Safety of Sildenafil in Premature Infants

Study Overview
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Brief Summary
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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 OOPD.

Detailed Description
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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.

Official Title
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Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

Conditions
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Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Sildenafil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 AST > 225 U/L < 72 hours prior to randomization ALT > 150 U/L < 72 hours prior to randomization

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 28 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil cohort 1<br>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<br>* Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.<br>* Other names: Revatio;|
| Placebo Comparator: Placebo cohort 1<br>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<br>* 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).<br>* Other names: sugar water;|
| Experimental: Sildenafil cohort 2<br>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<br>* Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.<br>* Other names: Revatio;|
| Placebo Comparator: Placebo cohort 2<br>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<br>* 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).<br>* Other names: sugar water;|
| Experimental: Sildenafil cohort 3<br>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<br>* Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.<br>* Other names: Revatio;|
| Placebo Comparator: Placebo cohort 3<br>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<br>* 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).<br>* Other names: sugar water;|

What is the study measuring?
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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 at risk of BDP. Safety will be assessed following initial study-specific procedure e.g., screening blood draws, dosing through 14 days post last study dose and it will be assessed by frequency and incidence of adverse events and serious adverse events. | 42 days for each participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volume of Distribution | Volume of distribution [ Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2, 2-3, 3-4, 4-5, within 15 min prior to next dose, and 16-24 hrs. after last dose.] | Samples collected after any dose following completion of 14 days of study drug administration. | 
| Clearance | Clearance [ Time Frame:8hr dosing: time frame: 0-15 min, 30-60 min, 1-2, 2-3, 3-4, 4-5, within 15 min prior to next dose, and 16-24 hrs. after last dose.] | Samples collected after any dose following completion of 14 days of study drug administration. | 
| Half-Life | Half-life [ Time Frame: 8hr. dosing: time frame: 0-15 min, 30-60 min, 1-2, 2-3, 3-4, 4-5, within 15 min prior to next dose, and 16-24 hrs. after last dose. | Samples collected after any dose following completion of 14 days of study drug administration. | 
| Area Under the Curve (AUC) | Area under the plasma concentration versus time curve (AUC) of sildenafil. [Time Frame: 8hr. dosing: time frame: 0-15 min, 30-60 min, 1-2, 2-3, 3-4, 4-5, within 15 min prior to next dose, and 16-24 hrs. after last dose.] | Samples collected after any dose following completion of 14 days of study drug administration. | 
| Peak Plasma Concentration | Maximum concentration Peak Plasma Concentration (Cmax) of sildenafil [Time Frame: 8hr. dosing: time frame: 0-15 min, 30-60 min, 1-2, 2-3, 3-4, 4-5, within 15 min prior to next dose, and 16-24 hrs. after last dose.] | Samples collected after any dose following completion of 14 days of study drug administration. | 
| Change in moderate-severe BPD or death risk from baseline | Moderate-severe BPD or death risk will be defined by the NICHD Neonatal Research Network BPD outcome estimator. https://neonatal.rti.org/ The BPD outcome estimator uses the following information to provide individual risk of BPD: Gestational age (weeks) Birth weight (g) Sex Maternal Race/Ethnicity Postnatal day Ventilation type (on the postnatal day of interest) FiO2 (%) (on the postnatal day of interest) | 36 weeks postmenstrual age |