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Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

Primary Purpose

Persistent Pulmonary Hypertension, Respiratory Failure

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Intravenous Sildenafil
Placebo
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Persistent Pulmonary Hypertension focused on measuring newborns, respiratory failure, pulmonary hypertension, treatment

Eligibility Criteria

undefined - 72 Hours (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Colorado Health Sciences Center
  • Northwestern Memorial Hospital
  • Anne and Robert H Lurie Children's Hospital of Chicago
  • Women's & Children's Hospital of Buffalo SUNY
  • Vanderbilt University
  • Primary Children's Medical Center, Utah
  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Intravenous Sildenafil

Placebo

Arm Description

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.

Outcomes

Primary Outcome Measures

Improvement in Oxygenation
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

Secondary Outcome Measures

Change in Pulmonary Arterial Pressure
Change in pulmonary arterial pressure as calculated by echocardiography
Duration of Supplemental O2
Age at Hospital Discharge
Duration of Mechanical Ventilation

Full Information

First Posted
July 15, 2011
Last Updated
January 30, 2019
Sponsor
University of Colorado, Denver
Collaborators
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
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1. Study Identification

Unique Protocol Identification Number
NCT01409031
Brief Title
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

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Terminated
Why Stopped
This trial was terminated early due to lack of recruitment.
Study Start Date
July 2011 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Persistent Pulmonary Hypertension, Respiratory Failure
Keywords
newborns, respiratory failure, pulmonary hypertension, treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intravenous Sildenafil
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Intravenous Sildenafil
Other Intervention Name(s)
Revatio
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
Improvement in Oxygenation
Time Frame
From baseline values at 4 and 24 hours
Title
Receipt of Standard Therapy at Any Point During the 7-day Treatment Period
Description
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
Secondary Outcome Measure Information:
Title
Change in Pulmonary Arterial Pressure
Description
Change in pulmonary arterial pressure as calculated by echocardiography
Time Frame
Baseline and 4 hours post study drug administration
Title
Duration of Supplemental O2
Time Frame
Participants will be on supplemental O2 an average of 2 weeks
Title
Age at Hospital Discharge
Time Frame
Participants will be followed for the duration of hospital stay, an expected average of 3 weeks
Title
Duration of Mechanical Ventilation
Time Frame
Participants will be on mechanical ventilation an average of 1 week

10. Eligibility

Sex
All
Maximum Age & Unit of Time
72 Hours
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Kinsella, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Health Sciences Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Anne and Robert H Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Women's & Children's Hospital of Buffalo SUNY
City
Buffalo
State/Province
New York
ZIP/Postal Code
14222
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Primary Children's Medical Center, Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

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Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

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