Describe the safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia and determine preliminary effectiveness and pharmacokinetics (PK) of sildenafil. Funding Source - FDA Office of Orphan Products Development (OOPD).
This will be a multi-center, randomized, placebo-controlled, sequential dose escalating, double masked, safety data study of sildenafil in premature infants. This is a Phase II study design, premature infants (inpatient in neonatal intensive care units) will be randomized in a dose escalating approach 3:1 (sildenafil: placebo) into 3 cohorts with escalating doses of sildenafil. There will be 40 randomized and dosed participants in each cohort for a total of up to 120 participants. Cohort 1 sildenafil dose will be 0.125 mg/kg q 8 hours IV or 0.25 mg/kg q 8 hours enteral. Cohort 2 sildenafil dose will be 0.5 mg/kg q 8 hours IV or 1.0 mg/kg q 8 hours enteral. Cohort 3 sildenafil dose will be 1 mg/kg q 8 hours IV or 2 mg/kg q 8 hours enteral.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
109
Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.
Infants randomized to the placebo group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug).
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
University of Florida College of Medicine Jacksonville-Wolfson Children's Hospital
Jacksonville, Florida, United States
Safety as Determined by Adverse Event Experienced by Participants
Description of safety of sildenafil in premature infants and assessed by frequency and incidence of adverse events (AEs) and serious adverse events. Both non-serious and serious adverse events were collected from the time of informed consent through Day 14 after the last study intervention. Serious adverse events were additionally collected through 28 days after the last study intervention. Retinopathy of prematurity (ROP), whether serious or non-serious, was collected through hospital discharge or transfer; hospitalization duration varied based on clinical course, the longest duration was up to 575 days.
Time frame: Nonserious AEs were collected through Day 14 post last intervention; SAEs through Day 28. Retinopathy of prematurity was assessed through discharge/transfer, up to 575 days after first treatment.
Volume of Distribution
Volume of distribution was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment.
Time frame: Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
Clearance
Clearance was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment.
Time frame: Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
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University of Florida Jacksonville Shands Medical Center
Jacksonville, Florida, United States
University of Illinois at Chicago
Chicago, Illinois, United States
Wesley Medical Center
Wichita, Kansas, United States
University of Kentucky
Lexington, Kentucky, United States
Ochsner Baptist Medical Center
New Orleans, Louisiana, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
Children's Hospital of Nevada at UMC
Las Vegas, Nevada, United States
Monmouth Medical Center
Long Branch, New Jersey, United States
...and 5 more locations
Half-Life
Half-life was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment.
Time frame: Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
Area Under the Curve (AUC)
Exposure, as measured by area under the plasma concentration-time curve (AUC), was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment.
Time frame: Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
Peak Plasma Concentration
Maximum plasma concentration (Cmax) was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment.
Time frame: Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
Change in Moderate-severe BPD or Death
Moderate-severe bronchopulmonary dysplasia (BPD) or death risk will be defined by the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) BPD outcome estimator. https://neonatal.rti.org/. The outcome measure is a reduction in moderate-severe BPD or death risk from day 1 of study drug to end of study drug administration. The BPD outcome estimator uses the following to calculate risk of BPD: Gestational age, Birth weight, Sex, Maternal Race/EthnicitylmPostnatal day, Ventilation type, Fraction of Inspired Oxygen The NICHD NRN BPD estimator calculates the risk of BPD (none, mild, moderate, severe) or death by postnatal day, as a percentage. For this protocol, outcomes will be dichotomized as none-mild vs. moderate-severe-death. Risk estimates will be recorded on days 7, 14, 21, and 28 of the study drug period, using the day closest to the participants postnatal age. For infants older than 28 days, the day 28 estimate will be applied.
Time frame: From the first day of study drug administration to the end of study drug administration, up to 28 days