-response evaluation. Infants in either group who showed subsequent deterioration with OI >25 on two consecutive measurements at least one hour apart, or a rapid deterioration with OI >30 on two consecutive measurements 15 minutes apart, received iNO therapy as part of standard medical management. Specific guidelines were followed for the use of high frequency ventilation and surfactant during study gas administration to prevent them from confounding the results of the study.

Study recruitment was discontinued after 3 years due to a persistent decline in enrollment.

Infants were given neurodevelopmental exams at 18-22 months corrected age.

  Eligibility

Ages Eligible for Study:   up to 14 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Infants born at >34 weeks gestational age
  • Require assisted ventilation for hypoxic respiratory failure
  • Have a diagnosis of primary persistent pulmonary hypertension (PPHN), respiratory distress syndrome, perinatal aspiration syndrome, pneumonia/sepsis, or suspected pulmonary hypoplasia
  • Have an oxygenation index >15 and <25 based on 2 arterial blood gases taken at least 15 minutes apart or an Fi02 >80%
  • In-dwelling arterial line
  • Parental consent

Exclusion Criteria:

  • Known structural congenital heart disease, except patent ductus arteriosus and atrial level shunts
  • Congenital diaphragmatic hernia
  • Use of high frequency jet ventilation at the time of randomization
  • Prior exposure to inhaled nitric oxide therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00005773

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Arizona
St. Joseph's Hospital
Phoenix, Arizona, United States, 85013
United States, California
Stanford University
Palo Alto, California, United States, 94304
San Diego Children's Hospital
San Diego, California, United States, 92130
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06504
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30303
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, Ohio
Cincinnati Children's Medical Center
Cincinnati, Ohio, United States, 45267
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States, 44106
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States, 02905
United States, Tennessee
University of Tennessee
Memphis, Tennessee, United States, 38163
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75235
University of Texas Health Science Center at Houston
Houston, Texas, United States, 77030
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Washington
University of Washington School of Medicine
Seattle, Washington, United States, 98195
Sponsors and Collaborators
Canadian Institutes of Health Research (CIHR)
INO Therapeutics
Investigators
Study Director: G. Ganesh Konduri, MD University of Wisconsin, Madison
Principal Investigator: Waldemar A. Carlo, MD University of Alabama at Birmingham
Principal Investigator: Carlos Fajardo, MD St. Joseph's Hospital
Principal Investigator: Krisa P. Van Meurs, MD Stanford University
Principal Investigator: Gail Knight, MD San Diego Children's Hospital
Principal Investigator: Richard A. Ehrenkranz, MD Yale University
Principal Investigator: Charles R. Bauer, MD University of Miami
Principal Investigator: Barbara J. Stoll, MD Emory University
Principal Investigator: Greg M. Sokol, MD Indiana University
Principal Investigator: Seetha Shankaran, MD Wayne State University
Principal Investigator: Lu-Ann Papile, MD University of New Mexico
Principal Investigator: Edward F. Donovan, MD Cincinnati Children's Medical Center
Study Director: Avroy A. Fanaroff, MD Case Western Reserve University, Rainbow Babies and Children's Hospital
Principal Investigator: William Oh, MD Brown University, Women & Infants Hospital of Rhode Island
Principal Investigator: Sheldon B. Korones, MD University of Tennessee
Principal Investigator: Abbot R. Laptook, MD University of Texas Southwestern Medical Center at Dallas
Principal Investigator: Mary Wearden, MD Texas Children's Hospital
Principal Investigator: Kathleen A. Kennedy, MD MPH The University of Texas Health Science Center, Houston
Principal Investigator: Dennis E. Mayock, MD University of Washington
  More Information

Additional Information:
Publications:
Responsible Party: G. Ganesh Konduri, Lead Principal Investigator, Medical College of Wisconsin, Children's Hospital of Wisconsin
ClinicalTrials.gov Identifier: NCT00005773     History of Changes
Other Study ID Numbers: NICHD-NRN-0019, U01HD019897, U10HD021364, U10HD021373, U10HD021385, U10HD021397, U10HD021415, U10HD027853, U10HD027856, U10HD027871, U10HD027880, U10HD027881, U10HD027904, U10HD034167, U10HD034216, U10HD040689, M01RR000070, M01RR000633, M01RR000750, M01RR000997, M01RR001032, M01RR006022, M01RR008084, M01RR016587
Study First Received: June 1, 2000
Last Updated: May 12, 2011
Health Authority: United States: Federal Government
United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
NICHD Neonatal Research Network
Hypertension, pulmonary
Hypoxic respiratory failure
Meconium aspiration
Methemoglobinemia
Nitric oxide
Oxygen inhalation therapy
Persistent Fetal Circulation Syndrome
Pneumonia, aspiration
Respiratory distress syndrome
Respiratory insufficiency
Severe respiratory failure

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Pneumonia
Pneumonia, Aspiration
Respiratory Distress Syndrome, Newborn
Respiratory Insufficiency
Syndrome
Cardiovascular Diseases
Disease
Infant, Newborn, Diseases
Infant, Premature, Diseases
Lung Diseases
Pathologic Processes
Respiration Disorders
Respiratory Tract Diseases
Respiratory Tract Infections
Vascular Diseases
Nitric Oxide
Anti-Asthmatic Agents
Antioxidants
Autonomic Agents
Bronchodilator Agents
Cardiovascular Agents
Endothelium-Dependent Relaxing Factors
Free Radical Scavengers
Gasotransmitters
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on October 23, 2014