Bronchopulmonary Dysplasia (BPD)
Conditions
Keywords
Bronchopulmonary dysplasia, Pulmonary, Surfactant, Steroids, Extremely low gestational age
Brief summary
This is a phase I/II open-label study to determine the lowest, safe, effective dose of budesonide given with calfactant as the vehicle.
Detailed description
This is a phase I/II open-label study to determine the lowest safe, effective dose of budesonide given with calfactant as the vehicle; the investigators will perform an unblinded dose escalation study. The investigators will administer four dosing levels of budesonide suspended in calfactant beginning with 0.025 mg/kg of budesonide administered to 8 extremely low gestational age newborns (ELGANs) who are intubated at 3-10 days of age. Daily doses (at the same dosage) will be administered to infants who remain intubated for a potential of 5 total doses in each patient. Subsequent groups of 8 infants each will receive 0.05 mg/kg, 0.10 mg/kg, and 0.15 mg/kg of budesonide in calfactant (up to 5 total doses in each patient). A total of up to 32 infants will be enrolled in the trial. The investigators will evaluate the clinical, laboratory and safety data from each group of treated infants to 28 days of age before moving to the next dosing level of budesonide.
Interventions
DRUGBudesonide in Calfactant
Budesonide in Calfactant
Sponsors
Thrasher Research Fund
University of Florida
Florida Hospital for Children
University of California, San Francisco
Cynthia McEvoy
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Days to 14 Days
Healthy volunteers
No
Inclusion criteria
1. \> 23 0/7 and \< 27 6/7 weeks of gestational age based on center's best estimate of due date (using earliest obstetrical ultrasound, last menstrual period, examination, and other pertinent available information) 2. Day of life 3-14 from the date and time of delivery, with the date of birth being DOL 0 3. Intubated and mechanically ventilated and do not anticipate extubation in next 24 hours
Exclusion criteria
1. Serious congenital malformations or chromosomal abnormality 2. Likely to be extubated in next 24 hours 3. Clinically unstable 4. Infants who have received systemic steroids prior to dosing with study medication. 5. Infants who have received Indocin, Ibuprofen, or acetaminophen ≤ 96 hours prior to enrollment window ending
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | 28 days of life for each dosing group | Dose escalation will be defined as effective at the dose level in which 5 of 8 infants achieve the following: 1. Extubation within 72 hours of first dose or after \< 3 doses-without re-intubation before 28 days of age 2. RSS on nasal continuous positive airway pressure (NCPAP) \< 1.5 or on nasal cannula Fi02 \<25% at \< 2L/min at 28 days of age, persisting for at least 72 hours. 3. Cumulative supplemental oxygen \< 4.2 from time of enrollment to 28 days of age 4 4. No respiratory support at 28 days, including no supplemental oxygen by nasal cannula AND a \> 50% suppression of the tracheal aspirate interleukin-8 (IL-8) or CCL2 (chemokine ligand 2) at 24-72 hours (or prior to extubation if occurs at \<24 hours after dosing) after the initial dose in 5 of 8 of the infants (this may be a different combination of 5 patients than those who met the above criteria). |
| The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | 28 days of life for each dosing group | Number of ELGANS with a clinical AND Cytokine response: a \> 50% suppression of the tracheal aspirate interleukin-8 or chemokine ligand 2 at 24-72 hours (or prior to extubation if occurs at \<24 hours after dosing) after the initial dose in 5 of 8 of the infants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serial Budesonide Levels, T 1/2 | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. |
| Adverse Events/Subject Safety | Through 28 days of life | Safety assessments will include the subject's vital signs, clinical laboratory testing, morbidities associated with prematurity, morbidities associated with administration of budesonide in calfactant, and Adverse Events (AE)s. Clinical parameters/ AEs of interest are those potentially consistent with elevated glucocorticoid levels and will be specifically evaluated. A Data and Safety Monitoring Board (DSMB) will be established to review safety data. All of the data will be reviewed to monitor subject safety. |
| Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | 28 days of life for each dosing group | Clinical respiratory status (RSS and oxygen requirement) around dosing and at 28 days of age will be compared between dosing groups and also compared to the matched historical control patients from the Trial of Late Surfactant:(TOLSURF) study. The respiratory severity score (RSS) is a simplified severity score consisting of the mean airway pressure (MAP) multiplied by the fraction of inspired oxygen (FiO2). This score ranges from 0 to 12, with a higher score indicating more severe disease. |
| Serial Budesonide Levels, AUC | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. |
| Serial Budesonide Levels, Peak | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 0.025 mg/kg Budesonide 0.025 mg/kg Budesonide in Calfactant
Budesonide in Calfactant: Budesonide in Calfactant | 8 |
| 0.050 mg/kg Budesonide 0.050 mg/kg Budesonide in Calfactant
Budesonide in Calfactant: Budesonide in Calfactant | 8 |
| 0.10 mg/kg Budesonide 0.10 mg/kg Budesonide in Calfactant
Budesonide in Calfactant: Budesonide in Calfactant | 9 |
| 0.15 mg/kg Budesonide 0.15 mg/kg Budesonide in Calfactant
Budesonide in Calfactant: Budesonide in Calfactant | 0 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 0.025 mg/kg Budesonide | 0.050 mg/kg Budesonide | 0.10 mg/kg Budesonide | 0.15 mg/kg Budesonide | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 8 Participants | 9 Participants | 0 Participants | 25 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 25.3 gestational age in weeks STANDARD_DEVIATION 1.64 | 25.3 gestational age in weeks STANDARD_DEVIATION 1.25 | 24.4 gestational age in weeks STANDARD_DEVIATION 0.89 | — | 25.0 gestational age in weeks STANDARD_DEVIATION 1.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 1 Participants | — | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 6 Participants | 8 Participants | — | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Number of participants that completed study | 8 Participants | 8 Participants | 8 Participants | 0 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | — | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | — | 1 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 | 0 Participants | — | 1 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 8 Participants | — | 21 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 9 participants | — | 25 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants | — | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 5 Participants | — | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 3 / 9 | 0 / 0 |
| other Total, other adverse events | 8 / 8 | 7 / 8 | 8 / 9 | 0 / 0 |
| serious Total, serious adverse events | 1 / 8 | 1 / 8 | 4 / 9 | 0 / 0 |
Outcome results
Primary
Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS)
Dose escalation will be defined as effective at the dose level in which 5 of 8 infants achieve the following: 1. Extubation within 72 hours of first dose or after \< 3 doses-without re-intubation before 28 days of age 2. RSS on nasal continuous positive airway pressure (NCPAP) \< 1.5 or on nasal cannula Fi02 \<25% at \< 2L/min at 28 days of age, persisting for at least 72 hours. 3. Cumulative supplemental oxygen \< 4.2 from time of enrollment to 28 days of age 4 4. No respiratory support at 28 days, including no supplemental oxygen by nasal cannula AND a \> 50% suppression of the tracheal aspirate interleukin-8 (IL-8) or CCL2 (chemokine ligand 2) at 24-72 hours (or prior to extubation if occurs at \<24 hours after dosing) after the initial dose in 5 of 8 of the infants (this may be a different combination of 5 patients than those who met the above criteria).
Time frame: 28 days of life for each dosing group
Population: Extremely low gestational age infants (ELGANs), born before 28 weeks gestation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.025 mg/kg Budesonide | Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | 1 Participants |
| 0.050 mg/kg Budesonide | Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | 0 Participants |
| 0.10 mg/kg Budesonide | Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | 0 Participants |
Primary
The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels.
Number of ELGANS with a clinical AND Cytokine response: a \> 50% suppression of the tracheal aspirate interleukin-8 or chemokine ligand 2 at 24-72 hours (or prior to extubation if occurs at \<24 hours after dosing) after the initial dose in 5 of 8 of the infants
Time frame: 28 days of life for each dosing group
Population: No patient at the 0.025 mg/kg or at the 0.05 mg/kg or at the 0.10 mg/kg dosing level met the criteria for the primary outcome of a clinical and cytokine response. Due to this lack of response, we were approved by the Thrasher Foundation to not perform the dosing at the 0.15 mg/kg dosing level.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.025 mg/kg Budesonide | The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | 0 Participants |
| 0.050 mg/kg Budesonide | The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | 0 Participants |
| 0.10 mg/kg Budesonide | The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | 0 Participants |
| 0.15 mg/kg Budesonide | The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | 0 Participants |
Secondary
Adverse Events/Subject Safety
Safety assessments will include the subject's vital signs, clinical laboratory testing, morbidities associated with prematurity, morbidities associated with administration of budesonide in calfactant, and Adverse Events (AE)s. Clinical parameters/ AEs of interest are those potentially consistent with elevated glucocorticoid levels and will be specifically evaluated. A Data and Safety Monitoring Board (DSMB) will be established to review safety data. All of the data will be reviewed to monitor subject safety.
Time frame: Through 28 days of life
Population: No SAEs were considered to be treatment related.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.025 mg/kg Budesonide | Adverse Events/Subject Safety | 8 Participants |
| 0.050 mg/kg Budesonide | Adverse Events/Subject Safety | 8 Participants |
| 0.10 mg/kg Budesonide | Adverse Events/Subject Safety | 8 Participants |
Secondary
Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age
Clinical respiratory status (RSS and oxygen requirement) around dosing and at 28 days of age will be compared between dosing groups and also compared to the matched historical control patients from the Trial of Late Surfactant:(TOLSURF) study. The respiratory severity score (RSS) is a simplified severity score consisting of the mean airway pressure (MAP) multiplied by the fraction of inspired oxygen (FiO2). This score ranges from 0 to 12, with a higher score indicating more severe disease.
Time frame: 28 days of life for each dosing group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.025 mg/kg Budesonide | Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | 4.59 Respiratory Severity Score | Standard Deviation 3.74 |
| 0.050 mg/kg Budesonide | Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | 4.94 Respiratory Severity Score | Standard Deviation 2.93 |
| 0.10 mg/kg Budesonide | Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | 3.74 Respiratory Severity Score | Standard Deviation 2.97 |
Secondary
Serial Budesonide Levels, AUC
The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses.
Time frame: At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 0.025 mg/kg Budesonide | Serial Budesonide Levels, AUC | 39.4 ng*h/mL |
| 0.050 mg/kg Budesonide | Serial Budesonide Levels, AUC | 37.2 ng*h/mL |
| 0.10 mg/kg Budesonide | Serial Budesonide Levels, AUC | 73.5 ng*h/mL |
Secondary
Serial Budesonide Levels, Peak
The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses.
Time frame: At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 0.025 mg/kg Budesonide | Serial Budesonide Levels, Peak | 7.70 ng/mL |
| 0.050 mg/kg Budesonide | Serial Budesonide Levels, Peak | 8.60 ng/mL |
| 0.10 mg/kg Budesonide | Serial Budesonide Levels, Peak | 18.7 ng/mL |
Secondary
Serial Budesonide Levels, T 1/2
The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses.
Time frame: At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 0.025 mg/kg Budesonide | Serial Budesonide Levels, T 1/2 | 3.78 h |
| 0.050 mg/kg Budesonide | Serial Budesonide Levels, T 1/2 | 3.20 h |
| 0.10 mg/kg Budesonide | Serial Budesonide Levels, T 1/2 | 3.20 h |