Bronchopulmonary Dysplasia
Conditions
Keywords
nitric oxide, surfactant, BPD, prematurity, neonates, iNO, pulmonary outcome, neurodevelopmental outcome, Infasurf, lung function, Surfactant Dysfunction, Bronchopulmonary Dysplasia
Brief summary
The purpose of this study is to determine if late doses of Infasurf surfactant given when patients are receiving inhaled nitric oxide will interact to improve surfactant function and increase survival without BPD in treated infants.
Detailed description
This is a multi-center, blinded, randomized controlled clinical trial to evaluate the effects of booster doses of exogenous surfactant (Infasurf®, calfactant) in addition to inhaled nitric oxide (iNO) on the outcome of survival without bronchopulmonary dysplasia (BPD, or chronic lung disease of prematurity, characterized by chronic lung dysfunction) at 36 weeks' post-menstrual age (PMA) in extremely low gestational age (ELGAN) infants that are at high risk of the development of BPD. This multi-center trial, with a planned enrollment of 524 infants, will also enable us to evaluate for any adverse effects of late surfactant treatment on short- and long-term outcomes, as we will be collecting data on effects of dosing of late surfactant, co-morbidities of prematurity and neurodevelopmental and pulmonary outcome at 1 year and 24 months corrected age. In addition, we will collect biological specimens for evaluation of the effects of late surfactant replacement therapy (administered as described in this trial) on surfactant function and inflammatory markers.
Interventions
DRUGInfasurf surfactant (ONY, Inc.)
Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.
DRUGSham (No Treatment)
Late doses of Sham (No treatment) will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Roberta Ballard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Days to 14 Days
Healthy volunteers
No
Inclusion criteria
* \<=28 0/7 weeks gestational age * Day of life 7-14 * Intubated and mechanically ventilated * Plan to treat with inhaled nitric oxide
Exclusion criteria
* Serious congenital malformations or chromosomal abnormalities * Life expectancy \<7 days from enrollment * Clinically unstable * Less tha 48 hours since last dose surfactant * Ability to obtain 36 week primary outcome information is unlikely
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival Without BPD at 36 Weeks Post Menstrual Age. | 36 weeks post menstrual age +/- 1 week | BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival Without BPD at 40 Weeks | 40 weeks PMA +/- 1 week | BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction. |
| Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | 1 year | Evaluation of respiratory outcome through the first 12 months after birth. questionnaires were administered by phone at 3,6,9 and 12 months to determine respiratory resource use (medications, home support, and hospitalization) No Pulmonary Morbidity (NoPM) was reported for infants who had no resource use in any quarter and Persistent PM was reported for infants having resource use in 3 or 4 quarters. |
| Pulmonary Outcomes Through 2 Years of Age | 2 years | Evaluation of pulmonary outcome at 24 months of age. Evaluation of persistent wheezing based on reported wheezing during both first and second year of life. |
| Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years. | 2 years | At 24 months corrected age, children underwent neuropsychological testing with the Bayley Scales of Infant Development-Third Edition (Bayley-3), and composite cognitive, language, and motor scores were collected as well as subscale scores in receptive and expressive speech and fine and gross motor. Infants with greater than one impairment as identified by testing were classified as having neurodevelopmental impairment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infasurf Surfactant (ONY, Inc.) Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8.
Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8. | 252 |
| Sham Infants already receiving inhaled nitric oxide will not receive additional doses of late surfactant (Infasurf). | 259 |
| Total | 511 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 18 | 22 |
Baseline characteristics
| Characteristic | Infasurf Surfactant (ONY, Inc.) | Sham | Total |
|---|---|---|---|
| Age, Continuous Gestational Age Weeks | 25.2 weeks STANDARD_DEVIATION 1.2 | 25.2 weeks STANDARD_DEVIATION 1.2 | 25.2 weeks STANDARD_DEVIATION 1.2 |
| Birthweight | 700.1 grams STANDARD_DEVIATION 173.2 | 702.3 grams STANDARD_DEVIATION 156 | 701 grams STANDARD_DEVIATION 160 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 33 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 227 Participants | 225 Participants | 452 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 99 Participants | 91 Participants | 190 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 134 Participants | 157 Participants | 291 Participants |
| Respiratory Severity Score (RSS) - MAP x FiO2 | 3.7 score on a scale STANDARD_DEVIATION 2.3 | 3.8 score on a scale STANDARD_DEVIATION 2.2 | 3.75 score on a scale STANDARD_DEVIATION 3.25 |
| Sex: Female, Male Female | 109 Participants | 121 Participants | 230 Participants |
| Sex: Female, Male Male | 143 Participants | 138 Participants | 281 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 29 / 252 | 24 / 259 |
| other Total, other adverse events | 141 / 252 | 153 / 259 |
| serious Total, serious adverse events | 29 / 252 | 24 / 259 |
Outcome results
Primary
Survival Without BPD at 36 Weeks Post Menstrual Age.
BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.
Time frame: 36 weeks post menstrual age +/- 1 week
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infasurf Surfactant (ONY, Inc.) | Survival Without BPD at 36 Weeks Post Menstrual Age. | 79 Participants |
| Sham | Survival Without BPD at 36 Weeks Post Menstrual Age. | 82 Participants |
p-value: 0.89unadj GEE
Secondary
Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years.
At 24 months corrected age, children underwent neuropsychological testing with the Bayley Scales of Infant Development-Third Edition (Bayley-3), and composite cognitive, language, and motor scores were collected as well as subscale scores in receptive and expressive speech and fine and gross motor. Infants with greater than one impairment as identified by testing were classified as having neurodevelopmental impairment.
Time frame: 2 years
Population: Neurodevelopmental testing occurred with only 322 participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infasurf Surfactant (ONY, Inc.) | Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years. | 28 percentage of participants |
| Sham | Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years. | 32 percentage of participants |
Secondary
Pulmonary Outcomes Through 2 Years of Age
Evaluation of pulmonary outcome at 24 months of age. Evaluation of persistent wheezing based on reported wheezing during both first and second year of life.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infasurf Surfactant (ONY, Inc.) | Pulmonary Outcomes Through 2 Years of Age | 91 Participants |
| Sham | Pulmonary Outcomes Through 2 Years of Age | 98 Participants |
Secondary
Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age
Evaluation of respiratory outcome through the first 12 months after birth. questionnaires were administered by phone at 3,6,9 and 12 months to determine respiratory resource use (medications, home support, and hospitalization) No Pulmonary Morbidity (NoPM) was reported for infants who had no resource use in any quarter and Persistent PM was reported for infants having resource use in 3 or 4 quarters.
Time frame: 1 year
Population: Infants who survived to discharge and had data from questionaires available
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infasurf Surfactant (ONY, Inc.) | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | Home respiratory support | 80 Participants |
| Infasurf Surfactant (ONY, Inc.) | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | No PM | 54 Participants |
| Infasurf Surfactant (ONY, Inc.) | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | Persistent PM | 74 Participants |
| Sham | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | Home respiratory support | 118 Participants |
| Sham | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | No PM | 47 Participants |
| Sham | Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age | Persistent PM | 75 Participants |
Secondary
Survival Without BPD at 40 Weeks
BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.
Time frame: 40 weeks PMA +/- 1 week
Population: Infants who were No BPD at 36 wk were imputed to be No BPD at 40 wk. Infants discharged on oxygen without a challenge test were assigned Yes BPD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infasurf Surfactant (ONY, Inc.) | Survival Without BPD at 40 Weeks | 148 Participants |
| Sham | Survival Without BPD at 40 Weeks | 140 Participants |
p-value: 0.33unadj GEE