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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT00005773
Other study ID # NICHD-NRN-0019
Secondary ID U01HD019897U10HD
Status Terminated
Phase Phase 3
First received June 1, 2000
Last updated September 22, 2017
Start date August 1998
Est. completion date August 2003

Study information

Verified date September 2017
Source NICHD Neonatal Research Network
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Terminated
Enrollment 302
Est. completion date August 2003
Est. primary completion date May 2001
Accepts healthy volunteers No
Gender All
Age group N/A to 14 Days
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

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).
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).

Locations

Country Name City State
United States University of New Mexico Albuquerque New Mexico
United States Emory University Atlanta Georgia
United States University of Alabama at Birmingham Birmingham Alabama
United States Cincinnati Children's Medical Center Cincinnati Ohio
United States Case Western Reserve University, Rainbow Babies and Children's Hospital Cleveland Ohio
United States University of Texas Southwestern Medical Center at Dallas Dallas Texas
United States Wayne State University Detroit Michigan
United States Texas Children's Hospital Houston Texas
United States University of Texas Health Science Center at Houston Houston Texas
United States Indiana University Indianapolis Indiana
United States University of Tennessee Memphis Tennessee
United States University of Miami Miami Florida
United States Yale University New Haven Connecticut
United States Stanford University Palo Alto California
United States St. Joseph's Hospital Phoenix Arizona
United States Brown University, Women & Infants Hospital of Rhode Island Providence Rhode Island
United States San Diego Children's Hospital San Diego California
United States University of Washington School of Medicine Seattle Washington

Sponsors (4)

Lead Sponsor Collaborator
NICHD Neonatal Research Network Canadian Institutes of Health Research (CIHR), Mallinckrodt, National Center for Research Resources (NCRR)

Country where clinical trial is conducted

United States, 

References & Publications (4)

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 an — View 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 nea — View 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. Review. — View 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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Death or use of extracorporeal membrane oxygenation (ECMO) Hospital discharge or 120 days of life
Secondary Use of iNO therapy based on the standard recommended threshold Hospital Discharge or 120 days of life
Secondary Progression to severe respiratory failure (OI>40) Severe respiratory failure, defined as OI >40 Hospital discharge or 120 days of life
Secondary Neurodevelopmental impairment 18-22 months corrected age
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