Respiratory Distress Syndrome
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and efficacy of lucinactant for inhalation administered as an aerosolized dose in two doses to preterm neonates 26 - 32 weeks gestational age who are receiving nasal continuous positive airway pressure (nCPAP) for Respiratory Distress Syndrome (RDS) compared to neonates receiving nCPAP alone.
Detailed description
The purpose of this study is to investigate the safety and efficacy of lucinactant for inhalation in preterm neonates 26 to 32 completed weeks post-menstrual age (PMA). Efficacy and safety are based on clinical evaluations. The endpoints specified are similar to those in Protocols 03-CL-1201 and 03-CL-1401 to allow for potential comparison and pooling of results. The objective of this study is to evaluate the safety and efficacy of lucinactant for inhalation in conjunction with nCPAP, compared to nCPAP alone, in preterm neonates with RDS, as assessed by the time to and incidence of respiratory failure and/or death due to RDS over the first 72 hours of life, the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks PMA, and change in physiologic parameters (FiO2 and PCO2) over the first 72 hours of life.
Interventions
DRUGLucinactant delivered via investigational delivery device
Lucinactant for inhalation refers to the active investigational agent lucinactant in combination with the investigational delivery device (drug-device combination product)
DRUGnCPAP
Nasal CPAP
Sponsors
Windtree Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
26 Weeks to 32 Weeks
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form (ICF) from legally authorized representative 2. 26 0/7 to 32 6/7 completed weeks gestation PMA 3. Successful implementation of non-invasive support or ventilation within 90 minutes after birth 4. Spontaneous breathing 5. Chest radiograph consistent with RDS 6. Within the first 20 hours after birth requires an nCPAP of 5 to 7 centimeters water (cmH2O) with a fraction of inspired oxygen (FiO2) of ≥ 0.25 (\>0.21 for neonates 26-28 weeks PMA) to 0.40 that is clinically indicated for at least 30 minutes to maintain oxygen by pulse oximetry (SpO2) of 90% to 95%. Transient (\<10 minutes) FiO2 excursions outside this range do not reset the 30-minute requirement.
Exclusion criteria
1. A heart rate that cannot be stabilized above 100 beats per minute (bpm) within 5 minutes of birth 2. Recurrent episodes of apnea requiring positive pressure ventilation (PPV) administered manually or mechanically through any patient interface 3. A 5 minute Apgar score \< 5 4. Major congenital malformation(s) or craniofacial abnormalities that preclude the use of nCPAP, diagnosed antenatally or immediately after birth 5. Clinically significant diseases or conditions other than RDS which could potentially interfere with cardiopulmonary function (e.g. congenital heart disease, hydrops fetalis or congenital infection) 6. A known or suspected chromosomal abnormality or syndrome 7. Premature rupture of membranes (PROM) \> 3 weeks 8. Hemodynamic instability requiring vasopressors or steroids for hemodynamic support and/or presumed clinical sepsis 9. A need for intubation and/or mechanical ventilation at any time before enrollment into the study 10. The administration (or plan for administration) of any the following: * Another investigational agent or investigational medical device * Any other surfactant agent * Systemic corticosteroids (other than antenatal steroids already received) 11. Presence of air leak (pneumothorax, pneumomediastinum, pneumopericardium, subcutaneous emphysema, or definite evidence of pulmonary interstitial emphysema (PIE)) on the baseline chest radiograph
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS) | 72 hours | Number of participants who had respiratory failure due to RDS or death due to RDS; known as nasal continuous positive airway pressure (nCPAP) failure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Respiratory Failure or Death Due to RDS | 72 hours | Incidence of Respiratory Failure or Death Due to RDS by Intubation or Failure Criteria |
| Time to nCPAP Failure | 72 hours | Time from birth to nCPAP Failure |
| Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling | 72 hours | The measure tests the differences between treatments on respiratory failure or death due to RDS using Poisson distribution modeling, which accounts for the time over which the event could have occurred. |
| Number of Participants With Bronchopulmonary Dysplasia (BPD) | 36 weeks post-menstrual age (PMA) | Summarizes the number of participants with BPD or alive without BPD |
Countries
Canada, Chile, Colombia, Hungary, Ireland, Netherlands, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) Lucinactant for inhalation with nCPAP; up to 2 repeat doses will be allowed if repeat dosing criteria are met.
Lucinactant delivered via investigational delivery device: Lucinactant for inhalation refers to the active investigational agent lucinactant in combination with the investigational delivery device (drug-device combination product)
nCPAP: Nasal CPAP | 73 |
| Aerosolized Lucinactant (80 mg TPL/kg) Lucinactant for inhalation with nCPAP; up to 2 repeat doses will be allowed if repeat dosing criteria are met.
Lucinactant delivered via investigational delivery device: Lucinactant for inhalation refers to the active investigational agent lucinactant in combination with the investigational delivery device (drug-device combination product)
nCPAP: Nasal CPAP | 76 |
| nCPAP Only nCPAP alone
nCPAP: Nasal CPAP | 72 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Aerosolized Lucinactant (80 mg TPL/kg) | Total | Aerosolized Lucinactant (40 mg TPL/kg) | nCPAP Only |
|---|---|---|---|---|
| Age, Customized Gestational Age | 30.7 weeks post menstrual age STANDARD_DEVIATION 1.17 | 30.7 weeks post menstrual age STANDARD_DEVIATION 1.19 | 30.8 weeks post menstrual age STANDARD_DEVIATION 1.24 | 30.7 weeks post menstrual age STANDARD_DEVIATION 1.17 |
| Apgar Score at Five Minutes | 8.0 Scores on a scale STANDARD_DEVIATION 1.02 | 8.1 Scores on a scale STANDARD_DEVIATION 0.97 | 8.1 Scores on a scale STANDARD_DEVIATION 0.9 | 8.1 Scores on a scale STANDARD_DEVIATION 1 |
| Appearance, Pulse, Grimace, Activity, and Respiration (Apgar) Score at One Minute | 6.5 Scores on a scale STANDARD_DEVIATION 1.71 | 6.6 Scores on a scale STANDARD_DEVIATION 1.69 | 6.7 Scores on a scale STANDARD_DEVIATION 1.74 | 6.8 Scores on a scale STANDARD_DEVIATION 1.61 |
| Birth Status Multiple Birth | 23 Participants | 74 Participants | 29 Participants | 22 Participants |
| Birth Status Single Birth | 53 Participants | 147 Participants | 44 Participants | 50 Participants |
| Birth Weight | 1505.8 grams STANDARD_DEVIATION 378.5 | 1503.4 grams STANDARD_DEVIATION 361.73 | 1557.0 grams STANDARD_DEVIATION 342.38 | 1446.4 grams STANDARD_DEVIATION 359.13 |
| Chorioamnionitis No | 73 Participants | 213 Participants | 70 Participants | 70 Participants |
| Chorioamnionitis Yes | 3 Participants | 8 Participants | 3 Participants | 2 Participants |
| Congenital Anomaly No | 76 Participants | 220 Participants | 72 Participants | 72 Participants |
| Congenital Anomaly Yes | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 61 Participants | 19 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 160 Participants | 54 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mode of Delivery Cesarean Section | 64 Participants | 176 Participants | 56 Participants | 56 Participants |
| Mode of Delivery Vaginal | 12 Participants | 45 Participants | 17 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 16 Participants | 4 Participants | 6 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 | 6 Participants | 19 Participants | 6 Participants | 7 Participants |
| Race (NIH/OMB) White | 64 Participants | 184 Participants | 62 Participants | 58 Participants |
| Region of Enrollment Canada | 2 participants | 9 participants | 4 participants | 3 participants |
| Region of Enrollment Chile | 15 participants | 39 participants | 13 participants | 11 participants |
| Region of Enrollment Colombia | 7 participants | 16 participants | 4 participants | 5 participants |
| Region of Enrollment Hungary | 3 participants | 18 participants | 6 participants | 9 participants |
| Region of Enrollment Ireland | 2 participants | 3 participants | 1 participants | 0 participants |
| Region of Enrollment Netherlands | 1 participants | 5 participants | 2 participants | 2 participants |
| Region of Enrollment Poland | 21 participants | 65 participants | 23 participants | 21 participants |
| Region of Enrollment United States | 25 participants | 66 participants | 20 participants | 21 participants |
| Ruptured Membranes Artificial | 60 Participants | 163 Participants | 50 Participants | 53 Participants |
| Ruptured Membranes Spontaneous | 16 Participants | 58 Participants | 23 Participants | 19 Participants |
| Sex: Female, Male Female | 39 Participants | 107 Participants | 31 Participants | 37 Participants |
| Sex: Female, Male Male | 37 Participants | 114 Participants | 42 Participants | 35 Participants |
| Steroid Use, Maternal No Steroids | 7 Participants | 14 Participants | 5 Participants | 2 Participants |
| Steroid Use, Maternal Used Steroids | 69 Participants | 207 Participants | 68 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 1 / 72 | 2 / 71 |
| other Total, other adverse events | 65 / 70 | 69 / 72 | 66 / 71 |
| serious Total, serious adverse events | 16 / 70 | 14 / 72 | 20 / 71 |
Outcome results
Primary
Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)
Number of participants who had respiratory failure due to RDS or death due to RDS; known as nasal continuous positive airway pressure (nCPAP) failure
Time frame: 72 hours
Population: Modified Intent-to-Treat; randomized subjects who received study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS) | 31 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS) | 32 Participants |
| nCPAP Only | Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS) | 31 Participants |
Comparison: Null hypothesis is no difference across treatment groupsp-value: 0.363Regression, Logistic
Comparison: Null hypothesis of no difference between treatmentsp-value: 0.36Regression, Logistic
Comparison: Null hypothesis of no difference between treatmentsp-value: 0.461Regression, Logistic
Secondary
Incidence of Respiratory Failure or Death Due to RDS
Incidence of Respiratory Failure or Death Due to RDS by Intubation or Failure Criteria
Time frame: 72 hours
Population: Modified Intent-to-Treat Population without Treatment Interruptions
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS | 28 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS | 14 Participants |
| nCPAP Only | Incidence of Respiratory Failure or Death Due to RDS | 31 Participants |
Comparison: Null hypothesis is no difference across treatment groupsp-value: 0.401Regression, Logistic
Comparison: Null hypothesis is no difference across treatment groupsp-value: 0.372Regression, Logistic
Comparison: Null hypothesis is no difference across treatment groupsp-value: 0.648Regression, Logistic
Secondary
Incidence of Respiratory Failure or Death Due to RDS
Incidence of Respiratory Failure or Death due to RDS by Intubation or Failure Criteria
Time frame: 28 days
Population: Modified Intent-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS | 35 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS | 32 Participants |
| nCPAP Only | Incidence of Respiratory Failure or Death Due to RDS | 31 Participants |
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.099Regression, Logistic
Comparison: Null hypothesis of no difference between treatmentsp-value: 0.09Regression, Logistic
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.461Regression, Logistic
Secondary
Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling
The measure tests the differences between treatments on respiratory failure or death due to RDS using Poisson distribution modeling, which accounts for the time over which the event could have occurred.
Time frame: 72 hours
Population: Modified Intent-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling | 31 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling | 32 Participants |
| nCPAP Only | Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling | 31 Participants |
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.312Regression, Linear
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.094Regression, Linear
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.414Regression, Linear
Secondary
Number of Participants With Bronchopulmonary Dysplasia (BPD)
Summarizes the number of participants with BPD or alive without BPD
Time frame: 36 weeks post-menstrual age (PMA)
Population: Modified Intent-to-Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Number of Participants With Bronchopulmonary Dysplasia (BPD) | BPD | 7 Participants |
| Aerosolized Lucinactant (40 mg TPL/kg) | Number of Participants With Bronchopulmonary Dysplasia (BPD) | Alive without BPD | 62 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Number of Participants With Bronchopulmonary Dysplasia (BPD) | BPD | 7 Participants |
| Aerosolized Lucinactant (80 mg TPL/kg) | Number of Participants With Bronchopulmonary Dysplasia (BPD) | Alive without BPD | 64 Participants |
| nCPAP Only | Number of Participants With Bronchopulmonary Dysplasia (BPD) | BPD | 10 Participants |
| nCPAP Only | Number of Participants With Bronchopulmonary Dysplasia (BPD) | Alive without BPD | 59 Participants |
Comparison: Null hypothesis of no treatment between treatmentsp-value: 0.534ANOVA
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.48ANOVA
Comparison: Null hypothesis of no difference between treatment groupsp-value: 0.313ANOVA
Secondary
Time to nCPAP Failure
Time from birth to nCPAP Failure
Time frame: 72 hours
Population: Modified Intent-to-Treat; randomized participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aerosolized Lucinactant (40 mg TPL/kg) | Time to nCPAP Failure | 39.3 hours | Standard Error 2.06 |
| Aerosolized Lucinactant (80 mg TPL/kg) | Time to nCPAP Failure | 44.8 hours | Standard Error 2.69 |
| nCPAP Only | Time to nCPAP Failure | 40.7 hours | Standard Error 2.44 |
Comparison: Null hypothesis of no difference across treatmentsp-value: 0.996Log Rank
Comparison: Null hypothesis of no difference between treatmentsp-value: 0.951Log Rank
Comparison: Null hypothesis of no difference between treatmentsp-value: 0.995Log Rank