Chronic Sildenafil for Severe Diaphragmatic Hernia

Official Title: “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.

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.

Intervention(s) in this Clinical Trial

• Drug: sildenafil
  • Sildenafil 0.5 mg/kg every 6 hours orally x 45 d
• Drug: Placebo
  • Placebo suspension (equal volume to experimental drug) x 45 days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Sildenafil x 45 days
• Placebo Comparator: 2
  • Placebo x 45 d

Primary Measures

• Estimated systolic pulmonary arterial pressure at final echocardiogram
  • Time Frame: 7 weeks
    Safety Issue?: No

Secondary Measures

• Systemic levels of vasoactive substances at the time of final echocardiogram
  • Time Frame: 7 weeks
    Safety Issue?: No
• Adverse effects of sildenafil therapy
  • Time Frame: 2 years
    Safety Issue?: Yes
• Somatic growth at 1 and 2 years of age
  • Time Frame: 2 years
    Safety Issue?: Yes
• Neurodevelopmental outcome at 1 and 2 years of age
  • Time Frame: 2 years
    Safety Issue?: Yes
• Respiratory status at 1 and 2 years of age
  • Time Frame: 2 years
    Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 42 Days

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of California, San Francisco Other

Overall Clinical Trial Officials and Contacts

Roberta L Keller, MD Principal Investigator University of California, San Francisco  

Overall Contact: Roberta L Keller, MD 415-514-3192 kellerr@peds.ucsf.edu

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00133679

Study ID Number: K23HL79922-01

ClinicalTrials.gov Identifier: NCT00133679

Health Authority: United States: Institutional Review Board