Hypoxic Respiratory Failure, Persistent Pulmonary Hypertension of the Newborn, PPHN
Conditions
Keywords
PPHN, neonates, sildanefil IV
Brief summary
Sildenafil is efficacious in newborns with persistent pulmonary hypertension and its use will reduce the need for inhaled nitric oxide.
Detailed description
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.
Interventions
DRUGsildanefil
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.
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Hours to 72 Hours
Healthy volunteers
No
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: 1. Idiopathic PPHN or 2. Meconium aspiration syndrome or 3. Sepsis or 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Laboratory Data | Screening, once daily for 3 days, every 48 hours thereafter till the end of infusion (up to Day 14) | 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). |
| Percentage of Participants Requiring Inhaled Nitric Oxide (iNO) or Extracorporeal Membrane Oxygenation (ECMO) | From start of infusion (baseline) up to Day 14 | Percentage of participants who required standard therapy (iNO or ECMO) after failure of study treatment. |
| Number of Participants With Adverse Events (AEs) Based on Severity | Baseline up to 28 days after last dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Hour 6, 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. |
| Duration of Mechanical Ventilation | Baseline up to 28 days after last dose | 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. |
| Population Pharmacokinetics of Sildenafil | 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 | 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. |
| 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 | — |
| Time to Receipt of Standard Therapy (Inhaled Nitric Oxide [iNO] or Extracorporeal Membrane Oxygenation [ECMO]) | Baseline up to 28 days after last dose | 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. |
| Change From Baseline in Oxygenation Index at Hour 6 and 12 | Baseline, Hour 6, 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. |
| Change From Baseline in Differential Saturation (Pre- And Post-ductal) at Hour 6 and 12 | Baseline, Hour 6, 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Duration of Study Medication | Baseline up to Day 14 | The duration of the infusion was determined as per investigator's discretion up to Day 7 or Day 14. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Sildenafil citrate administered intravenously at a loading dose of 0.1 mg/kg over 30 minutes infusion followed by a maintenance dose of 0.03 mg/kg/hr intravenous infusion up to 14 days, based on the need of individual participant. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Did not meet entrance criteria | 1 |
Baseline characteristics
| Characteristic | Sildenafil |
|---|---|
| Age, Continuous | 1.5 days STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
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).
Time frame: Screening, once daily for 3 days, every 48 hours thereafter till the end of infusion (up to Day 14)
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Primary
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.
Time frame: Baseline up to 28 days after last dose
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Primary
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.
Time frame: From start of infusion (baseline) up to Day 14
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
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.
Time frame: Baseline, Hour 6, 12
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
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.
Time frame: Baseline, Hour 6, 12
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
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.
Time frame: Baseline, Hour 6, 12
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
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.
Time frame: Baseline up to 28 days after last dose
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
Maximum Observed Plasma Concentration (Cmax) of Sildenafil Metabolite (UK-103320)
Time frame: 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
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Secondary
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.
Time frame: 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
Secondary
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.
Time frame: Baseline up to 28 days after last dose
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.
Other Pre-specified
Duration of Study Medication
The duration of the infusion was determined as per investigator's discretion up to Day 7 or Day 14.
Time frame: Baseline up to Day 14
Population: Data for this pre-specified outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early study termination.