Bronchopulmonary Dysplasia, Intraventricular Hemorrhage, Periventricular Leukomalacia, Prematurity
Conditions
Keywords
prematurity, nitric oxide, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, neurodevelopment
Brief summary
The purpose of this study is to determine whether inhaled nitric oxide improves the neurological outcome for premature infants.
Detailed description
With the advances in modern neonatal intensive care medicine in the last 20 years, survival of extremely preterm infants weighing less than 1500g (\< 3 lbs, 5 oz) has risen markedly. However, with this increased survival has come a marked increase in the number of infants with serious neurodevelopmental disabilities: Premature infants with birth weights less than 1500g who survive to go home are at significant risk for serious neurodevelopmental problems: cognitive and motor delays, blindness, deafness, and cerebral palsy. In a recent randomized, placebo-controlled clinical trial, we assessed whether giving mechanically ventilated preterm infants inhaled nitric oxide gas (iNO) for 1 week after birth decreased the incidence of death and chronic lung disease. An unanticipated outcome of that study (Schreiber et. al. 2003) and a subsequent study of those infants at 2 years of age (Mestan et. al. 2005) was that premature infants treated with inhaled nitric oxide (iNO) have improved neurodevelopmental outcomes and physical growth at 2 years corrected age, compared with placebo-treated infants (Mestan et. al. 2005). INO therapy, therefore, appears to be a new treatment to protect the premature brain during development outside the womb. The overall goal of this application is understand the efficacy of iNO treatment in improving neurodevelopmental outcomes in at-risk premature infants.
Interventions
DRUGinhaled nitric oxide
The amount of gas will be carefully controlled and adjusted to the level that best improves the function of subject's lungs. The subject will remain on inhaled nitric oxide until he/she reaches 33 weeks of gestation if assigned to the treatment arm, or until the 8th day of the study if he/she is assigned to the control arm.
DRUGoxygen
The amount of gas will be carefully controlled and adjusted to the level that best improves the function of the subject's lungs. Subjects in the control arm of the study will receive oxygen beginning on the 8th day of the study until he/she reaches 33 weeks of gestation.
Sponsors
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Hours to 72 Hours
Healthy volunteers
No
Inclusion criteria
* Prematurity (birthweight ≤ 1500g, \< 31 weeks gestation) * Requiring respiratory support * Admitted to the NICU at the University of Chicago
Exclusion criteria
* Severe congenital anomalies * Genetic syndromes * Extremely sick preterm infants requiring very high ventilatory pressures (OI ≥ 20) * Premature infants judged by the physician as nonviable
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurodevelopment | Two years | — |
| Bronchopulmonary Dysplasia (BPD) or Death | 36 weeks of age corrected (BPD) or before discharge (death) | Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Supplemental Oxygen Use | 40 weeks PMA | — |
| BPD or Death in Infants Weighing < 750g | 36 weeks of age corrected (BPD) or before discharge (death) | Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among infants \< 750g |
| Death | through discharge (up to 400 days) | Death before discharge |
| BPD or Death in Black Infants | 36 weeks of age corrected (BPD) or before discharge (death) | Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among Black infants |
| BPD or Death in Infants Weighing 750-999g | 36 weeks of age corrected (BPD) or before discharge (death) | Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among infants 750-999g |
| Bronchopulmonary Dysplasia | 36 weeks of age corrected | Need for respiratory support at 36 weeks post-menstrual age (PMA), either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90% |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| INO Control (Short iNO) INO will be given to infants in the control group for the first 7 days of the study gas, then O2 or room air, as clinically appropriate, on the 8th day, until 33 weeks corrected age
inhaled nitric oxide: The amount of gas will be carefully controlled and adjusted to the level that best improves the function of subject's lungs. The subject will remain on inhaled nitric oxide until he/she reaches 33 weeks of gestation if assigned to the treatment arm, or until the 8th day of the study if he/she is assigned to the control arm. | 138 |
| INO Treatment (Long iNO) The treatment group will receive iNO, combined with O2 or room air, until 33 weeks corrected age.
inhaled nitric oxide: The amount of gas will be carefully controlled and adjusted to the level that best improves the function of subject's lungs. The subject will remain on inhaled nitric oxide until he/she reaches 33 weeks of gestation if assigned to the treatment arm, or until the 8th day of the study if he/she is assigned to the control arm.
oxygen: The amount of gas will be carefully controlled and adjusted to the level that best improves the function of the subject's lungs. Subjects in the control arm of the study will receive oxygen beginning on the 8th day of the study until he/she reaches 33 weeks of gestation. | 135 |
| Total | 273 |
Baseline characteristics
| Characteristic | INO Control (Short iNO) | INO Treatment (Long iNO) | Total |
|---|---|---|---|
| Age, Continuous | 27.2 Weeks STANDARD_DEVIATION 2.2 | 26.8 Weeks STANDARD_DEVIATION 2.1 | 27.0 Weeks STANDARD_DEVIATION 2.2 |
| Race/Ethnicity, Customized Black | 99 Participants | 91 Participants | 190 Participants |
| Race/Ethnicity, Customized Non-black | 39 Participants | 44 Participants | 83 Participants |
| Region of Enrollment United States | 138 participants | 135 participants | 273 participants |
| Sex: Female, Male Female | 63 Participants | 63 Participants | 126 Participants |
| Sex: Female, Male Male | 75 Participants | 72 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 138 | 13 / 135 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 53 / 138 | 61 / 135 |
Outcome results
Primary
Bronchopulmonary Dysplasia (BPD) or Death
Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge
Time frame: 36 weeks of age corrected (BPD) or before discharge (death)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | Bronchopulmonary Dysplasia (BPD) or Death | 65 Participants |
| INO Treatment (Long iNO) | Bronchopulmonary Dysplasia (BPD) or Death | 83 Participants |
p-value: 0.017Chi-squared
Primary
Neurodevelopment
Time frame: Two years
Population: Data were not collected (due to funding cuts).
Secondary
BPD or Death in Black Infants
Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among Black infants
Time frame: 36 weeks of age corrected (BPD) or before discharge (death)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | BPD or Death in Black Infants | 50 Participants |
| INO Treatment (Long iNO) | BPD or Death in Black Infants | 53 Participants |
p-value: 0.28Chi-squared
Secondary
BPD or Death in Infants Weighing 750-999g
Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among infants 750-999g
Time frame: 36 weeks of age corrected (BPD) or before discharge (death)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | BPD or Death in Infants Weighing 750-999g | 20 Participants |
| INO Treatment (Long iNO) | BPD or Death in Infants Weighing 750-999g | 36 Participants |
p-value: <0.001Chi-squared
Secondary
BPD or Death in Infants Weighing < 750g
Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%, or death before discharge among infants \< 750g
Time frame: 36 weeks of age corrected (BPD) or before discharge (death)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | BPD or Death in Infants Weighing < 750g | 36 Participants |
| INO Treatment (Long iNO) | BPD or Death in Infants Weighing < 750g | 37 Participants |
p-value: 0.72Chi-squared
Secondary
Bronchopulmonary Dysplasia
Need for respiratory support at 36 weeks post-menstrual age (PMA), either as positive pressure or supplemental oxygen to maintain oxygen saturations \>90%
Time frame: 36 weeks of age corrected
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | Bronchopulmonary Dysplasia | 51 Participants |
| INO Treatment (Long iNO) | Bronchopulmonary Dysplasia | 71 Participants |
p-value: 0.009Chi-squared
Secondary
Death
Death before discharge
Time frame: through discharge (up to 400 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | Death | 19 Participants |
| INO Treatment (Long iNO) | Death | 13 Participants |
p-value: 0.288Chi-squared
Secondary
Supplemental Oxygen Use
Time frame: 40 weeks PMA
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INO Control (Short iNO) | Supplemental Oxygen Use | 30 Participants |
| INO Treatment (Long iNO) | Supplemental Oxygen Use | 28 Participants |
p-value: 0.97Chi-squared