Infant, NewbornPhase 3Early iNONCT00005773
Early Inhaled Nitric Oxide for Respiratory Failure in Newborns
A Phase 3 study testing Inhaled Nitric Oxide and Standard iNO therapy in people with Infant, Newborn and Hypertension, Pulmonary, run by NICHD Neonatal Research Network at 18 sites in United States.
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. 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 and Standard iNO therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 302 participants
- Where
- 18 sitesUnited States
- Study dates
- Aug 1998to Aug 2003
- 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
- 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
Who cannot join
- 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
Trial locations and contacts
18 sites in 1 country.
18 sites in 1 country
United States18 sites
University of New Mexico
Albuquerque, New Mexico, 87131
Emory University
Atlanta, Georgia, 30303
University of Alabama at Birmingham
Birmingham, Alabama, 35233
Cincinnati Children's Medical Center
Cincinnati, Ohio, 45267
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, 44106
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, 75235
Wayne State University
Detroit, Michigan, 48201
Texas Children's Hospital
Houston, Texas, 77030
University of Texas Health Science Center at Houston
Houston, Texas, 77030
Indiana University
Indianapolis, Indiana, 46202
University of Tennessee
Memphis, Tennessee, 38163
University of Miami
Miami, Florida, 33136
Yale University
New Haven, Connecticut, 06504
Stanford University
Palo Alto, California, 94304
St. Joseph's Hospital
Phoenix, Arizona, 85013
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, 02905
San Diego Children's Hospital
San Diego, California, 92130
University of Washington School of Medicine
Seattle, Washington, 98195
About this study
Official title: Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure
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.
Read the 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.
- Conditions
- Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome, Pneumonia, Aspiration, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency
- Being tested
- Inhaled Nitric Oxide, Standard iNO therapy
- 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
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 therapyDrug
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).
| Study group | Role | What they receive |
|---|---|---|
| Early iNO Management | Experimental | Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25. Receives: Drug: Inhaled Nitric Oxide |
| Standard iNO management | Active comparator | 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). Receives: Drug: Standard iNO therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Death or use of extracorporeal membrane oxygenation (ECMO)
Measured: Hospital discharge or 120 days of life
Secondary outcomes (3)
Use of iNO therapy based on the standard recommended threshold
Measured: Hospital Discharge or 120 days of life
Progression to severe respiratory failure (OI>40)
Severe respiratory failure, defined as OI >40
Measured: Hospital discharge or 120 days of life
Neurodevelopmental impairment
Measured: 18-22 months corrected age
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 startAug 1998
- Primary completionMay 2001
- Study completionAug 2003
Why it stopped: Halted after 3 years because of a persistent decline in enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)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
- 302 participants (actual)
Sponsor and investigators
- Lead sponsor
- NICHD Neonatal Research Network
- Sponsor type
- Research network
- Collaborators
- National Center for Research Resources (NCRR), Canadian Institutes of Health Research (CIHR), Mallinckrodt
- Investigators
- G. Ganesh Konduri, MD, Study director, University of Wisconsin, MadisonWaldemar A. Carlo, MD, Principal investigator, University of Alabama at BirminghamCarlos Fajardo, MD, Principal investigator, St. Joseph's HospitalKrisa P. Van Meurs, MD, Principal investigator, Stanford UniversityGail Knight, MD, Principal investigator, San Diego Children's HospitalRichard A. Ehrenkranz, MD, Principal investigator, Yale UniversityCharles R. Bauer, MD, Principal investigator, University of MiamiBarbara J. Stoll, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00005773
- Sponsor's protocol ID
- NICHD-NRN-0019
- Other IDs
- U01HD019897, U10HD021364, U10HD021373, U10HD021385, U10HD021397, U10HD021415, U10HD027853, U10HD027856
- Acronym
- Early iNO
- Status last verified
- Sep 2017
- First submitted
- 1 Jun 2000
- Last updated
- 26 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 10053039Sokol 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 14510322Konduri 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.
PubMed 14993550Konduri 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.
PubMed 17307536
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
- Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure
- ClinicalTrials.gov ID
- NCT00005773
- Acronym / sponsor ID
- Early iNO / NICHD-NRN-0019
- 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: Halted after 3 years because of a persistent decline in enrollment
- Enrolment
- 302 participants (actual)
- Lead sponsor
- NICHD Neonatal Research NetworkResearch network
- Collaborators
- National Center for Research Resources (NCRR), Canadian Institutes of Health Research (CIHR), Mallinckrodt
- Study start
- Aug 1998
- Primary completion
- May 2001 (actual)
- Study completion
- Aug 2003 (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.
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.
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 |
|---|---|---|
| Early iNO Management | Experimental | Drug: Inhaled Nitric OxideInitiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25. |
| Standard iNO management | Active comparator | Drug: Standard iNO therapyBegin 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). |
Who may qualify
- Ages
- Up to 14 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (4 listed)
- 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
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 OxideStudy 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). | Drug | Early iNO Management |
| Standard iNO therapyBegin 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). | Drug | Standard iNO management |
Primary outcome
Death or use of extracorporeal membrane oxygenation (ECMO)
Time frame: Hospital discharge or 120 days of life
3 secondary outcomes
Use of iNO therapy based on the standard recommended threshold
Time frame: Hospital Discharge or 120 days of life
Progression to severe respiratory failure (OI>40)
Time frame: Hospital discharge or 120 days of life
Neurodevelopmental impairment
Time frame: 18-22 months corrected age
Results and safety
The study was stopped early (reason given: Halted after 3 years because of a persistent decline in enrollment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2017.
- Background: PubMed 10053039Sokol 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.
- Background: 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.
- Results publication: PubMed 14993550Konduri 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 publication: PubMed 17307536Konduri 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.
- NICHD Neonatal Research NetworkLink provided by the sponsor.
Related trials for Infant, Newborn
Not yet recruitingPhase 2/3
A Pivotal Safety and Immunogenicity GBS-NN/NN2 Vaccine Maternal Immunisation Trial
Streptococcus Agalactiae Infection, Neonatal Sepsis
RecruitingObservational study
Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia
Fanconi Anemia, Inherited Bone Marrow Failure Syndrome
Active, not recruitingPhase 1
A Study of the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BCX17725
Netherton Syndrome
Recruiting
Comparing Surfactant Administration Through Supraglottic Airway and Thin Catheter for Preterm Infants
Surfactant, Respiratory Distress Syndrome (Neonatal)
Not yet recruitingObservational study
Clinical Genetics Branch Eligibility Screening Survey
Melanoma, Li-Fraumeni Syndrome
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.
G. Ganesh Konduri, MD study director
University of Wisconsin, Madison
Waldemar A. Carlo, MD principal investigator
University of Alabama at Birmingham
Carlos Fajardo, MD principal investigator
St. Joseph's Hospital
18 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inhaled Nitric Oxide and Standard iNO therapy in people with Infant, Newborn and Hypertension, Pulmonary, run by NICHD Neonatal Research Network at 18 sites in United States.
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 4 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 18 sites in United States. 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. 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: Halted after 3 years because of a persistent decline in enrollment). 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 use of extracorporeal membrane oxygenation (ECMO) (time frame: 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 NCT00005773, which also lists 4 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.