Persistent Pulmonary Hypertension, Respiratory Failure
Conditions
Keywords
newborns, respiratory failure, pulmonary hypertension, treatment
Brief summary
The purpose of this study is to determine whether intravenous sildenafil reduces pulmonary artery pressure and improves oxygenation in near-term and term infants with persistent pulmonary hypertension.
Detailed description
Term infants with respiratory failure and persistent pulmonary hypertension (PPHN) are among the most critically ill infants in the NICU, with significant mortality and morbidity reported even for infants with moderate disease. Currently, management is largely supportive, and includes oxygen, mechanical ventilation (conventional or high frequency ventilation), and exogenous surfactant therapy. Inhaled nitric oxide (iNO) is a pulmonary vasodilator that was approved for the treatment of hypoxic respiratory failure (HRF) and PPHN of the newborn in 1999 based on clinical trials showing a reduction in the need for rescue treatment with extracorporeal membrane oxygenation (ECMO). One promising therapy to decrease pulmonary arterial pressure and improve oxygenation is sildenafil. Sildenafil is a cGMP-specific phosphodiesterase inhibitor that causes relatively selective pulmonary vasodilation. The use of intravenous (IV) sildenafil was recently FDA approved for use in adults in PPHN. A pilot trial studying dose response and pharmacokinetics in 36 term newborns with PPHN found that IV sildenafil was well tolerated and has the potential to induce marked improvements in oxygenation. The data from this pilot trial provided background to support the dosing regimen for this Phase II trial. We hypothesize that IV sildenafil will acutely reduce pulmonary artery pressure and improve oxygenation in near-term and term infants with PPHN, thus reducing the need for rescue therapy iNO and/or ECMO.
Interventions
DRUGIntravenous Sildenafil
0.4 mg/kg bolus, followed by a continuous infusion of 1.6 mg/kg/day or an equivalent volume of placebo (D5W); infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days.
OTHERPlacebo
An equivalent volume of placebo (D5W)infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
State University of New York at Buffalo
Vanderbilt University
Ann & Robert H Lurie Children's Hospital of Chicago
University of Utah
University of Alabama at Birmingham
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 72 Hours
Healthy volunteers
No
Inclusion criteria
* Signed informed consent from legally acceptable guardian * PPHN or hypoxemic respiratory failure associated with: * Idiopathic PPHN * Meconium aspiration syndrome * Respiratory distress syndrome * Sepsis * Pneumonia * Greater than or equal to 35 weeks gestation * Age at enrollment less than 72 hours * Moderate hypoxemic respiratory failure, with 12\<OI\<35 (oxygenation index, calculated as FiO2 \* mean airway pressure \* 100 / postductal PaO2) * Absence of structural heart disease (except patent ductus arteriosus, atrial septal defect \<1cm, or muscular ventricular septal defect \< 2mm) * Absence of lethal congenital anomaly * Not participating in another concurrent experimental study
Exclusion criteria
* Prior or immediate need for iNO or ECMO * Profound hypoxemia: qualifying PaO2 \<30 mmHg, from a blood gas drawn within 30 minutes of starting study drug infusion. * Hypotension: Mean arterial pressure \<35 mmHg * Congenital heart disease, except patent ductus arteriosus, atrial septal defect \<1cm, or muscular ventricular septal defect \<2mm * Congenital diaphragmatic hernia or lung hypoplasia syndromes, diagnosed on the basis of prolonged oligohydramnios * Active seizures * Apgar score of \<3 at 5 minutes * Bleeding diathesis * Receipt of any other experimental drug or device * Receipt of any prohibited concurrent medication: * Potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole and protease inhibitors) * Endothelin antagonists (e.g. Tracleer/bosentan) * Intravenous nitrates or nitric oxide donors * Known hereditary degenerative retinal disorders such as retinitis pigmentosa. * In the opinion of the investigator, a subject who is not likely to complete the study or would be considered inappropriate for the study, for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Oxygenation | From baseline values at 4 and 24 hours | — |
| Receipt of Standard Therapy at Any Point During the 7-day Treatment Period | 7-day treatment period | Receipt of standard therapy (inhaled nitric oxide \[iNO\] and/or extracorporeal membrane oxygenation \[ECMO\]) at any point during the 7-day treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Arterial Pressure | Baseline and 4 hours post study drug administration | Change in pulmonary arterial pressure as calculated by echocardiography |
| Duration of Supplemental O2 | Participants will be on supplemental O2 an average of 2 weeks | — |
| Age at Hospital Discharge | Participants will be followed for the duration of hospital stay, an expected average of 3 weeks | — |
| Duration of Mechanical Ventilation | Participants will be on mechanical ventilation an average of 1 week | — |
Countries
United States
Participant flow
Recruitment details
This trial was terminated early due to lack of recruitment.
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Sildenafil Intravenous Sildenafil: 0.4 mg/kg bolus, followed by a continuous infusion of 1.6 mg/kg/day or an equivalent volume of placebo (D5W); infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days. | 1 |
| Placebo 0.4 mg/kg bolus, followed by a continuous infusion of 1.6 mg/kg/day or an equivalent volume of placebo (D5W); infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days.
Placebo: An equivalent volume of placebo (D5W)infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days. | 2 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | transferred to other hosp | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Intravenous Sildenafil | Placebo |
|---|---|---|---|
| Age, Customized <=1 days old | 3 participants | 1 participants | 2 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 0 / 1 | 0 / 2 |
| serious Total, serious adverse events | 0 / 1 | 1 / 2 |
Outcome results
Primary
Improvement in Oxygenation
Time frame: From baseline values at 4 and 24 hours
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.
Primary
Receipt of Standard Therapy at Any Point During the 7-day Treatment Period
Receipt of standard therapy (inhaled nitric oxide \[iNO\] and/or extracorporeal membrane oxygenation \[ECMO\]) at any point during the 7-day treatment period
Time frame: 7-day treatment period
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.
Secondary
Age at Hospital Discharge
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.
Secondary
Change in Pulmonary Arterial Pressure
Change in pulmonary arterial pressure as calculated by echocardiography
Time frame: Baseline and 4 hours post study drug administration
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.
Secondary
Duration of Mechanical Ventilation
Time frame: Participants will be on mechanical ventilation an average of 1 week
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.
Secondary
Duration of Supplemental O2
Time frame: Participants will be on supplemental O2 an average of 2 weeks
Population: This trial was terminated early due to lack of recruitment. No participants completed the study. Data required to assess this outcome measure was not collected.