Study To Investigate Safety And Efficacy Of Sildenafil In The Newborns With Persistent Pulmonary Hypertension (PPHN)

Study Overview
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Brief Summary
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Sildenafil is efficacious in newborns with persistent pulmonary hypertension and its use will reduce the need for inhaled nitric oxide.

Detailed Description
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Letter to investigator dated 18 June 2012 that study was to be terminated. Study terminated due to evolved and widespread use of standard of care, relevance of study questioned. No safety reasons or issues.

Official Title
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A Single Arm Single Centre Study To Investigate Safety And Efficacy Of Sildenafil In Near Term And Term Newborns With Persistent Pulmonary Hypertension Of The Newborn (PPHN)

Conditions
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PPHN, Persistent Pulmonary Hypertension of the Newborn, Hypoxic Respiratory Failure

Intervention / Treatment
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* Drug: sildanefil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 72 hours of age; and > or = to 34 weeks gestational age. Persistent Pulmonary Hypertension of the Newborn or Hypoxic respiratory failure associated with: Idiopathic PPHN or Meconium aspiration syndrome or Sepsis or Pneumonia Oxygenation Index (OI) >15 and <60 calculated Exclusion Criteria: Patients already receiving inhaled nitric oxide (iNO) on referral. Prior or immediate need for full Cardio Pulmonary Resuscitation or Extracorporeal Membrane Oxygenation (ECMO). Life threatening or lethal congenital anomaly. Large left to right intracardiac or ductal shunting (diagnosed from echocardiogram on admission to GOSH). Clinically significant active seizures as per clinical judgment. Bleeding diathesis as per clinical judgment

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 72 Hours

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: one<br> | Drug: sildanefil<br>* Intravenous sildenafil citrate will be administered as a loading dose of 0.1 mg/kg given over 30 minutes. This will be followed by a maintenance treatment consisting of an intravenous infusion of 0.03 mg/kg/hr. The duration of the infusion will be determined by the need of the individual patient, but will be reviewed at Day 7 if still ongoing, and will not continue past Day 14.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Requiring Inhaled Nitric Oxide (iNO) or Extracorporeal Membrane Oxygenation (ECMO) | Percentage of participants who required standard therapy (iNO or ECMO) after failure of study treatment. | From start of infusion (baseline) up to Day 14 | 
| Number of Participants With Adverse Events (AEs) Based on Severity | AE:any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE:AE resulting in any of following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience; persistent/significant disability/incapacity; congenital anomaly. Severity criteria: mild=does not interfere with participant's usual function; moderate=interferes to some extent with participant's usual function and severe=interferes significantly with participant's usual function. | Baseline up to 28 days after last dose | 
| Number of Participants With Abnormal Laboratory Data | Criteria for potentially clinically significant (PCS) laboratory values: hematocrit 29.2 percent (%); white blood cell (WBC) count 5.0*10^3, lymphocyte absolute 0.88*10^3, total neutrophils absolute 12.07*10^3, eosinophils absolute 0.50*10^3 per cubic millimeter (/mm^3); calcium 6.8 milligram/deciliter (mg/dL); venous bicarbonate 47.0 milliequivalent/liter (meq/L). | Screening, once daily for 3 days, every 48 hours thereafter till the end of infusion (up to Day 14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Oxygenation Index at Hour 6 and 12 | Oxygenation Index (OI) was calculated as the product of fraction of inspired oxygen (FiO2) and Mean Airway Pressure divided by partial pressure of oxygen in arterial blood [(FiO2*Mean Airway Pressure)/PaO2] measured in centimeter of water/millimeter of mercury (cmH2O/mmHg). FiO2 is the measure of oxygen concentration that is breathed. Mean airway pressure is defined as an average of the airway pressure throughout the respiratory cycle. PaO2 is the measure of oxygen level in the arterial blood. | Baseline, Hour 6, 12 | 
| Change From Baseline in Differential Saturation (Pre- And Post-ductal) at Hour 6 and 12 | Differential oxygenation saturation between preductal and postductal sites as measured by pulse oximetry. A difference of greater than (>) 5 percent (%) to 10% in saturation indicates right-to-left shunt through the ductus arteriosus. Oxygenation saturation is measured as percentage of hemoglobin binding sites occupied by oxygen in the blood. | Baseline, Hour 6, 12 | 
| Change From Baseline in Ratio of Partial Pressure of Oxygen in Arterial Blood to the Fraction of Inspired Oxygen (P/F) at Hour 6 and 12 | The ratio of partial pressure of arterial oxygen and fraction of inspired oxygen is a comparison between the oxygen level in the arterial blood and the oxygen concentration that is breathed. It helps to determine the degree of any problems with how the lungs transfer oxygen to the blood. | Baseline, Hour 6, 12 | 
| Duration of Mechanical Ventilation | The number of days from the start to the stop of mechanical ventilation, if multiple ventilations occurred during the follow-up, the sum of the duration of each ventilation was used for analyses. Mechanical ventilation was defined as use of mechanical assistance or replacement of spontaneous breathing. | Baseline up to 28 days after last dose | 
| Time to Receipt of Standard Therapy (Inhaled Nitric Oxide [iNO] or Extracorporeal Membrane Oxygenation [ECMO]) | Time from start of treatment up to introduction of standard therapy. If participants did not receive standard therapy within 14 days after initiation of the study treatment, then Day 14 was the censoring time. | Baseline up to 28 days after last dose | 
| Population Pharmacokinetics of Sildenafil | Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Pre-dose, 5 and 30 minutes post-loading infusion, within 48 to 72, 96 to 120 hours during infusion, within 4 to 8, 18 to 24 and 44 to 48 hours post-maintenance infusion | 
| Maximum Observed Plasma Concentration (Cmax) of Sildenafil Metabolite (UK-103320) |  | Pre-dose, 5 and 30 minutes post-loading infusion, within 48 to 72, 96 to 120 hours during infusion, within 4 to 8, 18 to 24 and 44 to 48 hours post-maintenance infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PPHN, neonates, sildanefil IV