Bronchopulmonary Dysplasia, Premature Birth, Respiratory Distress Syndrome, Newborn
Conditions
Keywords
Double-blind, Low Birth Weight, Surfactant, Placebo-Controlled, Premature Birth
Brief summary
SURFAXIN® (lucinactant) treatment will be examined in very low birth weight infants to prevent development of chronic lung disease, commonly known as bronchopulmonary dysplasia (BPD), in premature infants who have required continued intubation and received surfactants for the prevention or treatment of respiratory distress syndrome (RDS).
Detailed description
Determine the safety and tolerability of SURFAXIN administration in the first weeks of life as a therapeutic approach for prevention of BPD. Determine whether treatment with SURFAXIN during the first two to three weeks of life can decrease the proportion of infants on mechanical ventilation or oxygen or the incidence of death or BPD in VLBW infants when assessed at 28 days of life and 36 weeks post-menstrual age (as determined by the need for supplemental oxygen).
Interventions
DRUGLucinactant 175 mg/kg
Administered via slow intra-tracheal instillation at a dose of 175 mg/kg (5.8 mL/kg of a 30-mg/mL suspension). Initial treatment given no later than 1 hour after randomization. Additional treatments were administered every 48 hours up to a maximum of 5 doses (up to day of life (DOL) 18).
DRUGLucinactant 90 mg/kg
Administered via slow intra-tracheal instillation at a dose of 90 mg/kg (3.0 mL/kg of a 30-mg/mL suspension). Initial treatment given no later than 1 hour after randomization. Additional treatments were administered every 48 hours up to a maximum of 5 doses (up to DOL 18).
DRUGPlacebo
Sham air was administered via slow intratracheal instillation at a dose of 3.0 mL/kg volume of air. The initial treatment was given no later than 1 hour after randomization. Additional treatment were administered every 48 hours up to a maximum of 5 doses (up to DOL 18).
Sponsors
Windtree Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Days to 10 Days
Healthy volunteers
No
Inclusion criteria
* Premature infants between 600 and 900 grams birth weight * Intubated and on mechanical ventilation * Sustained (\>= 30 minutes) fraction of inspired oxygen (FiO₂) \>= 0.30 within 8 hours prior to randomization
Exclusion criteria
* Mother has prolonged rupture of membranes ≥ 2 weeks * Culture-proven sepsis * High grade intraventricular hemorrhage (IVH) * Congenital heart disease * Congential anomalies inconsistent with life or likely to confound efficacy or safety endpoints * FiO₂≥ 0.80 and mean airway pressure (MAP) ≥ 12 cmH2O at day of life (DOL) 3 * FiO₂\< 0.25 at any time between meeting the entry criteria to immediately prior to randomization * Concomitant use of any other surfactant within the first 48 hours of life * Prior use of nitric oxide * Prior use of steroids * Current participation in any other clinical trial or has received an experimental drug or used an experimental device
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks | 36 weeks post-menstrual age (PMA) | Number of participants who died or developed BPD, defined as oxygen requirement at 36 Weeks post-menstrual age |
| All-cause Mortality | 36 weeks PMA | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BPD at 28 Days | 28 days of life | BPD at 28 days of life, as determined by the need for supplemental oxygen |
| BPD at 36 Weeks | 36 weeks PMA | BPD at 36 weeks PMA as determined by the need for supplemental oxygen |
| Area Under the Curve for Fraction of Inspired Oxygen (FiO₂) | 15 minutes prior to dose 1, 2 hours post dose 1, 6 hours post dose 1, 24 hours post dose 1, and daily from Study Day 2 to Study Day 25 and Day of Life 28 | AUC for FiO₂calculated using the trapezoidal rule. Missing data imputed using last observation carried forward |
| Duration of Supplemental Oxygen | 36 weeks PMA | Number of days receiving supplemental oxygen through 36 weeks PMA |
| Incidence of Death or BPD at 28 Days | 28 days of life | Death or BPD, defined as oxygen requirement at 28 days of life |
| Days in Hospital | 36 weeks PMA | The number of days spent in the hospital through 36 weeks PMA |
| Area Under the Curve for Mean Arterial Pressure (MAP) | 15 minutes prior to dose 1, 2 hours post dose 1, 6 hours post dose 1, 24 hours post dose 1, and daily from Study Day 2 to Study Day 25, and day of life 28 | AUC for MAP (in mm Hg) calculated using the trapezoidal rule. Missing data imputed using last observation carried forward |
| Days Receiving Mechanical Ventilation (MV) | 36 weeks PMA | Number of days receiving mechanical ventilation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SURFAXIN High Dose SURFAXIN (lucinactant) at 175 mg/kg | 45 |
| SURFAXIN Low Dose SURFAXIN (lucinactant) at 90 mg/kg | 47 |
| Placebo Sham air using 3.0 mL/kg volume of air | 44 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrew from study medication | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | SURFAXIN High Dose | SURFAXIN Low Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 45 Participants | 47 Participants | 44 Participants | 136 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 |
| Gestational Age | 26.1 weeks STANDARD_DEVIATION 1.68 | 25.5 weeks STANDARD_DEVIATION 1.43 | 25.7 weeks STANDARD_DEVIATION 1.36 | 25.8 weeks STANDARD_DEVIATION 1.49 |
| Region of Enrollment Chile | 8 participants | 10 participants | 7 participants | 25 participants |
| Region of Enrollment Hungary | 3 participants | 3 participants | 2 participants | 8 participants |
| Region of Enrollment Poland | 17 participants | 14 participants | 16 participants | 47 participants |
| Region of Enrollment United States | 17 participants | 20 participants | 19 participants | 56 participants |
| Sex: Female, Male Female | 21 Participants | 17 Participants | 27 Participants | 65 Participants |
| Sex: Female, Male Male | 24 Participants | 30 Participants | 17 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 45 / 45 | 47 / 47 | 44 / 44 |
| serious Total, serious adverse events | 33 / 45 | 36 / 47 | 35 / 44 |
Outcome results
Primary
All-cause Mortality
Time frame: 36 weeks PMA
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SURFAXIN High Dose | All-cause Mortality | 5 participants |
| SURFAXIN Low Dose | All-cause Mortality | 14 participants |
| Placebo | All-cause Mortality | 7 participants |
Comparison: Null hypothesis: No difference between treatment groupsp-value: 0.5Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference between treatment groupsp-value: 0.146Cochran-Mantel-Haenszel
Primary
Incidence of Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks
Number of participants who died or developed BPD, defined as oxygen requirement at 36 Weeks post-menstrual age
Time frame: 36 weeks post-menstrual age (PMA)
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SURFAXIN High Dose | Incidence of Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks | 26 participants |
| SURFAXIN Low Dose | Incidence of Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks | 37 participants |
| Placebo | Incidence of Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks | 29 participants |
Comparison: Null hypothesis: No difference between treatment groupsp-value: 0.476Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference between treatment groupsp-value: 0.208Cochran-Mantel-Haenszel
Secondary
Area Under the Curve for Fraction of Inspired Oxygen (FiO₂)
AUC for FiO₂calculated using the trapezoidal rule. Missing data imputed using last observation carried forward
Time frame: 15 minutes prior to dose 1, 2 hours post dose 1, 6 hours post dose 1, 24 hours post dose 1, and daily from Study Day 2 to Study Day 25 and Day of Life 28
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SURFAXIN High Dose | Area Under the Curve for Fraction of Inspired Oxygen (FiO₂) | 0.39 Percent O₂*hour | Standard Deviation 0.14 |
| SURFAXIN Low Dose | Area Under the Curve for Fraction of Inspired Oxygen (FiO₂) | 0.41 Percent O₂*hour | Standard Deviation 0.16 |
| Placebo | Area Under the Curve for Fraction of Inspired Oxygen (FiO₂) | 0.38 Percent O₂*hour | Standard Deviation 0.17 |
p-value: 0.843ANOVA
p-value: 0.543ANOVA
p-value: 0.537ANOVA
Secondary
Area Under the Curve for Mean Arterial Pressure (MAP)
AUC for MAP (in mm Hg) calculated using the trapezoidal rule. Missing data imputed using last observation carried forward
Time frame: 15 minutes prior to dose 1, 2 hours post dose 1, 6 hours post dose 1, 24 hours post dose 1, and daily from Study Day 2 to Study Day 25, and day of life 28
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SURFAXIN High Dose | Area Under the Curve for Mean Arterial Pressure (MAP) | 5.99 arterial pressure (mm Hg)*hour | Standard Deviation 3.38 |
| SURFAXIN Low Dose | Area Under the Curve for Mean Arterial Pressure (MAP) | 6.93 arterial pressure (mm Hg)*hour | Standard Deviation 4.13 |
| Placebo | Area Under the Curve for Mean Arterial Pressure (MAP) | 6.34 arterial pressure (mm Hg)*hour | Standard Deviation 3.56 |
p-value: 0.813ANOVA
p-value: 0.449ANOVA
p-value: 0.275ANOVA
Secondary
BPD at 28 Days
BPD at 28 days of life, as determined by the need for supplemental oxygen
Time frame: 28 days of life
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SURFAXIN High Dose | BPD at 28 Days | 42 participants |
| SURFAXIN Low Dose | BPD at 28 Days | 44 participants |
| Placebo | BPD at 28 Days | 38 participants |
p-value: 0.267Cochran-Mantel-Haenszel
p-value: 0.313Cochran-Mantel-Haenszel
p-value: 0.944Cochran-Mantel-Haenszel
Secondary
BPD at 36 Weeks
BPD at 36 weeks PMA as determined by the need for supplemental oxygen
Time frame: 36 weeks PMA
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SURFAXIN High Dose | BPD at 36 Weeks | 26 participants |
| SURFAXIN Low Dose | BPD at 36 Weeks | 37 participants |
| Placebo | BPD at 36 Weeks | 29 participants |
p-value: 0.476Cochran-Mantel-Haenszel
p-value: 0.208Cochran-Mantel-Haenszel
p-value: 0.046Cochran-Mantel-Haenszel
Secondary
Days in Hospital
The number of days spent in the hospital through 36 weeks PMA
Time frame: 36 weeks PMA
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SURFAXIN High Dose | Days in Hospital | 65.8 days | Standard Deviation 11.72 |
| SURFAXIN Low Dose | Days in Hospital | 70.0 days | Standard Deviation 10.06 |
| Placebo | Days in Hospital | 68.6 days | Standard Deviation 9.57 |
p-value: 0.311ANOVA
p-value: 0.516ANOVA
p-value: 0.094ANOVA
Secondary
Days Receiving Mechanical Ventilation (MV)
Number of days receiving mechanical ventilation
Time frame: 36 weeks PMA
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SURFAXIN High Dose | Days Receiving Mechanical Ventilation (MV) | 30.1 days | Standard Deviation 23.3 |
| SURFAXIN Low Dose | Days Receiving Mechanical Ventilation (MV) | 42.1 days | Standard Deviation 26.4 |
| Placebo | Days Receiving Mechanical Ventilation (MV) | 35.8 days | Standard Deviation 23.2 |
p-value: 0.285ANOVA
p-value: 0.229ANOVA
p-value: 0.03ANOVA
Secondary
Duration of Supplemental Oxygen
Number of days receiving supplemental oxygen through 36 weeks PMA
Time frame: 36 weeks PMA
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SURFAXIN High Dose | Duration of Supplemental Oxygen | 55.3 days | Standard Deviation 16.8 |
| SURFAXIN Low Dose | Duration of Supplemental Oxygen | 63.0 days | Standard Deviation 19.3 |
| Placebo | Duration of Supplemental Oxygen | 55.7 days | Standard Deviation 23.4 |
p-value: 0.483ANOVA
p-value: 0.123ANOVA
p-value: 0.006ANOVA
Secondary
Incidence of Death or BPD at 28 Days
Death or BPD, defined as oxygen requirement at 28 days of life
Time frame: 28 days of life
Population: A sample size of 70 per arm is sufficient to demonstrate a 20% relative risk reduction. All randomized infants were analyzed (intent-to-treat)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SURFAXIN High Dose | Incidence of Death or BPD at 28 Days | 42 participants |
| SURFAXIN Low Dose | Incidence of Death or BPD at 28 Days | 44 participants |
| Placebo | Incidence of Death or BPD at 28 Days | 38 participants |
p-value: 0.267Cochran-Mantel-Haenszel
p-value: 0.313Cochran-Mantel-Haenszel