Clinical trial NCT00016523: Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure
Official title: Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Infant, Newborn
Infant, Low Birth Weight
Infant, Small for Gestational Age
Infant, Premature
Respiratory Distress Syndrome (RDS)
Sepsis
Pneumonia
Hypertension, Pulmonary
Keywords: NICHD Neonatal Research Network
Extremely Low Birth Weight (ELBW)
Very Low Birth Weight (VLBW)
Prematurity
Inhaled nitric oxide
Aspiration syndrome
Idiopathic pulmonary hypertension
Pulmonary hypoplasia
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
First posted: 2001-05-16
Enrollment: 420
Sex: ALL
Maximum age (years): 120
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This multicenter trial tested whether inhaled nitric oxide would reduce death or the need for oxygen in preterm infants (less than 34 weeks gestational age) with severe lung disease.

Detailed description: This multicenter, randomized, double-masked, controlled clinical trial evaluated the efficacy of inhaled nitric oxide (iNO) in the treatment of the preterm infant with respiratory failure secondary to respiratory distress syndrome (RDS), sepsis/pneumonia, aspiration syndrome, idiopathic pulmonary hypertension and/or suspected pulmonary hypoplasia.

Infants were followed until death or discharge to home. The trial compared iNO therapy to mock gas delivery as the control, and otherwise incorporated conventional management strategies (including treatment with surfactant and high frequency ventilation as adjuncts to iNO therapy).

During the initial dosing, iNO was started at 5 ppm and could be increased to 10 ppm. If the infant did not respond, study gas was discontinued. For infants who responded to study gas, a gradual weaning was initiated. The total exposure to study gas did not exceed 336 hours (14 days). Infants were monitored for signs of toxicity.

Medical and neurodevelopmental outcome of surviving infants were assessed at 18 to 22 months corrected age by masked, certified examiners.

Eligibility criteria: Inclusion Criteria

* Any infant with a birth weight 401 - 1500 grams and \< 34 weeks gestational age with an OI (mean Paw x FiO2 x 100/PaO2) \> 10 on two consecutive blood gases at least 30 minutes apart, but no more than 12 hours apart.

or

* Infants \> 1500 grams and \< 34 weeks gestational age will be entered in the Larger Preemie Pilot Study if they have an OI greater than or equal to 15 on two consecutive blood gases at least 30 minutes apart, but no more than 12 hours apart.
* Infants requiring assisted ventilation with a diagnosis of RDS/HMD, pneumonia and/or sepsis, aspiration syndrome, idiopathic pulmonary hypertension, or suspected pulmonary hypoplasia associated with PROM and/or oligohydramnios.
* Greater than or equal to 4 hours after one dose of surfactant.
* Less than or equal to 120 hours of age.
* All infants must have an indwelling arterial line.

Exclusion Criteria

* Any infant in whom a decision has been made not to provide full treatment (e.g. chromosomal anomalies or severe birth asphyxia).
* Known structural congenital heart disease, except patent ductus arteriosus and atrial-level shunts.
* Infants with any major abnormality involving the respiratory system such as congenital diaphragmatic hernia, tracheoesophageal fistula or cystic fibrosis.
* Any bleeding diathesis considered to be clinically significant or thrombocytopenia with platelet count \< 50,000.
* Prior enrollment into a conflicting clinical trial such as the Neonatal Network Surfactant CPAP trial.Inclusion Criteria

Primary outcomes:
measure: Death or Bronchopulmonary Dysplasia
timeFrame: At 36 weeks post-conceptional age
Secondary outcomes:
measure: Intraventricular Hemorrhage Grade III and IV
timeFrame: At 36 weeks post-conceptional age
measure: Days on assisted ventilation
timeFrame: At 36 weeks post-conceptional age
measure: Length of hospitalization
timeFrame: At hospital discharge
measure: Retinopathy of prematurity
timeFrame: At hospital discharge
measure: Air leaks
timeFrame: At 36 weeks post-conceptual age
measure: Days on oxygen
timeFrame: At 36 weeks post-conceptual age
measure: Supplemental oxygen
timeFrame: At 36 weeks post-conceptual age
measure: Neurodevelopmental outcome
timeFrame: 18-22 months corrected age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Wake Forest University
state: North Carolina
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Stanford University
name: Krisa P. Van Meurs, MD
role: STUDY_DIRECTOR
affiliation: University of Alabama at Birmingham
name: Waldemar A. Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R. Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Edward F. Donovan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: James A. Lemons, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Shahnaz Duara, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Charles R. Rosenfeld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Jon E. Tyson, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Richard A. Ehrenkranz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University
name: T. Michael O'Shea, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Neil N. Finer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Dale L. Phelps, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Mark L. Hudak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Robin H. Steinhorn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Wisconsin, Milwaukee
name: G. Ganesh Konduri, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, Higgins RD, Oh W, Hudak ML, Laptook AR, Shankaran S, Finer NN, Carlo WA, Kennedy KA, Fridriksson JH, Steinhorn RH, Sokol GM, Konduri GG, Aschner JL, Stoll BJ, D'Angio CT, Stevenson DK; Preemie Inhaled Nitric Oxide Study. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005 Jul 7;353(1):13-22. doi: 10.1056/NEJMoa043927.
citation: Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, Das A, Higgins RD, Stevenson DK. Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure. J Perinatol. 2007 Jun;27(6):347-52. doi: 10.1038/sj.jp.7211690. Epub 2007 Apr 19.
citation: Hintz SR, Slovis T, Bulas D, Van Meurs KP, Perritt R, Stevenson DK, Poole WK, Das A, Higgins RD; NICHD Neonatal Research Network. Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants. J Pediatr. 2007 Jun;150(6):592-6, 596.e1-5. doi: 10.1016/j.jpeds.2007.02.012.
citation: Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A, Stevenson DK, Ehrenkranz RA, Lemons JA, Vohr BR, Heyne R, Childers DO, Peralta-Carcelen M, Dusick A, Johnson YR, Morris B, Dillard R, Vaucher Y, Steichen J, Adams-Chapman I, Konduri G, Myers GJ, de Ungria M, Tyson JE, Higgins RD; NICHD Neonatal Research Network. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr. 2007 Jul;151(1):16-22, 22.e1-3. doi: 10.1016/j.jpeds.2007.03.017.
citation: Ambalavanan N, Van Meurs KP, Perritt R, Carlo WA, Ehrenkranz RA, Stevenson DK, Lemons JA, Poole WK, Higgins RD; NICHD Neonatal Research Network, Bethesda, MD. Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure. J Perinatol. 2008 Jun;28(6):420-6. doi: 10.1038/jp.2008.18. Epub 2008 Mar 13.
citation: Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE, Stevenson DK; NICHD Neonatal Research Network. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009 Apr;26(4):317-22. doi: 10.1055/s-0028-1104743. Epub 2008 Dec 9.