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Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants (Fenaki)

Primary Purpose

Patent Ductus Arteriosus (PDA), Acute Kidney Injury (AKI)

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fenoldopam
0.9%NS
Sponsored by
Medical College of Wisconsin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Patent Ductus Arteriosus (PDA)

Eligibility Criteria

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

Inclusion Criteria:

  1. Gestational age at birth 23 0/7 to 27 6/7 weeks by best obstetrical dating
  2. No previous exposure to indomethacin
  3. Clinical determination to use indomethacin to attempt closure of PDA
  4. No known congenital abnormalities involving the kidneys, heart or lungs
  5. No preexisting renal dysfunction, defined as serum creatinine > 1.0 mg/dl, or urine output <1.0 ml/kg/hour over the previous 24 hours.

Exclusion Criteria:

  1. Enrollment in concurrent study in which interventions may contribute confounding variables or have competing outcomes
  2. Infants with antenatally or postnatally diagnosed renal or urinary tract abnormalities
  3. Infants with umbilical cord or infant blood pH below 7.0 at any time before enrollment
  4. Attending physician unwilling to have infant participate in study
  5. Absence of informed consent

Sites / Locations

  • University of Iowa

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Control

Fenoldopam

Arm Description

Infants in the Placebo arm will receive 0.9% sodium chloride (0.1 ml/hr). If, after 6 hrs there is not a clinically concerning decrease in blood pressure, as determined by attending physician, the rate of infusion (in this arm the placebo) will be increased to 0.2 ml/kg/hr. This rate will be continued throughout the remainder of the study.

Infants in the experimental arm will receive fenoldopam (60 ug/ml; 0.1 ml/hr to provide 0.1ug/kg/min). If, after 6 hrs there is not a clinically concerning decrease in blood pressure, as determined by attending physician, the rate of infusion will be increased to 0.2 ml/kg/hr (0.2 ug/kg/min for infants receiving fenoldopam). This rate will be continued throughout the remainder of the study.

Outcomes

Primary Outcome Measures

Changes in Urine Output (ml/kg/hr)
Urine will be collected and measured in 6 hour increments beginning 6 hours prior to starting fenoldopam or placebo infusion. The first dose of indomethacin will be given 12 hours after starting fenoldopam or placebo. Two additional doses of indomethacin will be given 12 hours apart. Urine will continue to be collected and volume measured in 6 hour increments up to 24 hrs after the last dose of indomethacin. To summarize, urine will be collected and measured from time -6 hours to 0 hours. Fenoldapam or placebo will be initiated at time 0 hrs, indomethacin given at time 12, 24 and 36 hours, and urine collected and measured to time 60 hours.
Serum Levels of Fenoldopam During Infusion of the Drug and Following Discontinuation of the Drug Will be Measured by Liquid Chromatography and Mass Spectroscopy.
Blood samples for determination of serum fenoldopam levels will be obtained immediately prior to starting the infusion of fenoldopam (time 0 hour), continue through the 48 hour period of fenoldopam infusion and continue for an additional 12 hours after stopping the fenoldopam infusion.
Change in Levels of Serum Albumin (mg/dl)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Changes in Serum Creatinine (mg/dl)
Serum creatinine will be measured immediately prior to first dose of indomethacin, immediately prior to the third dose of indomethacin (24 hr later) and 24 hours after the third dose of indomethacin
Serum Levels of Fenoldopam Will be Related the Changes in Urine Volume
We will relate serum levels of fenoldopam to changes in urine volume over the duration of time of fenoldopam infusion and after discontinuation of infusion. This constitutes part of the pharmacodynamic analysis
Serum Levels of Fenoldopam Will be Related to Absolute and Relative Changes in Serum Creatinine
We will relate serum levels of fenoldopam to serum creatinine values over the duration of time of fenoldopam infusion and after discontinuation of infusion. This constitutes part of the pharmacodynamic analysis
Change in Levels of Serum Beta 2 Macroglobulin (mcg/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Serum Cystatin C (mcg/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Serum Epidermal Growth Factor (EGF) (ng/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Serum Osteopontin (ng/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Serum Uromodulin (mg/dl)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Level of Urine Albumin (mg/dl)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Level of Urine Beta 2 Macroglobulin (mcg/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Level of Urine Cystatin C (mcg/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Urine Epidermal Growth Factor (EGF) (ng/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Urine Osteopontin (ng/ml)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Change in Levels of Urine Uromodulin (mg/dl)
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period

Secondary Outcome Measures

Full Information

First Posted
October 27, 2015
Last Updated
August 22, 2022
Sponsor
Medical College of Wisconsin
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1. Study Identification

Unique Protocol Identification Number
NCT02620761
Brief Title
Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants
Acronym
Fenaki
Official Title
Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Terminated
Why Stopped
Inability to recruit patients
Study Start Date
February 6, 2019 (Actual)
Primary Completion Date
January 31, 2020 (Actual)
Study Completion Date
January 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical College of Wisconsin

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators will conduct a prospective, blinded, randomized, placebo-controlled trial with a sample size of 20 patients in each of the two arms (fenoldopam vs placebo) based upon a difference in serum creatinine by one standard deviation. Fluid and salt intake will be held constant within clinical parameters and carefully measured. Fenoldopam will be started at 0.1 ug/kg/min. If, after 6 hrs there is no decrease in blood pressure, the dose will be increased to 0.2 ug/kg/min. This dose will be continued throughout the remainder of the study. A study of pediatric patients previously provided to the FDA showed no hypotension at a dose of 0.2 ug/kg/min. Fenoldopam will be started 12 hrs before the first dose of indomethacin and discontinued 12 hrs after the 3rd dose of indomethacin. Study samples will include both blood and urine. The primary outcome will be a reduction in renal dysfunction, as determined by creatinine and urine output over the course of treatment. Additional outcomes will include determination of known and novel metabolomic urine markers of renal dysfunction.
Detailed Description
Hypotheses The investigators primary hypothesis is that fenoldopam reduces renal dysfunction associated with indomethacin administration for closure of patent ductus arteriosus in preterm infants. A secondary endpoint or measured outcome will be the determination of fenoldopam pharmacokinetics in the premature population. Lastly, the investigators hypothesize that urine and serum acute kidney injury (AKI) biomarkers will be superior to contemporary neonatal AKI definitions in their ability to identify renal injury. Specific Aims Evaluate the effect of fenoldopam on renal function in preterm infants administered indomethacin Determination of fenoldopam pharmacokinetic and pharmacodynamic profiles in preterm infants Define whether newly identified biomarkers of renal dysfunction are more sensitive markers of renal dysfunction following indomethacin than traditional markers including urine output and serum creatinine. Study design The study will be a prospective, blinded, randomized, placebo controlled trial. Fenoldopam will be started at 0.1 ug/kg/min. If, after 6 hrs there is no decrease in blood pressure, the dose will be increased to 0.2 ug/kg/min and continued throughout the remainder of the study. The previous study in pediatric patients showed no hypotension at a dose of 0.2 ug/kg/min. Fenoldopam will be started 12 hrs before the first dose of indomethacin and discontinued 12 hrs after the 3rd dose of indomethacin. Describe study population or sample material preterm infants born at less than or equal to 28 weeks gestation with patent ductus arteriosus in whom attempted medical closure with indomethacin is indicated as decided upon by the attending physician Sample size/power of primary endpoint Sample size is 20 patients in each of the two arms (fenoldopam vs placebo) based upon an improvement in serum creatinine by one standard deviation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patent Ductus Arteriosus (PDA), Acute Kidney Injury (AKI)

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
Infants in the Placebo arm will receive 0.9% sodium chloride (0.1 ml/hr). If, after 6 hrs there is not a clinically concerning decrease in blood pressure, as determined by attending physician, the rate of infusion (in this arm the placebo) will be increased to 0.2 ml/kg/hr. This rate will be continued throughout the remainder of the study.
Arm Title
Fenoldopam
Arm Type
Experimental
Arm Description
Infants in the experimental arm will receive fenoldopam (60 ug/ml; 0.1 ml/hr to provide 0.1ug/kg/min). If, after 6 hrs there is not a clinically concerning decrease in blood pressure, as determined by attending physician, the rate of infusion will be increased to 0.2 ml/kg/hr (0.2 ug/kg/min for infants receiving fenoldopam). This rate will be continued throughout the remainder of the study.
Intervention Type
Drug
Intervention Name(s)
Fenoldopam
Intervention Description
Randomized to receive Fenoldopam or 0.9%NS
Intervention Type
Drug
Intervention Name(s)
0.9%NS
Other Intervention Name(s)
normal saline
Intervention Description
Randomized to receive Fenoldopam or 0.9%NS
Primary Outcome Measure Information:
Title
Changes in Urine Output (ml/kg/hr)
Description
Urine will be collected and measured in 6 hour increments beginning 6 hours prior to starting fenoldopam or placebo infusion. The first dose of indomethacin will be given 12 hours after starting fenoldopam or placebo. Two additional doses of indomethacin will be given 12 hours apart. Urine will continue to be collected and volume measured in 6 hour increments up to 24 hrs after the last dose of indomethacin. To summarize, urine will be collected and measured from time -6 hours to 0 hours. Fenoldapam or placebo will be initiated at time 0 hrs, indomethacin given at time 12, 24 and 36 hours, and urine collected and measured to time 60 hours.
Time Frame
66 hrs - from 6 hrs before beginning of fenoldopam or placebo infusion up to 24 hours after the last dose of indomethacin
Title
Serum Levels of Fenoldopam During Infusion of the Drug and Following Discontinuation of the Drug Will be Measured by Liquid Chromatography and Mass Spectroscopy.
Description
Blood samples for determination of serum fenoldopam levels will be obtained immediately prior to starting the infusion of fenoldopam (time 0 hour), continue through the 48 hour period of fenoldopam infusion and continue for an additional 12 hours after stopping the fenoldopam infusion.
Time Frame
60 hours
Title
Change in Levels of Serum Albumin (mg/dl)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Changes in Serum Creatinine (mg/dl)
Description
Serum creatinine will be measured immediately prior to first dose of indomethacin, immediately prior to the third dose of indomethacin (24 hr later) and 24 hours after the third dose of indomethacin
Time Frame
48 hours
Title
Serum Levels of Fenoldopam Will be Related the Changes in Urine Volume
Description
We will relate serum levels of fenoldopam to changes in urine volume over the duration of time of fenoldopam infusion and after discontinuation of infusion. This constitutes part of the pharmacodynamic analysis
Time Frame
60 hours
Title
Serum Levels of Fenoldopam Will be Related to Absolute and Relative Changes in Serum Creatinine
Description
We will relate serum levels of fenoldopam to serum creatinine values over the duration of time of fenoldopam infusion and after discontinuation of infusion. This constitutes part of the pharmacodynamic analysis
Time Frame
60 hours
Title
Change in Levels of Serum Beta 2 Macroglobulin (mcg/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Levels of Serum Cystatin C (mcg/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Levels of Serum Epidermal Growth Factor (EGF) (ng/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Levels of Serum Osteopontin (ng/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Levels of Serum Uromodulin (mg/dl)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Level of Urine Albumin (mg/dl)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hr
Title
Change in Level of Urine Beta 2 Macroglobulin (mcg/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Level of Urine Cystatin C (mcg/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hr
Title
Change in Levels of Urine Epidermal Growth Factor (EGF) (ng/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hr
Title
Change in Levels of Urine Osteopontin (ng/ml)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs
Title
Change in Levels of Urine Uromodulin (mg/dl)
Description
Period from just prior to first dose of indomethacin (time point 12 hours) to 24 hours beyond last dose of indomethacin ( which is time point 60 hours). Thus, this aspect of study takes place between time point 12 hr and time point 60 hr, which is a 48 hour period
Time Frame
48 hrs

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Days
Maximum Age & Unit of Time
28 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Gestational age at birth 23 0/7 to 27 6/7 weeks by best obstetrical dating No previous exposure to indomethacin Clinical determination to use indomethacin to attempt closure of PDA No known congenital abnormalities involving the kidneys, heart or lungs No preexisting renal dysfunction, defined as serum creatinine > 1.0 mg/dl, or urine output <1.0 ml/kg/hour over the previous 24 hours. Exclusion Criteria: Enrollment in concurrent study in which interventions may contribute confounding variables or have competing outcomes Infants with antenatally or postnatally diagnosed renal or urinary tract abnormalities Infants with umbilical cord or infant blood pH below 7.0 at any time before enrollment Attending physician unwilling to have infant participate in study Absence of informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Segar, MD
Organizational Affiliation
University of Iowa
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States

12. IPD Sharing Statement

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Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants

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