Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

Phase 2

Terminated

• Conditions: Persistent Pulmonary Hypertension; Respiratory Failure
• Interventions: Drug: Intravenous Sildenafil; Other: Placebo

• Registration Number: NCT01409031
• Lead Sponsor: University of Colorado, Denver

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.

Study Timeline

• Study Start: 2011-07
• Study First Submitted: 2011-07-15
• Study First Submitted QC: 2011-08-02
• Study First Posted: 2011-08-03
• Primary Completion: 2013-10
• Study Completion: 2013-10
• Status Verified: 2019-01
• Results First Submitted: 2019-01-04
• Results First Submitted QC: 2019-01-30
• Last Update Submitted: 2019-01-30
• Results First Posted: 2019-02-01
• Last Update Posted: 2019-02-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 3

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intravenous Sildenafil	Intravenous Sildenafil	-
Placebo	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Duration of Supplemental O2	Participants will be on supplemental O2 an average of 2 weeks
Change in Pulmonary Arterial Pressure	Baseline and 4 hours post study drug administration	Change in pulmonary arterial pressure as calculated by echocardiography
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

Trial Locations

Locations (7)

Anne and Robert H Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

University of Colorado Health Sciences Center; 🇺🇸 Aurora, Colorado, United States

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Vanderbilt University; 🇺🇸 Nashville, Tennessee, United States

Women's & Children's Hospital of Buffalo SUNY; 🇺🇸 Buffalo, New York, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Primary Children's Medical Center, Utah; 🇺🇸 Salt Lake City, Utah, United States