Bronchopulmonary Dysplasia
Conditions
Keywords
Bronchopulmonary Dysplasia, BPD
Brief summary
This phase 3, multi-center, double blind, placebo-controlled, randomized clinical trial will attempt to demonstrate if preterm infants who require mechanical ventilation and/or positive pressure support at any point during days 5 to 14 after birth may benefit from treatment with iNO.
Detailed description
Multi-center, double blind, placebo-controlled, randomized clinical trial. Infants who meet all enrollment criteria at any point during days 5 to 14 after birth will be randomized to inhaled NO starting at 20 ppm, or matching placebo, by means of a blinded INOvent® delivery device. All infants will receive 24 days of therapy, following a dose reduction schedule. Infants who are extubated before 24 days will continue therapy via nasal continuous positive airway pressure (CPAP) or nasal cannula to complete 24 days' of therapy. The primary outcome measure will be survival without BPD at 36 weeks gestational age using a physiologic assessment of BPD.
Interventions
DRUGInhaled Nitric Oxide
Inhaled Nitric Oxide will be administered continuously starting at 20ppm into the inspiratory limb of the ventilator circuit in mechanically ventilated subject using an INOvent delivery system of by nasal cannula as needed for 24 days of therapy.
DRUGPlacebo
Nitrogen gas will be administered in the same manner as the experimental drug.
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Days to 14 Days
Healthy volunteers
No
Inclusion criteria
* Preterm infants who are: 1. 500 to 1250 grams at birth 2. \< 30 weeks gestational age 3. 5 to 14 days of age (inclusive) at the time of entry 4. Requiring mechanical ventilation or for those infants ≤ 800 grams, positive pressure support (including CPAP) for respiratory insufficiency on days 5 to 14 days of age (inclusive)
Exclusion criteria
1. Preterm infants with life-threatening anomalies (cranial, cardiac, thoracic, chromosomal) or congenital diaphragmatic hernia with lung hypoplasia, or any subject who will not receive complete intensive care 2. Preterm infants with bilateral Grade 4 intraventricular hemorrhage (IVH) 3. Subjects who are dependent on right to left shunting to maintain the systemic circulation 4. Preterm infants who received prior iNO therapy 5. Use of another investigational agent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Survival Without BPD at 36 Weeks | Baseline, 36 weeks PMA |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Birth Hospitalization | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | — |
| Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | — |
| Number and Percentage of Participants With Use of Postnatal Corticosteroids for Any Medical Reason | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | — |
| Days of Airway Pressure Support - Intent-to-treat Population | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | Airway pressure support includes conventional mechanical ventilation, conventional, high frequency oscillatory ventilation, jet, continuous positive airway pressure, and other. |
| Number of Days of Oxygen Use | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | — |
| Severity of Bronchopulmonary Dysplasia | 36 weeks | Severity of bronchopulmonary dysplasia defined by the fraction of inspired O2 concentration (FiO2) requirement. |
| Systemic Use of Postnatal Corticosteroids for Any Medical Reason | Through hospital discharge, an average of 105 days for placebo and 108 days for INO | — |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Nitric Oxide Inhaled Nitric Oxide
Inhaled Nitric Oxide: Inhaled Nitric Oxide will be administered continuously starting at 20ppm into the inspiratory limb of the ventilator circuit in mechanically ventilated subject using an INOvent delivery system of by nasal cannula as needed for 24 days of therapy. | 229 |
| Placebo Nitrogen Placebo
Placebo: Nitrogen gas will be administered in the same manner as the experimental drug. | 222 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 15 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Inhaled Nitric Oxide | Placebo | Total |
|---|---|---|---|
| Age, Customized | 229 participants | 222 participants | 451 participants |
| Race/Ethnicity, Customized American Indian | 1 participants | 12 participants | 13 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 5 participants | 6 participants |
| Race/Ethnicity, Customized Black | 55 participants | 62 participants | 117 participants |
| Race/Ethnicity, Customized Hispanic | 40 participants | 48 participants | 88 participants |
| Race/Ethnicity, Customized Other | 11 participants | 10 participants | 21 participants |
| Race/Ethnicity, Customized Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 120 participants | 85 participants | 205 participants |
| Region of Enrollment Canada | 20 participants | 19 participants | 39 participants |
| Region of Enrollment United States | 209 participants | 203 participants | 412 participants |
| Sex: Female, Male Female | 114 Participants | 106 Participants | 220 Participants |
| Sex: Female, Male Male | 115 Participants | 116 Participants | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 229 | 8 / 220 |
| other Total, other adverse events | 169 / 229 | 143 / 220 |
| serious Total, serious adverse events | 105 / 229 | 100 / 220 |
Outcome results
Primary
Survival Without BPD at 36 Weeks
Time frame: Baseline, 36 weeks PMA
Population: Subjects with missing primary outcome or who crossed over to open-label iNO during the blinded treatment period were considered as failures
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled Nitric Oxide | Survival Without BPD at 36 Weeks | Alive without BPD at 36 weeks GA | 80 participants |
| Inhaled Nitric Oxide | Survival Without BPD at 36 Weeks | Death or had BPD at 36 weeks GA | 149 participants |
| Placebo | Survival Without BPD at 36 Weeks | Alive without BPD at 36 weeks GA | 70 participants |
| Placebo | Survival Without BPD at 36 Weeks | Death or had BPD at 36 weeks GA | 152 participants |
p-value: 0.427Mantel Haenszel
Secondary
Days of Airway Pressure Support - Intent-to-treat Population
Airway pressure support includes conventional mechanical ventilation, conventional, high frequency oscillatory ventilation, jet, continuous positive airway pressure, and other.
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide | Days of Airway Pressure Support - Intent-to-treat Population | 53.7 Days | Standard Deviation 42.16 |
| Placebo | Days of Airway Pressure Support - Intent-to-treat Population | 55.3 Days | Standard Deviation 40.45 |
Secondary
Length of Birth Hospitalization
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
Population: Number of subjects within the Intent-to-treat population with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide | Length of Birth Hospitalization | 108.3 Days | Standard Deviation 54.03 |
| Placebo | Length of Birth Hospitalization | 105.0 Days | Standard Deviation 36.69 |
Secondary
Number and Percentage of Participants With Use of Postnatal Corticosteroids for Any Medical Reason
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
Population: Intent-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Any Medical Reason | 154 Participants |
| Placebo | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Any Medical Reason | 145 Participants |
Secondary
Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
Population: Intent-to-treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inhaled Nitric Oxide | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia | Yes | 95 Participants |
| Inhaled Nitric Oxide | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia | No | 134 Participants |
| Placebo | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia | Yes | 91 Participants |
| Placebo | Number and Percentage of Participants With Use of Postnatal Corticosteroids for Bronchopulmonary Dysplasia | No | 131 Participants |
Secondary
Number of Days of Oxygen Use
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
Population: Number of subjects within the Intent-to-treat population with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide | Number of Days of Oxygen Use | 91.0 Days | Standard Deviation 59.26 |
| Placebo | Number of Days of Oxygen Use | 88.0 Days | Standard Deviation 40.91 |
Secondary
Severity of Bronchopulmonary Dysplasia
Severity of bronchopulmonary dysplasia defined by the fraction of inspired O2 concentration (FiO2) requirement.
Time frame: 36 weeks
Population: Number of subjects within the Intent-to-treat population with available data
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inhaled Nitric Oxide | Severity of Bronchopulmonary Dysplasia | 0 = None | 1 Participants |
| Inhaled Nitric Oxide | Severity of Bronchopulmonary Dysplasia | 1 = Mild | 80 Participants |
| Inhaled Nitric Oxide | Severity of Bronchopulmonary Dysplasia | 2 = Moderate | 83 Participants |
| Inhaled Nitric Oxide | Severity of Bronchopulmonary Dysplasia | 3 = Severe | 43 Participants |
| Placebo | Severity of Bronchopulmonary Dysplasia | 3 = Severe | 55 Participants |
| Placebo | Severity of Bronchopulmonary Dysplasia | 0 = None | 2 Participants |
| Placebo | Severity of Bronchopulmonary Dysplasia | 2 = Moderate | 82 Participants |
| Placebo | Severity of Bronchopulmonary Dysplasia | 1 = Mild | 72 Participants |
Secondary
Systemic Use of Postnatal Corticosteroids for Any Medical Reason
Time frame: Through hospital discharge, an average of 105 days for placebo and 108 days for INO
Population: Intent-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide | Systemic Use of Postnatal Corticosteroids for Any Medical Reason | 144 Participants |
| Placebo | Systemic Use of Postnatal Corticosteroids for Any Medical Reason | 131 Participants |