Bronchopulmonary Dysplasia, Pulmonary Hypertension
Conditions
Brief summary
Inhaled nitric oxide (iNO) is an effective treatment for pulmonary hypertension (PH) in term and near-term infants. Preterm infants are at risk for early PH that is associated with high risk for bronchopulmonary dysplasia or death. In multiple clinical trials, iNO treatment was not effective for BPD prevention. However, infants were not screened for PH and iNO treatment was not targeted for PH. iNO treatment for PH in preterm infants is controversial due to lack of evidence. The study team hypothesizes that early diagnosis of PH (72-96 hours of life) and iNO treatment will decrease the incidence of death and bronchopulmonary dysplasia and improve oxygenation in extremely preterm infants. 1. To determine if iNO treatment of extremely preterm infants with early pulmonary hypertension as established with echocardiographic evidence at 72-96 hours of age will decrease incidence of death or BPD. 2. To determine if iNO treatment of extremely preterm infants with early PH will decrease the pulmonary artery pressure and improve oxygenation within 72 hours of intervention.
Detailed description
This is a single center, blinded, randomized control clinical trial to evaluate the effects of inhaled nitric oxide on the outcome of survival and incidence of bronchopulmonary dysplasia. This trial has a planned enrollment of 138 infants with 68 infants with delayed pulmonary transition assigned to either the treatment or placebo group. There is no enrollment restriction based on gender, ethnicity, or race. Enrollment is expected to take 36 months with an additional 12 months for data analysis.Infants with early pulmonary hypertension will be randomized to the treatment or placebo group. Treatment will continue until resolution of pulmonary hypertension or through Day 14, whichever comes first. Serial echocardiograms will be performed every 48 hours +/-12 hours until Day 14. Oxygen saturation levels will be averaged every 24 hour period following enrollment. This study will provide evidence for the beneficial effects of early diagnosis and treatment of pulmonary hypertension in preterm infants.
Interventions
DRUGinhaled nitric oxide
inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension
DRUGPlacebo
placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension
Sponsors
Mallinckrodt
Thrasher Research Fund
AdventHealth
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Masked randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
23 Weeks to 29 Weeks
Healthy volunteers
No
Inclusion criteria
Step 1: * Birth between 23 weeks and 0 days and 29 weeks and 6 days. * Positive pressure ventilation at 72-96 hours of age Step 2: * Early pulmonary hypertension
Exclusion criteria
Step 1: * Death prior to 12 hours of age or first echocardiogram * Chromosomal anomalies * Major congenital anomalies * Myocardial dysfunction * Complex cardiac defect * Dependent on right to left shunting of blood Step 2: * Excessive pulmonary blood flow (left to right shunt across PDA) * Pulmonary blood flow obstruction secondary to pulmonary vein stenosis * Mitral valve stenosis * Cor triata * Aortic valve atresia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death | 36 weeks post menstrual age | Incidence of death |
| Bronchopulmonary (BPD) Dysplasia (Yes/no) | 36 weeks post menstrual age | Incidence of bronchopulmonary dysplasia as determined by need for positive pressure ventilation or supplemental oxygen after room air challenge test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Hypertension | Duration of treatment or up to Day 14 | Pulmonary arterial pressure will be evaluated every 24-48 hours after enrollment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group - Active inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first.
inhaled nitric oxide: inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension | 16 |
| Treatment Group - Placebo Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first.
Placebo: placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension | 16 |
| Control Group Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension | 0 |
| Total | 32 |
Baseline characteristics
| Characteristic | Treatment Group - Placebo | Control Group | Treatment Group - Active | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 0 Participants | 16 Participants | 32 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 3 days STANDARD_DEVIATION 1 | — | 3 days STANDARD_DEVIATION 1 | 3 days STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 0 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 8 Participants | 0 Participants | 7 Participants | 15 Participants |
| Region of Enrollment United States | 16 Participants | 0 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 11 Participants | 0 Participants | 11 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 1 / 16 |
| other Total, other adverse events | 14 / 16 | 14 / 16 |
| serious Total, serious adverse events | 2 / 16 | 5 / 16 |
Outcome results
Primary
Bronchopulmonary (BPD) Dysplasia (Yes/no)
Incidence of bronchopulmonary dysplasia as determined by need for positive pressure ventilation or supplemental oxygen after room air challenge test
Time frame: 36 weeks post menstrual age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group - Active | Bronchopulmonary (BPD) Dysplasia (Yes/no) | 10 Participants |
| Treatment Group - Placebo | Bronchopulmonary (BPD) Dysplasia (Yes/no) | 9 Participants |
Primary
Death
Incidence of death
Time frame: 36 weeks post menstrual age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group - Active | Death | 1 Participants |
| Treatment Group - Placebo | Death | 1 Participants |
Secondary
Pulmonary Hypertension
Pulmonary arterial pressure will be evaluated every 24-48 hours after enrollment.
Time frame: Duration of treatment or up to Day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group - Active | Pulmonary Hypertension | 11 Participants |
| Treatment Group - Placebo | Pulmonary Hypertension | 15 Participants |