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

Primary Purpose

Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Inhaled Nitric Oxide
Standard iNO therapy
Sponsored by
NICHD Neonatal Research Network
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infant, Newborn focused on measuring 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

Eligibility Criteria

undefined - 14 Days (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • St. Joseph's Hospital
  • Stanford University
  • San Diego Children's Hospital
  • Yale University
  • University of Miami
  • Emory University
  • Indiana University
  • Wayne State University
  • University of New Mexico
  • Cincinnati Children's Medical Center
  • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Brown University, Women & Infants Hospital of Rhode Island
  • University of Tennessee
  • University of Texas Southwestern Medical Center at Dallas
  • Texas Children's Hospital
  • University of Texas Health Science Center at Houston
  • University of Washington School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Early iNO Management

Standard iNO management

Arm Description

Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25.

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).

Outcomes

Primary Outcome Measures

Death or use of extracorporeal membrane oxygenation (ECMO)

Secondary Outcome Measures

Use of iNO therapy based on the standard recommended threshold
Progression to severe respiratory failure (OI>40)
Severe respiratory failure, defined as OI >40
Neurodevelopmental impairment

Full Information

First Posted
June 1, 2000
Last Updated
September 22, 2017
Sponsor
NICHD Neonatal Research Network
Collaborators
National Center for Research Resources (NCRR), Canadian Institutes of Health Research (CIHR), Mallinckrodt
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1. Study Identification

Unique Protocol Identification Number
NCT00005773
Brief Title
Early Inhaled Nitric Oxide for Respiratory Failure in Newborns
Acronym
Early iNO
Official Title
Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Terminated
Why Stopped
Halted after 3 years because of a persistent decline in enrollment
Study Start Date
August 1998 (undefined)
Primary Completion Date
May 2001 (Actual)
Study Completion Date
August 2003 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
NICHD Neonatal Research Network
Collaborators
National Center for Research Resources (NCRR), Canadian Institutes of Health Research (CIHR), Mallinckrodt

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome, Pneumonia, Aspiration, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
302 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Early iNO Management
Arm Type
Experimental
Arm Description
Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25.
Arm Title
Standard iNO management
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Inhaled Nitric Oxide
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Standard iNO therapy
Intervention Description
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).
Primary Outcome Measure Information:
Title
Death or use of extracorporeal membrane oxygenation (ECMO)
Time Frame
Hospital discharge or 120 days of life
Secondary Outcome Measure Information:
Title
Use of iNO therapy based on the standard recommended threshold
Time Frame
Hospital Discharge or 120 days of life
Title
Progression to severe respiratory failure (OI>40)
Description
Severe respiratory failure, defined as OI >40
Time Frame
Hospital discharge or 120 days of life
Title
Neurodevelopmental impairment
Time Frame
18-22 months corrected age

10. Eligibility

Sex
All
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
G. Ganesh Konduri, MD
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Waldemar A. Carlo, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Carlos Fajardo, MD
Organizational Affiliation
St. Joseph's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Krisa P. Van Meurs, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gail Knight, MD
Organizational Affiliation
San Diego Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard A. Ehrenkranz, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Charles R. Bauer, MD
Organizational Affiliation
University of Miami
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Barbara J. Stoll, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Greg M. Sokol, MD
Organizational Affiliation
Indiana University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Seetha Shankaran, MD
Organizational Affiliation
Wayne State University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lu-Ann Papile, MD
Organizational Affiliation
University of New Mexico
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Edward F. Donovan, MD
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Avroy A. Fanaroff, MD
Organizational Affiliation
Case Western Reserve University, Rainbow Babies and Children's Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
William Oh, MD
Organizational Affiliation
Brown University, Women & Infants Hospital of Rhode Island
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sheldon B. Korones, MD
Organizational Affiliation
University of Tennessee
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Abbot R. Laptook, MD
Organizational Affiliation
University of Texas, Southwestern Medical Center at Dallas
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mary Wearden, MD
Organizational Affiliation
Baylor College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kathleen A. Kennedy, MD MPH
Organizational Affiliation
The University of Texas Health Science Center, Houston
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dennis E. Mayock, MD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
St. Joseph's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
San Diego Children's Hospital
City
San Diego
State/Province
California
ZIP/Postal Code
92130
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06504
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Wayne State University
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
Cincinnati Children's Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Case Western Reserve University, Rainbow Babies and Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Brown University, Women & Infants Hospital of Rhode Island
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02905
Country
United States
Facility Name
University of Tennessee
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38163
Country
United States
Facility Name
University of Texas Southwestern Medical Center at Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas Health Science Center at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Washington School of Medicine
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10053039
Citation
Sokol GM, Van Meurs KP, Wright LL, Rivera O, Thorn WJ 3rd, Chu PM, Sams RL. Nitrogen dioxide formation during inhaled nitric oxide therapy. Clin Chem. 1999 Mar;45(3):382-7.
Results Reference
background
PubMed Identifier
14510322
Citation
Sokol GM, Ehrenkranz RA. Inhaled nitric oxide therapy in neonatal hypoxic respiratory failure: insights beyond primary outcomes. Semin Perinatol. 2003 Aug;27(4):311-9. doi: 10.1016/s0146-0005(03)00043-0.
Results Reference
background
PubMed Identifier
14993550
Citation
Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A; Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004 Mar;113(3 Pt 1):559-64. doi: 10.1542/peds.113.3.559.
Results Reference
result
PubMed Identifier
17307536
Citation
Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A, Johnson Y; Neonatal Inhaled Nitric Oxide Study Group. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr. 2007 Mar;150(3):235-40, 240.e1. doi: 10.1016/j.jpeds.2006.11.065.
Results Reference
result
Links:
URL
http://neonatal.rti.org/
Description
NICHD Neonatal Research Network

Learn more about this trial

Early Inhaled Nitric Oxide for Respiratory Failure in Newborns

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