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

Primary Purpose

Bronchopulmonary Dysplasia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Furosemide Cohort 1
Furosemide Cohort 2
Furosemide Cohort 3
Placebo
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Bronchopulmonary Dysplasia

Eligibility Criteria

7 Days - 28 Days (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Arkansas Children's Hospital/University of Arkansas for Medical Sciences
  • Loma Linda University Medical Center
  • University of Florida Jacskonville Shands Medical Center
  • Wolfson Children's Hospital
  • John's Hopkins Al Children's Hospital
  • South Miami Hospital
  • University of Illinois at Chicago
  • Wesley Medical Center
  • University of Kentucky Medical Center
  • Floating Hospital for Children at Tufts Medical Center
  • UMass Memorial Medical Center
  • University of Michigan Medical Center
  • Children's Mercy Hospital and Clinics
  • University Medical Center of Southern Nevada
  • The University of North Carolina at Chapel Hill/North Carolina Children's Hospital
  • New Hanover Regional Medical Center
  • MetroHealth Medical Center
  • Nationwide Children's Hospital/The Ohio State University
  • University of Oklahoma Health Sciences Center
  • Virginia Commonwealth University
  • West Virginia University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Placebo Comparator

Experimental

Experimental

Placebo Comparator

Placebo Comparator

Arm Label

Furosemide Cohort 1

Placebo Cohort 1

Furosemide Cohort 2

Furosemide Cohort 3

Placebo Cohort 2

Placebo Cohort 3

Arm Description

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.

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).

Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days.

Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days.

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).

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
August 4, 2015
Last Updated
November 29, 2021
Sponsor
University of North Carolina, Chapel Hill
Collaborators
Duke University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), The Emmes Company, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02527798
Brief Title
Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia (BPD)
Official Title
Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
November 27, 2015 (Actual)
Primary Completion Date
October 15, 2019 (Actual)
Study Completion Date
October 15, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
Duke University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), The Emmes Company, LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchopulmonary Dysplasia

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
82 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Furosemide Cohort 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo Cohort 1
Arm Type
Placebo Comparator
Arm Description
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).
Arm Title
Furosemide Cohort 2
Arm Type
Experimental
Arm Description
Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days.
Arm Title
Furosemide Cohort 3
Arm Type
Experimental
Arm Description
Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days.
Arm Title
Placebo Cohort 2
Arm Type
Placebo Comparator
Arm Description
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).
Arm Title
Placebo Cohort 3
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Furosemide Cohort 1
Other Intervention Name(s)
Lasix
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Furosemide Cohort 2
Other Intervention Name(s)
Lasix
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Furosemide Cohort 3
Other Intervention Name(s)
Lasix
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
sugar water
Intervention Description
Sugar water will be administered in a equivalent volume as drug intervention.
Primary Outcome Measure Information:
Title
Safety as Determined by Adverse Events
Description
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
Secondary Outcome Measure Information:
Title
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment
Description
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
Title
Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined
Description
Moderate-severe BPD or death risk was defined using the NICHD Neonatal Research Network BPD outcome estimator.
Time Frame
36 weeks postmenstrual age
Title
Clearance
Description
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.
Title
Volume of Distribution
Description
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.
Title
Half-life
Description
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.
Title
Area Under the Plasma Concentration Versus Time Curve
Description
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Days
Maximum Age & Unit of Time
28 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew Laughon, MD, MPH
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jason E Lang, MD, MPH
Organizational Affiliation
Duke University
Official's Role
Study Chair
Facility Information:
Facility Name
Arkansas Children's Hospital/University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Loma Linda University Medical Center
City
Loma Linda
State/Province
California
ZIP/Postal Code
92354
Country
United States
Facility Name
University of Florida Jacskonville Shands Medical Center
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Wolfson Children's Hospital
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
John's Hopkins Al Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
South Miami Hospital
City
South Miami
State/Province
Florida
ZIP/Postal Code
33143
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Wesley Medical Center
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67214
Country
United States
Facility Name
University of Kentucky Medical Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Floating Hospital for Children at Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
UMass Memorial Medical Center
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01605
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-4225
Country
United States
Facility Name
Children's Mercy Hospital and Clinics
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
University Medical Center of Southern Nevada
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89102
Country
United States
Facility Name
The University of North Carolina at Chapel Hill/North Carolina Children's Hospital
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7596
Country
United States
Facility Name
New Hanover Regional Medical Center
City
Wilmington
State/Province
North Carolina
ZIP/Postal Code
28403
Country
United States
Facility Name
MetroHealth Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Nationwide Children's Hospital/The Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
West Virginia University
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States

12. IPD Sharing Statement

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

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