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

Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia

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

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: Furosemide Cohort 1; Other: Placebo; Drug: Furosemide Cohort 2; Drug: Furosemide Cohort 3

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.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital/University of Arkansas for Medical Sciences
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacskonville Shands Medical Center
    • Jacksonville, Florida, United States, 32209
      • Wolfson Children's Hospital
    • Saint Petersburg, Florida, United States, 33701
      • John's Hopkins Al Children's Hospital
    • South Miami, Florida, United States, 33143
      • South Miami Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts Medical Center
    • Worcester, Massachusetts, United States, 01605
      • UMass Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-4225
      • University of Michigan Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital and Clinics
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7596
      • The University of North Carolina at Chapel Hill/North Carolina Children's Hospital
    • Wilmington, North Carolina, United States, 28403
      • New Hanover Regional Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital/The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 4 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: Lasix
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water
Experimental: 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.	Drug: 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.; Other Names: Lasix
Experimental: 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.	Drug: 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.; Other Names: Lasix
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Duke University; The Emmes Company, LLC
• Investigators: Principal Investigator: Matthew Laughon, MD, MPH, University of North Carolina, Chapel Hill; Study Chair: Jason E Lang, MD, MPH, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2015
• Primary Completion (Actual): October 15, 2019
• Study Completion (Actual): October 15, 2019

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: August 17, 2015
• First Posted (Estimate): August 19, 2015

Study Record Updates

• Last Update Posted (Actual): December 28, 2021
• Last Update Submitted That Met QC Criteria: November 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Furosemide
• Other Study ID Numbers: 15-1978; HHSN27500033 (Other Grant/Funding Number: National Institute of Child Health and Human Development (NICHD)); HHSN27500035 (Other Grant/Funding Number: NICHD); 5R01FD005101-02 (U.S. FDA Grant/Contract)