Inhaled Nitric Oxide Study for Respiratory Failure in Newborns (NINOS)

This study has been terminated.
(Results showed statistically significant benefit in the experimental group)
Medical Research Council of Canada
National Center for Research Resources (NCRR)
Information provided by:
NICHD Neonatal Research Network Identifier:
First received: June 1, 2000
Last updated: June 3, 2015
Last verified: June 2015
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.

Condition Intervention Phase
Infant, Newborn
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Pneumonia, Aspiration
Respiratory Distress Syndrome, Newborn
Respiratory Insufficiency
Drug: Inhaled nitric oxide
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Randomized Inhaled Nitric Oxide Study (NINOS) in Full-Term and Nearly Full-Term Infants With Hypoxic Respiratory Failure

Resource links provided by NLM:

Further study details as provided by NICHD Neonatal Research Network:

Primary Outcome Measures:
  • Death or initiation of ECMO [ Time Frame: Before hospital discharge or 120 days of life ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • PaO2 levels, oxygenation index, and alveolar-arterial oxygen gradient [ Time Frame: 30 minutes after drug administration ] [ Designated as safety issue: Yes ]
  • Neurodevelopmental outcome [ Time Frame: 18-22 Months Corrected Age ] [ Designated as safety issue: No ]
  • Duration of hospital stay [ Time Frame: At hospital discharge ] [ Designated as safety issue: No ]
  • Duration of assisted ventilation, air leaks, or chronic lung disease [ Time Frame: At hospital discharge ] [ Designated as safety issue: Yes ]
  • Transfers for ECMO [ Time Frame: At hospital discharge ] [ Designated as safety issue: Yes ]
  • Meeting ECMO criteria [ Time Frame: At hospital discharge ] [ Designated as safety issue: Yes ]

Enrollment: 235
Study Start Date: October 1995
Study Completion Date: May 1998
Primary Completion Date: May 1996 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Inhaled Nitric Oxide
Inhaled Nitric Oxide (iNO)
Drug: Inhaled nitric oxide
Inhaled Nitric oxide at a concentration of 20 ppm
Placebo Comparator: Oxygen
100% oxygen
Drug: Placebo
100% Oxygen

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.


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

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
  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 identifier: NCT00005776

  Show 20 Study Locations
Sponsors and Collaborators
NICHD Neonatal Research Network
Medical Research Council of Canada
National Center for Research Resources (NCRR)
Study Director: Richard A. Ehrenkranz, MD Yale University
Principal Investigator: David K. Stevenson, MD Stanford University
Principal Investigator: Raymond Bain, PhD George Washington University
Principal Investigator: James A. Lemons, 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 Children's Hospital Medical Center, Cincinnati
Principal Investigator: Avroy A. Fanaroff, MD Case Western Reserve University, Rainbow Babies and Children's Hospital
Principal Investigator: William William Oh, MD Brown University, Women & Infants Hospital of Rhode Island
Principal Investigator: Sheldon B. Korones, MD University of Tennessee
Principal Investigator: Mary Wearden, MD Texas Children's Hospital
Principal Investigator: N. Singhal, MD Foothills Hospital, Calgary, Canada
Principal Investigator: Neil N. Finer, MD Royal Alexandra Hospital
Principal Investigator: A. Solimano, MD British Columbia Children's Hospital
Principal Investigator: C. Fajardo, MD Health Sciences Center, Winnipeg, Manitoba
Principal Investigator: H. Kirpalani, MD McMaster University
Principal Investigator: R. Walker, MD Children's Hospital of Eastern Ontario
Principal Investigator: A. Johnston, MD Montreal Children's Hospital of the MUHC
Principal Investigator: P. Blanchard, MD Université de Sherbrooke, Sherbrooke, Quebec
Principal Investigator: K. Sankarhan, MD Royal University Hospital, Saskatoon, Saskatchewan
  More Information

Additional Information:
Responsible Party: Richard A. Ehrenkranz, NRN Lead Study Investigator, Yale University School of Medicine Identifier: NCT00005776     History of Changes
Other Study ID Numbers: NICHD-NRN-0014  U01HD019897  U10HD021364  U10HD021373  U10HD021385  U10HD021397  U10HD021415  U10HD027851  U10HD027853  U10HD027856  U10HD027871  U10HD027880  U10HD027881  U10HD027904  U10HD034167  U10HD034216  M01RR000070  M01RR000750  M01RR000997  M01RR001032  M01RR006022  M01RR008084 
Study First Received: June 1, 2000
Last Updated: June 3, 2015
Health Authority: United States: Federal Government
United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by NICHD Neonatal Research Network:
Pneumonia, aspiration
NICHD Neonatal Research Network
Hypertension, pulmonary
Hypoxic respiratory failure
Meconium aspiration
Nitric oxide
Oxygen inhalation therapy
Persistent Fetal Circulation Syndrome
Respiratory distress syndrome
Respiratory insufficiency
Severe respiratory failure

Additional relevant MeSH terms:
Pneumonia, Aspiration
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Pulmonary Valve Insufficiency
Respiratory Distress Syndrome, Adult
Respiratory Distress Syndrome, Newborn
Respiratory Insufficiency
Cardiovascular Diseases
Heart Diseases
Heart Valve Diseases
Infant, Newborn, Diseases
Infant, Premature, Diseases
Lung Diseases
Pathologic Processes
Respiration Disorders
Respiratory Tract Diseases
Respiratory Tract Infections
Nitric Oxide
Anti-Asthmatic Agents
Autonomic Agents
Bronchodilator Agents
Endothelium-Dependent Relaxing Factors
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents processed this record on May 26, 2016