Bronchopulmonary Dysplasia
Conditions
Brief summary
This study will describe the safety of furosemide in premature infants at risk of bronchopulmonary dysplasia and determine the preliminary effectiveness and pharmacokinetics (PK) of furosemide. Funding Source - FDA OOPD
Detailed description
Infants will receive a placebo or furosemide for 28 days. Blood samples will be collected for pharmacokinetic analysis.Premature infants will be randomized to receive placebo or furosemide in a dose escalating approach. Follow up information will be collected up to 7 days after the last dose and at 36 weeks post menstrual age. The final study assessment will occur at the time of discharge, early termination or transfer.
Interventions
DRUGFurosemide Cohort 1
furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.
DRUGFurosemide Cohort 2
furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.
DRUGFurosemide Cohort 3
furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.
OTHERPlacebo
Sugar water will be administered in a equivalent volume as drug intervention.
Sponsors
Duke University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Emmes Company, LLC
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Days to 28 Days
Healthy volunteers
No
Inclusion criteria
1. Receiving positive airway pressure (nasal continuous airway pressure, nasal intermittent positive pressure ventilation, or nasal cannula flow \> 1LPM) or mechanical ventilation (high frequency or conventional) 2. \< 29 weeks gestational age at birth 3. 7-28 days postnatal age at time of first study dose
Exclusion criteria
1. Exposure to any diuretic ≤ 72 hours prior to first study dose 2. Previous enrollment and dosing in current study, Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia 3. Hemodynamically significant patent ductus arteriosus, as determined by the investigator 4. Major congenital anomaly (e.g. congenital diaphragmatic hernia, congenital pulmonary adenomatoid malformation) 5. Meconium aspiration syndrome 6. Known allergy to any diuretic 7. Serum creatinine \>1.7 mg/dL \< 24 hours prior to first study dose 8. BUN \>50 mg/dL \< 24 hours prior to first study dose 9. Na \<125 mmol/L \< 24 hours prior to first study dose 10. K ≤2.5 mmol/L \< 24 hours prior to first study dose 11. Ca ≤ 6 mg/dL \< 24 hours prior to first study dose 12. Indirect bilirubin \>10 mg/dL \< 24 hours prior to first study dose 13. Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Determined by Adverse Events | 35 days for each participant | Safety was assessed following the initial study-specific procedure (e.g., screening blood draws, dosing) through 7 days post last study dose by frequency and incidence of adverse events and serious adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined | 36 weeks postmenstrual age | Moderate-severe BPD or death risk was defined using the NICHD Neonatal Research Network BPD outcome estimator. |
| Clearance | After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration. | Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point. |
| Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Risk measured weekly through Week 4 | Moderate-severe BPD or death risk was defined by the NICHD Neonatal Research Network (NRN) BPD outcome estimator which provides an estimate of the risk of BPD (none, mild, moderate, severe) or death by postnatal day and is presented as a percentage. For this protocol, the categories were dichotomized to none-mild vs. moderate-severe-death. The risk of BPD or death was defined by the NICHD NRN BPD estimator on days 7, 14, 21 and 28 of study drug using the closest day available from the BPD estimator. The BPD estimator includes infants up to 28 postnatal days; for infants in this protocol older than that, 28-day estimates are used. |
| Half-life | After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration. | Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point. |
| Area Under the Plasma Concentration Versus Time Curve | After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration. | Population PK data were collected from the two Furosemide cohorts and includes all 39 active drug recipients. |
| Volume of Distribution | After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration. | Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point. |
Countries
United States
Participant flow
Pre-assignment details
Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Participants by arm
| Arm | Count |
|---|---|
| Furosemide Cohort 1 Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days.
Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review. | 31 |
| Placebo Cohort 1 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug).
Placebo: Sugar water will be administered in a equivalent volume as drug intervention. | 9 |
| Furosemide Cohort 2 Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days.
Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review. | 30 |
| Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug).
Placebo: Sugar water will be administered in a equivalent volume as drug intervention. | 10 |
| Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days.
Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review. | 0 |
| Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug).
Placebo: Sugar water will be administered in a equivalent volume as drug intervention. | 0 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Did not receive intervention | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Reason undisclosed | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Furosemide Cohort 1 | Placebo Cohort 1 | Furosemide Cohort 2 | Placebo Cohort 2 | Total | Placebo Cohort 3 | Furosemide Cohort 3 |
|---|---|---|---|---|---|---|---|
| Age, Customized Gestational Age | 26.4 weeks STANDARD_DEVIATION 1.4 | 26.3 weeks STANDARD_DEVIATION 1.9 | 25.6 weeks STANDARD_DEVIATION 1.4 | 25.5 weeks STANDARD_DEVIATION 1.8 | 26.0 weeks STANDARD_DEVIATION 1.5 | — | — |
| Age, Customized Post Natal Age | 17 Days STANDARD_DEVIATION 7 | 18 Days STANDARD_DEVIATION 7 | 22 Days STANDARD_DEVIATION 6 | 24 Days STANDARD_DEVIATION 4 | 20 Days STANDARD_DEVIATION 7 | — | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 7 Participants | 2 Participants | 12 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 8 Participants | 22 Participants | 8 Participants | 66 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 7 Participants | 9 Participants | 3 Participants | 29 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 4 Participants | 0 Participants | 7 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 2 Participants | 16 Participants | 6 Participants | 42 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 31 Participants | 9 Participants | 30 Participants | 10 Participants | 80 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 17 Participants | 5 Participants | 16 Participants | 3 Participants | 41 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 14 Participants | 7 Participants | 39 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 9 | 1 / 30 | 0 / 10 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 28 / 31 | 9 / 9 | 28 / 30 | 9 / 10 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 5 / 31 | 1 / 9 | 6 / 30 | 0 / 10 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Safety as Determined by Adverse Events
Safety was assessed following the initial study-specific procedure (e.g., screening blood draws, dosing) through 7 days post last study dose by frequency and incidence of adverse events and serious adverse events.
Time frame: 35 days for each participant
Population: Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3. Data are reported for the safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Furosemide Cohort 1 | Safety as Determined by Adverse Events | 123 Events |
| Placebo Cohort 1 | Safety as Determined by Adverse Events | 29 Events |
| Furosemide Cohort 2 | Safety as Determined by Adverse Events | 100 Events |
| Placebo Cohort 2 | Safety as Determined by Adverse Events | 49 Events |
| Total | Safety as Determined by Adverse Events | 293 Events |
Secondary
Area Under the Plasma Concentration Versus Time Curve
Population PK data were collected from the two Furosemide cohorts and includes all 39 active drug recipients.
Time frame: After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration.
Population: Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Furosemide Cohort 1 | Area Under the Plasma Concentration Versus Time Curve | 2165 mg*h/L |
| Placebo Cohort 1 | Area Under the Plasma Concentration Versus Time Curve | 6016 mg*h/L |
| Furosemide Cohort 2 | Area Under the Plasma Concentration Versus Time Curve | 4639 mg*h/L |
Secondary
Clearance
Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.
Time frame: After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration.
Population: Data was collected from the Furosemide cohort 1 and 2, and combined. In total 39 active drug recipients participated in the population PK.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Furosemide Cohort 1 | Clearance | 16.3 (mL/h/kg) |
| Placebo Cohort 1 | Clearance | 21.8 (mL/h/kg) |
| Furosemide Cohort 2 | Clearance | 18 (mL/h/kg) |
Secondary
Half-life
Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.
Time frame: After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration.
Population: Data were collected from the two Furosemide cohorts and the combined analysis includes all 39 active drug recipients who participated in the population PK .
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Furosemide Cohort 1 | Half-life | 9.8 hours |
| Placebo Cohort 1 | Half-life | 7.3 hours |
| Furosemide Cohort 2 | Half-life | 8.8 hours |
Secondary
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment
Moderate-severe BPD or death risk was defined by the NICHD Neonatal Research Network (NRN) BPD outcome estimator which provides an estimate of the risk of BPD (none, mild, moderate, severe) or death by postnatal day and is presented as a percentage. For this protocol, the categories were dichotomized to none-mild vs. moderate-severe-death. The risk of BPD or death was defined by the NICHD NRN BPD estimator on days 7, 14, 21 and 28 of study drug using the closest day available from the BPD estimator. The BPD estimator includes infants up to 28 postnatal days; for infants in this protocol older than that, 28-day estimates are used.
Time frame: Risk measured weekly through Week 4
Population: Data are reported for the safety population. Overall 82 participants were randomized, but 2 were not dosed. 80 participants were analyzed for BPD status.~Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Furosemide Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 3 | 52.1 percent probability of BPD or death risk | Standard Deviation 28 |
| Furosemide Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 0 | 57.9 percent probability of BPD or death risk | Standard Deviation 20.5 |
| Furosemide Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 4 | 44.0 percent probability of BPD or death risk | Standard Deviation 23.6 |
| Furosemide Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 1 | 55.4 percent probability of BPD or death risk | Standard Deviation 21.2 |
| Furosemide Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 2 | 52.1 percent probability of BPD or death risk | Standard Deviation 23.3 |
| Placebo Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 3 | 40.4 percent probability of BPD or death risk | Standard Deviation 25.2 |
| Placebo Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 2 | 56.2 percent probability of BPD or death risk | Standard Deviation 21.8 |
| Placebo Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 1 | 55.5 percent probability of BPD or death risk | Standard Deviation 20.6 |
| Placebo Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 4 | 40.9 percent probability of BPD or death risk | Standard Deviation 27.9 |
| Placebo Cohort 1 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 0 | 52.8 percent probability of BPD or death risk | Standard Deviation 23 |
| Furosemide Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 2 | 61 percent probability of BPD or death risk | Standard Deviation 18.3 |
| Furosemide Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 0 | 66.7 percent probability of BPD or death risk | Standard Deviation 16.8 |
| Furosemide Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 1 | 65.9 percent probability of BPD or death risk | Standard Deviation 17.5 |
| Furosemide Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 3 | 61.3 percent probability of BPD or death risk | Standard Deviation 18.2 |
| Furosemide Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 4 | 53.0 percent probability of BPD or death risk | Standard Deviation 20.6 |
| Placebo Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 4 | 54.4 percent probability of BPD or death risk | Standard Deviation 34.1 |
| Placebo Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 0 | 70.9 percent probability of BPD or death risk | Standard Deviation 22.2 |
| Placebo Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 3 | 57.9 percent probability of BPD or death risk | Standard Deviation 30.7 |
| Placebo Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 2 | 65.0 percent probability of BPD or death risk | Standard Deviation 18.4 |
| Placebo Cohort 2 | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 1 | 71.6 percent probability of BPD or death risk | Standard Deviation 20.4 |
| Total | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 2 | 57.6 percent probability of BPD or death risk | Standard Deviation 20.9 |
| Total | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 3 | 54.9 percent probability of BPD or death risk | Standard Deviation 25.4 |
| Total | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 0 | 62.3 percent probability of BPD or death risk | Standard Deviation 20.2 |
| Total | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 4 | 48.2 percent probability of BPD or death risk | Standard Deviation 25 |
| Total | Moderate-Severe BPD or Death Risk Throughout Weekly Treatment | Week 1 | 61.4 percent probability of BPD or death risk | Standard Deviation 20.3 |
Secondary
Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined
Moderate-severe BPD or death risk was defined using the NICHD Neonatal Research Network BPD outcome estimator.
Time frame: 36 weeks postmenstrual age
Population: Data are reported for the safety population. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Furosemide Cohort 1 | Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined | 17 Participants |
| Placebo Cohort 1 | Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined | 22 Participants |
| Furosemide Cohort 2 | Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined | 6 Participants |
| Placebo Cohort 2 | Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined | 6 Participants |
Secondary
Volume of Distribution
Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.
Time frame: After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration.
Population: Data was collected from the Furosemide Cohort 1 and Cohort 2 and combined. In total, 39 active drug recipients participated in the population PK.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Furosemide Cohort 1 | Volume of Distribution | 236.7 mL |
| Placebo Cohort 1 | Volume of Distribution | 242.8 mL |
| Furosemide Cohort 2 | Volume of Distribution | 242.8 mL |