Chronic Sildenafil for Severe Diaphragmatic Hernia

The purpose of this study is to test if sildenafil is effective in the treatment of infants with severe congenital diaphragmatic hernia (determined by the presence of prolonged pulmonary hypertension or prolonged oxygen supplementation on mechanical ventilation), as measured by the estimated pulmonary artery systolic pressure following treatment.

Study Overview

• Status: Terminated
• Conditions: Hernia, Diaphragmatic; Hypertension, Pulmonary; Hypoplasia, Pulmonary
• Intervention / Treatment: Drug: sildenafil; Drug: Placebo

Detailed Description

Congenital diaphragmatic hernia (CDH) is a condition characterized by pulmonary parenchymal and vascular hypoplasia. Severe CDH carries a high rate of mortality, and significant morbidity among survivors. This proposal is a randomized, blinded, placebo-controlled study designed to evaluate the efficacy and potential mechanisms of activity of sildenafil, a phosphodiesterase-5 inhibitor, for treatment of severe CDH. Infants who meet criteria at ≥10d of age predicting a poor outcome [death or chronic lung disease (CLD) severe enough to require hospital discharge on supplemental oxygen (O2)] will be eligible for the study. Infants whose parents consent for the study will undergo an initial echocardiogram to assess the degree of pulmonary hypertension. They will then begin either sildenafil or placebo therapy for a 45d course. A final echocardiogram will be performed after the experimental drug course is completed. The pulmonary arterial systolic pressure estimate during hyperoxic conditions will be compared between the sildenafil and placebo groups. Infants from either group who have severely elevated pulmonary arterial pressure (despite supplemental O2) will be considered for open-label sildenafil, which will continue after hospital discharge, depending on the results of a cardiac catheterization performed for clinical care.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • San Francisco, California, United States, 94143
      • University of California San Francisco Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Congenital diaphragmatic hernia
• 10-42 days (d) of age
• Significant illness severity as demonstrated by:

• Receiving assisted ventilation and

  • FiO2 >= 0.40 at 10-14d of age, or
  • FiO2 >= 0.40 for >=48hours at 15-27d of age, or
  • FiO2 >= 0.35 at 28-42d of age
• Or, need for extracorporeal support at >=10d of age
• Or, estimated pulmonary arterial or right ventricular systolic pressure of >= 2/3 systemic pressure at 14-42d of age

Exclusion Criteria:

• Structural congenital heart disease (other than patent ductus arteriosus or patent foramen ovale/atrial septal defect [ASD] or non-hemodynamically significant ventricular septal defect [VSD])

• Sildenafil contraindicated (until condition resolves):

  • Unable to absorb oral medication, or
  • Unstable systemic blood pressure, or
  • Receiving a drug that may interfere with sildenafil metabolism, or
  • Renal insufficiency
  • Hepatic insufficiency Previous use of sildenafil

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Sildenafil x 45 days	Drug: sildenafil; Sildenafil 0.5 mg/kg every 6 hours orally x 45 d; Other Names: Viagra, Revatio
Placebo Comparator: 2; Placebo x 45 d	Drug: Placebo; Placebo suspension (equal volume to experimental drug) x 45 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Estimated Systolic Pulmonary Arterial Pressure at Final Echocardiogram	7 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Systemic Levels of Vasoactive Substances at the Time of Final Echocardiogram	7 weeks
Adverse Effects of Sildenafil Therapy	2 years
Somatic Growth at 1 and 2 Years of Age	2 years
Neurodevelopmental Outcome at 1 and 2 Years of Age	2 years
Respiratory Status at 1 and 2 Years of Age	2 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Ann & Robert H Lurie Children's Hospital of Chicago; Children's Hospital Los Angeles
• Investigators: Principal Investigator: Roberta L Keller, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 22, 2005
• First Submitted That Met QC Criteria: August 22, 2005
• First Posted (Estimate): August 23, 2005

Study Record Updates

• Last Update Posted (Actual): January 13, 2021
• Last Update Submitted That Met QC Criteria: January 12, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Nitric oxide; Chronic lung disease; cyclic guanosine monophosphate; phosphodiesterase inhibitor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Pathological Conditions, Anatomical; Internal Hernia; Hypertension; Hernia; Hypertension, Pulmonary; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: K23HL079922-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No