Safety of Sildenafil in Premature Infants (SIL02)

Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

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).

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: Sildenafil; Other: Placebo

Detailed Description

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
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Health Sciences Centre Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacksonville Shands Medical Center
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine Jacksonville-Wolfson Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40356
      • University of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • Ochsner Baptist Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Children's Hospital of Nevada at UMC
  • New Jersey
    • Long Branch, New Jersey, United States, 07740
      • Monmouth Medical Center
  • New York
    • New Hyde Park, New York, United States, 11040
      • Cohen Children's Medical Center of NY
    • Rochester, New York, United States, 14642
      • Golisano Children's Hospital - University of Rochester Medical Center
  • North Carolina
    • Raleigh, North Carolina, United States, 27610
      • WakeMed Health and Hospitals
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 4 weeks (Child)
• Accepts Healthy Volunteers: No

Description

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 (inclusive) days postnatal age at time of randomization

Exclusion Criteria:

• Currently receiving vasopressors
• Currently receiving inhaled nitric oxide
• Baseline mean arterial pressure < gestational age (in weeks) plus postnatal age (in weeks) within 2 hours of sildenafil administration
• Known allergy to sildenafil
• Known sickle cell disease
• Aspartate Aminotransferase (AST) > 225 U/L < 72 hours prior to randomization
• Alanine Aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sildenafil cohort 1; Within cohort 1 infants will be randomized using a 3:1 scheme to receive sildenafil or placebo. Infants randomized to sildenafil will receive 0.125 mg/kg daily every 8 hours intravenously (IV), or 0.25 mg/kg daily every 8 hours enterally for 28 days.	Drug: Sildenafil; Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.; Other Names: Revatio
Placebo Comparator: Placebo cohort 1; Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.	Other: 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).; Other Names: sugar water
Experimental: Sildenafil cohort 2; Cohort 2 infants will receive sildenafil 0.5 mg/kg daily every 8 hours intravenously (IV) or 1 mg/kg daily every 8 hours enterally for 28 days.	Drug: Sildenafil; Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.; Other Names: Revatio
Placebo Comparator: Placebo cohort 2; Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.	Other: 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).; Other Names: sugar water
Experimental: Sildenafil cohort 3; Cohort 3 infants will receive sildenafil 1 mg/kg daily every 8 hours intravenously (IV) or 2 mg/kg daily every 8 hours enterally for 28 days.	Drug: Sildenafil; Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.; Other Names: Revatio
Placebo Comparator: Placebo cohort 3; Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.	Other: 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).; Other Names: sugar water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration.
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.	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.	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.	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.	From the first day of study drug administration to the end of study drug administration, up to 28 days

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Duke University; The Emmes Company, LLC
• Investigators: Principal Investigator: Matthew M Laughon, MD, MPH, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2018
• Primary Completion (Actual): March 1, 2025
• Study Completion (Actual): March 1, 2025

Study Registration Dates

• First Submitted: April 17, 2017
• First Submitted That Met QC Criteria: May 3, 2017
• First Posted (Actual): May 5, 2017

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Bronchopulmonary Dysplasia; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Purines; Sulfonamides; Sulfones; Piperazines; Sildenafil Citrate
• Other Study ID Numbers: 17-2436; R01FD006099-01 (U.S. FDA Grant/Contract); 75N94022F00001 (Other Grant/Funding Number: NICHD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No