Clinical trial NCT00005776: Inhaled Nitric Oxide Study for Respiratory Failure in Newborns
Official title: The Randomized Inhaled Nitric Oxide Study (NINOS) in Full-Term and Nearly Full-Term Infants With Hypoxic Respiratory Failure
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: 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
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: Medical Research Council of Canada
name: National Center for Research Resources (NCRR)
First posted: 2000-06-02
Enrollment: 235
Sex: ALL
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Respiratory failure in term newborns is associated with increased rates of death and long-term neurodevelopmental problems. This large international multicenter trial randomized newborns who had failed to respond to intensive care, including high levels of ventilator support, to receive either inhaled nitric oxide (iNO) or 100 percent oxygen to test whether iNO would decrease their risk of dying or requiring temporary lung bypass. Infants were followed during their initial hospitalization; their outcome was assessed at 18 to 24 mos of age.

Detailed description: Respiratory failure in term newborns is associated with significant morbidity and mortality, despite maximal conventional therapy. Neonates with pulmonary hypertension have been treated with iNO, a selective pulmonary vasodilator. This multicenter, double-masked placebo-controlled randomized trial tested whether iNO would reduce the risk of death and/or the initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. The sample size was based on a reduction of the primary event (death or ECMO) from 50 percent to 30 percent; 90 percent power; and a two-tailed Type I error of 0.05.

Infants were evaluated at baseline for pulmonary, cardiac, bleeding status, and therapies received. Those who were greater than 34 wks gestation and 14 days old or less and required assisted ventilation with an OI (mean airway pressure x FiO2 divided by the PaO2 x 100) greater than 25 were eligible. They were randomly assigned to receive iNO at 20 ppm or 100 percent oxygen as a control. Infants whose PaO2 increased by less than 20 mm Hg after 30 minutes were studied at 80ppm iNO or control gas.; MetHg and NO2 concentrations were monitored regularly. Management, including surfactant administration, included prospectively defined criteria for study gas response, escalation, reinitiation, and weaning. The maximum total time on study gas was 336 hrs (after 240 hrs, the INO concentration was required to be no more than 5 ppm). Patients were followed to death, discharge, or 120 days and evaluated at 18-24 mos by a masked certified examiner.

Eligibility criteria: Inclusion Criteria:

* Greater than 34 wks gestational age
* One or more of the following diagnoses: primary pulmonary hypertension of the newborn, respiratory distress syndrome, perinatal aspiration syndrome, pneumonia/sepsis, suspected pulmonary hypoplasia
* Oxygenation Index (OI) greater than 15 and less than 25 on 2 arterial blood gases at least 15 min apart
* Indwelling arterial line
* Echocardiography before randomization
* Parental consent

Exclusion Criteria:

* Congenital diaphragmatic hernia
* Known congenital heart disease
* Decision not to provide full therapy

Primary outcomes:
measure: Death or initiation of ECMO
timeFrame: Before hospital discharge or 120 days of life
Secondary outcomes:
measure: PaO2 levels, oxygenation index, and alveolar-arterial oxygen gradient
timeFrame: 30 minutes after drug administration
measure: Neurodevelopmental outcome
timeFrame: 18-22 Months Corrected Age
measure: Duration of hospital stay
timeFrame: At hospital discharge
measure: Duration of assisted ventilation, air leaks, or chronic lung disease
timeFrame: At hospital discharge
measure: Transfers for ECMO
timeFrame: At hospital discharge
measure: Meeting ECMO criteria
timeFrame: At hospital discharge
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington, D.C.
country: United States
facility: George Washington University
state: District of Columbia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Memphis
country: United States
facility: University of Tennessee
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Health Sciences Center
state: Manitoba
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Sherbrooke,
country: Canada
facility: Université de Sherbrooke,
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: Yale University
name: Richard A. Ehrenkranz, MD
role: STUDY_DIRECTOR
affiliation: Stanford University
name: David K. Stevenson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: George Washington University
name: Raymond Bain, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: James A. Lemons, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Lu-Ann Papile, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Edward F. Donovan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Avroy A. Fanaroff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: William William Oh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Tennessee
name: Sheldon B. Korones, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: Mary Wearden, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Foothills Hospital, Calgary, Canada
name: N. Singhal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Alexandra Hospital
name: Neil N. Finer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: British Columbia Children's Hospital
name: A. Solimano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Health Sciences Center, Winnipeg, Manitoba
name: C. Fajardo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: H. Kirpalani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Eastern Ontario
name: R. Walker, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Montreal Children's Hospital of the MUHC
name: A. Johnston, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Université de Sherbrooke, Sherbrooke, Quebec
name: P. Blanchard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal University Hospital, Saskatoon, Saskatchewan
name: K. Sankarhan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997 Feb 27;336(9):597-604. doi: 10.1056/NEJM199702273360901.
citation: Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics. 1997 Jun;99(6):838-45. doi: 10.1542/peds.99.6.838.
citation: Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr. 2000 May;136(5):611-7. doi: 10.1067/mpd.2000.104826.
citation: Sokol GM, Fineberg NS, Wright LL, Ehrenkranz RA. Changes in arterial oxygen tension when weaning neonates from inhaled nitric oxide. Pediatr Pulmonol. 2001 Jul;32(1):14-9. doi: 10.1002/ppul.1083.
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.