Clinical trial NCT02620761: Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants
Official title: Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Patent Ductus Arteriosus (PDA)
Acute Kidney Injury (AKI)
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2015-12-03
Enrollment: 1
Sex: ALL
Minimum age (years): 0
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Urine Output (ml/kg/hr)
timeFrame: 66 hrs - from 6 hrs before beginning of fenoldopam or placebo infusion up to 24 hours after the last dose of indomethacin
measure: Serum Levels of Fenoldopam During Infusion of the Drug and Following Discontinuation of the Drug Will be Measured by Liquid Chromatography and Mass Spectroscopy.
timeFrame: 60 hours
measure: Change in Levels of Serum Albumin (mg/dl)
timeFrame: 48 hrs
measure: Changes in Serum Creatinine (mg/dl)
timeFrame: 48 hours
measure: Serum Levels of Fenoldopam Will be Related the Changes in Urine Volume
timeFrame: 60 hours
measure: Serum Levels of Fenoldopam Will be Related to Absolute and Relative Changes in Serum Creatinine
timeFrame: 60 hours
measure: Change in Levels of Serum Beta 2 Macroglobulin (mcg/ml)
timeFrame: 48 hrs
measure: Change in Levels of Serum Cystatin C (mcg/ml)
timeFrame: 48 hrs
measure: Change in Levels of Serum Epidermal Growth Factor (EGF) (ng/ml)
timeFrame: 48 hrs
measure: Change in Levels of Serum Osteopontin (ng/ml)
timeFrame: 48 hrs
measure: Change in Levels of Serum Uromodulin (mg/dl)
timeFrame: 48 hrs
measure: Change in Level of Urine Albumin (mg/dl)
timeFrame: 48 hr
measure: Change in Level of Urine Beta 2 Macroglobulin (mcg/ml)
timeFrame: 48 hrs
measure: Change in Level of Urine Cystatin C (mcg/ml)
timeFrame: 48 hr
measure: Change in Levels of Urine Epidermal Growth Factor (EGF) (ng/ml)
timeFrame: 48 hr
measure: Change in Levels of Urine Osteopontin (ng/ml)
timeFrame: 48 hrs
measure: Change in Levels of Urine Uromodulin (mg/dl)
timeFrame: 48 hrs
Secondary outcomes:
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
Study officials:
affiliation: University of Iowa
name: Jeffrey Segar, MD
role: PRINCIPAL_INVESTIGATOR
References: