Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia (BPD)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia

Conditions
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Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Furosemide Cohort 1
* Drug: Furosemide Cohort 2
* Drug: Furosemide Cohort 3
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) < 29 weeks gestational age at birth 7-28 days postnatal age at time of first study dose Exclusion Criteria: Exposure to any diuretic ≤ 72 hours prior to first study dose Previous enrollment and dosing in current study, Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia Hemodynamically significant patent ductus arteriosus, as determined by the investigator Major congenital anomaly (e.g. congenital diaphragmatic hernia, congenital pulmonary adenomatoid malformation) Meconium aspiration syndrome Known allergy to any diuretic Serum creatinine >1.7 mg/dL < 24 hours prior to first study dose BUN >50 mg/dL < 24 hours prior to first study dose Na <125 mmol/L < 24 hours prior to first study dose K ≤2.5 mmol/L < 24 hours prior to first study dose Ca ≤ 6 mg/dL < 24 hours prior to first study dose Indirect bilirubin >10 mg/dL < 24 hours prior to first study dose Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 28 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Furosemide Cohort 1<br>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. | Drug: Furosemide Cohort 1<br>* 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.<br>* Other names: Lasix;|
| Placebo Comparator: Placebo Cohort 1<br>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). | Other: Placebo<br>* Sugar water will be administered in a equivalent volume as drug intervention.<br>* Other names: sugar water;|
| Experimental: Furosemide Cohort 2<br>Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. | Drug: Furosemide Cohort 2<br>* 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.<br>* Other names: Lasix;|
| Experimental: Furosemide Cohort 3<br>Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. | Drug: Furosemide Cohort 3<br>* 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.<br>* Other names: Lasix;|
| Placebo Comparator: Placebo Cohort 2<br>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). | Other: Placebo<br>* Sugar water will be administered in a equivalent volume as drug intervention.<br>* Other names: sugar water;|
| Placebo Comparator: Placebo Cohort 3<br>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). | Other: Placebo<br>* Sugar water will be administered in a equivalent volume as drug intervention.<br>* Other names: sugar water;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 35 days for each participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Risk measured weekly through Week 4 | 
| 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. | 36 weeks postmenstrual age | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. |