Infant, NewbornPhase 3NINOSNCT00005776
Inhaled Nitric Oxide Study for Respiratory Failure in Newborns
A Phase 3 study testing Inhaled nitric oxide in people with Infant, Newborn and Hypertension, Pulmonary, run by NICHD Neonatal Research Network at 20 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages Up to 14 days
- Conditions the study is for
- Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome
- What is being tested?
- Inhaled nitric oxide
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 235 participants
- Where
- 20 sitesin 2 countries
- Study dates
- Oct 1995to May 1998
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 14 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- Congenital diaphragmatic hernia
- Known congenital heart disease
- Decision not to provide full therapy
Trial locations and contacts
20 sites in 2 countries.
20 sites in 2 countries
United States11 sites
University of New Mexico
Albuquerque, New Mexico, 87131
Cincinnati Children's Medical Center
Cincinnati, Ohio, 45267
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, 44106
Wayne State University
Detroit, Michigan, 48201
Texas Children's Hospital
Houston, Texas, 77030
Indiana University
Indianapolis, Indiana, 46202
University of Tennessee
Memphis, Tennessee, 38163
Yale University
New Haven, Connecticut, 06504
Stanford University
Palo Alto, California, 94304
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, 02905
George Washington University
Washington D.C., District of Columbia, 20052
Canada9 sites
Foothills Hospital
Calgary, Alberta
Royal Alexandra Hospital
Edmonton, Alberta
McMaster University
Hamilton, Ontario
Montreal Children's Hospital
Montreal, Quebec
Children's Hospital of Eastern Ontario
Ottawa, Ontario
Royal University Hospital
Saskatoon, Saskatchewan
Université de Sherbrooke,
Sherbrooke, Quebec
British Columbia Children's Hospital
Vancouver, British Columbia
Health Sciences Center
Winnipeg, Manitoba
About this study
Official title: The Randomized Inhaled Nitric Oxide Study (NINOS) in Full-Term and Nearly Full-Term Infants With Hypoxic Respiratory Failure
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.
Read the 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.
- Conditions
- Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome, Pneumonia, Aspiration, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency
- Being tested
- Inhaled nitric oxide, Placebo
- 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
- Medical subject headings
- Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome, Pneumonia, Aspiration, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency, Meconium Aspiration Syndrome, Methemoglobinemia, Respiratory Distress Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inhaled nitric oxideDrug
Inhaled Nitric oxide at a concentration of 20 ppm
PlaceboDrug
100% Oxygen
| Study group | Role | What they receive |
|---|---|---|
| Inhaled Nitric Oxide | Experimental | Inhaled Nitric Oxide (iNO) Receives: Drug: Inhaled nitric oxide |
| Oxygen | Placebo comparator | 100% oxygen Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Death or initiation of ECMO
Measured: Before hospital discharge or 120 days of life
Secondary outcomes (6)
PaO2 levels, oxygenation index, and alveolar-arterial oxygen gradient
Measured: 30 minutes after drug administration
Neurodevelopmental outcome
Measured: 18-22 Months Corrected Age
Duration of hospital stay
Measured: At hospital discharge
Duration of assisted ventilation, air leaks, or chronic lung disease
Measured: At hospital discharge
Transfers for ECMO
Measured: At hospital discharge
Meeting ECMO criteria
Measured: At hospital discharge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jun 2000 (estimated)
- Study startOct 1995
- Primary completionMay 1996
- Study completionMay 1998
Why it stopped: Results showed statistically significant benefit in the experimental group
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Infant, NewbornStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 235 participants (actual)
Sponsor and investigators
- Lead sponsor
- NICHD Neonatal Research Network
- Sponsor type
- Research network
- Collaborators
- Medical Research Council of Canada, National Center for Research Resources (NCRR)
- Investigators
- Richard A. Ehrenkranz, MD, Study director, Yale UniversityDavid K. Stevenson, MD, Principal investigator, Stanford UniversityRaymond Bain, PhD, Principal investigator, George Washington UniversityJames A. Lemons, MD, Principal investigator, Indiana UniversitySeetha Shankaran, MD, Principal investigator, Wayne State UniversityLu-Ann Papile, MD, Principal investigator, University of New MexicoEdward F. Donovan, MD, Principal investigator, Children's Hospital Medical Center, CincinnatiAvroy A. Fanaroff, MD, Principal investigator, Case Western Reserve University, Rainbow Babies and Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00005776
- Sponsor's protocol ID
- NICHD-NRN-0014
- Other IDs
- U01HD019897, U10HD021364, U10HD021373, U10HD021385, U10HD021397, U10HD021415, U10HD027851, U10HD027853
- Acronym
- NINOS
- Status last verified
- Sep 2017
- First submitted
- 1 Jun 2000
- Last updated
- 26 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 9036320Inhaled 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.
PubMed 9190553Inhaled 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.
PubMed 10802492Sokol 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.
PubMed 11416871Sokol 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.
PubMed 14510322
Study at a glance
From the registry record, last updated by the sponsor on 26 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Randomized Inhaled Nitric Oxide Study (NINOS) in Full-Term and Nearly Full-Term Infants With Hypoxic Respiratory Failure
- ClinicalTrials.gov ID
- NCT00005776
- Acronym / sponsor ID
- NINOS / NICHD-NRN-0014
- 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
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Results showed statistically significant benefit in the experimental group
- Enrolment
- 235 participants (actual)
- Lead sponsor
- NICHD Neonatal Research NetworkResearch network
- Collaborators
- Medical Research Council of Canada, National Center for Research Resources (NCRR)
- Study start
- Oct 1995
- Primary completion
- May 1996 (actual)
- Study completion
- May 1998 (actual)
- First posted
- 2 Jun 2000 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Inhaled Nitric Oxide | Experimental | Drug: Inhaled nitric oxideInhaled Nitric Oxide (iNO) |
| Oxygen | Placebo comparator | Drug: Placebo100% oxygen |
Who may qualify
- Ages
- Up to 14 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (3 listed)
- Congenital diaphragmatic hernia
- Known congenital heart disease
- Decision not to provide full therapy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inhaled nitric oxideInhaled Nitric oxide at a concentration of 20 ppm | Drug | Inhaled Nitric Oxide |
| Placebo100% Oxygen | Drug | Oxygen |
Primary outcome
Death or initiation of ECMO
Time frame: Before hospital discharge or 120 days of life
6 secondary outcomes
PaO2 levels, oxygenation index, and alveolar-arterial oxygen gradient
Time frame: 30 minutes after drug administration
Neurodevelopmental outcome
Time frame: 18-22 Months Corrected Age
Duration of hospital stay
Time frame: At hospital discharge
Duration of assisted ventilation, air leaks, or chronic lung disease
Time frame: At hospital discharge
Transfers for ECMO
Time frame: At hospital discharge
Meeting ECMO criteria
Time frame: At hospital discharge
Results and safety
The study was stopped early (reason given: Results showed statistically significant benefit in the experimental group). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2017.
- Results publication: PubMed 9036320Neonatal 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.
- Results publication: PubMed 9190553Inhaled 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.
- Results publication: PubMed 10802492Inhaled 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.
- Results publication: PubMed 11416871Sokol 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.
- Results publication: PubMed 14510322Sokol 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.
- NICHD Neonatal Research NetworkLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard A. Ehrenkranz, MD study director
Yale University
David K. Stevenson, MD principal investigator
Stanford University
Raymond Bain, PhD principal investigator
George Washington University
20 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inhaled nitric oxide in people with Infant, Newborn and Hypertension, Pulmonary, run by NICHD Neonatal Research Network at 20 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Results showed statistically significant benefit in the experimental group). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Death or initiation of ECMO (time frame: Before hospital discharge or 120 days of life). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00005776, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2017.