Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

This study has been terminated.
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01409031
First received: July 15, 2011
Last updated: December 9, 2014
Last verified: December 2014
  Purpose

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.


Condition Intervention Phase
Persistent Pulmonary Hypertension
Respiratory Failure
Drug: Intravenous Sildenafil
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase II Trial of Sildenafil in Newborns With Persistent Pulmonary Hypertension

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Improvement in oxygenation [ Time Frame: From baseline values at 4 and 24 hours ] [ Designated as safety issue: No ]
  • Receipt of standard therapy at any point during the 7-day treatment period [ Time Frame: 7-day treatment period ] [ Designated as safety issue: No ]
    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:
  • Change in pulmonary arterial pressure [ Time Frame: Baseline and 4 hours post study drug administration ] [ Designated as safety issue: No ]
    Change in pulmonary arterial pressure as calculated by echocardiography

  • Duration of supplemental O2 [ Time Frame: Participants will be on supplemental O2 an average of 2 weeks ] [ Designated as safety issue: No ]
  • Age at hospital discharge [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks ] [ Designated as safety issue: No ]
  • Duration of mechanical ventilation [ Time Frame: Participants will be on mechanical ventilation an average of 1 week ] [ Designated as safety issue: No ]

Enrollment: 4
Study Start Date: July 2011
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.

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

Ages Eligible for Study:   up to 72 Hours
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 •≥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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01409031

Locations
United States, Colorado
University of Colorado Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Illinois
Anne and Robert H Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60614
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611
United States, New York
Women's & Children's Hospital of Buffalo SUNY
Buffalo, New York, United States, 14222
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Utah
Primary Children's Medical Center, Utah
Salt Lake City, Utah, United States, 84113
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Colorado, Denver
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
Investigators
Principal Investigator: John Kinsella, MD University of Colorado, Denver
  More Information

No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01409031     History of Changes
Other Study ID Numbers: 10-1211, 1U01HL102235
Study First Received: July 15, 2011
Last Updated: December 9, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by University of Colorado, Denver:
newborns
respiratory failure
pulmonary hypertension
treatment

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Respiratory Insufficiency
Cardiovascular Diseases
Lung Diseases
Respiration Disorders
Respiratory Tract Diseases
Vascular Diseases
Sildenafil
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Therapeutic Uses
Urological Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on July 01, 2015