Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants

NCT02620761 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: DK113073-01A1
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (17)

• 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.

  66 hrs - from 6 hrs before beginning of fenoldopam or placebo infusion up to 24 hours after the last dose of indomethacin

• 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.

  60 hours

• 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

  48 hrs

• 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

  48 hours

• 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

  60 hours

• 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

  60 hours

• 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

  48 hrs

• 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

  48 hrs

• 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

  48 hrs

• 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

  48 hrs

• 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

  48 hrs

• 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

  48 hr

• 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

  48 hrs

• 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

  48 hr

• 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

  48 hr

• 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

  48 hrs

• 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

  48 hrs

Study Arms (2)

Control

PLACEBO COMPARATOR

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.

Drug: 0.9%NS

Fenoldopam

EXPERIMENTAL

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.

Drug: Fenoldopam

Interventions

Fenoldopam DRUG

Randomized to receive Fenoldopam or 0.9%NS

Fenoldopam

0.9%NS DRUG

Randomized to receive Fenoldopam or 0.9%NS

Also known as: normal saline

Control

Eligibility Criteria

• Age: 0 Days - 28 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (1)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Related Publications (1)

• Esezobor CI, Bhatt GC, Effa EE, Hodson EM. Fenoldopam for preventing and treating acute kidney injury. Cochrane Database Syst Rev. 2024 Nov 28;11(11):CD012905. doi: 10.1002/14651858.CD012905.pub2.

  PMID: 39607014 DERIVED

MeSH Terms

Conditions

Ductus Arteriosus, Patent; Acute Kidney Injury

Interventions

Fenoldopam; Saline Solution

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Jeffrey Segar
• Organization: Medical College of Wisconsin

jsegar@mcw.edu

14143377702

Study Officials

• Jeffrey Segar, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: October 27, 2015
• First Posted: December 3, 2015
• Study Start: February 6, 2019
• Primary Completion: January 31, 2020
• Study Completion: January 31, 2020
• Last Updated: September 16, 2022
• Results First Posted: September 16, 2022

Record last verified: 2022-08

Locations

US (1)