Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

Phase II Trial of Sildenafil in Newborns With Persistent Pulmonary Hypertension

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.

Study Overview

• Status: Terminated
• Conditions: Respiratory Failure; Persistent Pulmonary Hypertension
• Intervention / Treatment: Drug: Intravenous Sildenafil; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Sciences Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60614
      • Anne and Robert H Lurie Children's Hospital of Chicago
  • New York
    • Buffalo, New York, United States, 14222
      • Women's & Children's Hospital of Buffalo SUNY
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center, Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous Sildenafil	Drug: 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.; Other Names: Revatio
Placebo Comparator: 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.	Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Oxygenation		From baseline values at 4 and 24 hours
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	7-day treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Arterial Pressure	Change in pulmonary arterial pressure as calculated by echocardiography	Baseline and 4 hours post study drug administration
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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham; Vanderbilt University; Ann & Robert H Lurie Children's Hospital of Chicago; University of Utah; State University of New York at Buffalo
• Investigators: Principal Investigator: John Kinsella, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: July 15, 2011
• First Submitted That Met QC Criteria: August 2, 2011
• First Posted (Estimate): August 3, 2011

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: January 30, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: treatment; respiratory failure; pulmonary hypertension; newborns
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Hypertension; Respiratory Insufficiency; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 10-1211; 1U01HL102235 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No