Clinical trial NCT01409031: Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension
Official title: Phase II Trial of Sildenafil in Newborns With Persistent Pulmonary Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Persistent Pulmonary Hypertension
Respiratory Failure
Keywords: newborns
respiratory failure
pulmonary hypertension
treatment
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: State University of New York at Buffalo
name: Vanderbilt University
name: Ann & Robert H Lurie Children's Hospital of Chicago
name: University of Utah
name: University of Alabama at Birmingham
First posted: 2011-08-03
Enrollment: 3
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Improvement in Oxygenation
timeFrame: From baseline values at 4 and 24 hours
measure: Receipt of Standard Therapy at Any Point During the 7-day Treatment Period
timeFrame: 7-day treatment period
Secondary outcomes:
measure: Change in Pulmonary Arterial Pressure
timeFrame: Baseline and 4 hours post study drug administration
measure: Duration of Supplemental O2
timeFrame: Participants will be on supplemental O2 an average of 2 weeks
measure: Age at Hospital Discharge
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks
measure: Duration of Mechanical Ventilation
timeFrame: Participants will be on mechanical ventilation an average of 1 week
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Anne and Robert H Lurie Children's Hospital of Chicago
state: Illinois
city: Buffalo
country: United States
facility: Women's & Children's Hospital of Buffalo SUNY
state: New York
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center, Utah
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Colorado, Denver
name: John Kinsella, MD
role: PRINCIPAL_INVESTIGATOR
References: