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 pulmonary vascular resistance following treatment.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2011

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 cardiac catheterization to assess the degree of pulmonary hypertension and the pulmonary vascular resistance. They will then begin either sildenafil or placebo therapy for a 45d course. A final cardiac catheterization will be performed after the experimental drug course is completed. The pulmonary vascular resistance and pulmonary arterial pressure during hyperoxic conditions will be compared between the sildenafil and placebo groups. Infants from either group who have severely elevated pulmonary arterial pressure or pulmonary vascular resistance at the final cardiac catheterization (despite supplemental O2) will be started on sildenafil, which will continue after hospital discharge.

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

• Pulmonary vascular resistance at final cardiac catheterization
  • Time Frame: 7 weeks
    Safety Issue?: No

Secondary Measures

• Pulmonary arterial pressure at final cardiac catheterization
  • Time Frame: 7 weeks
    Safety Issue?: No
• Pulmonary metabolism of vasoactive substances at final cardiac catheterization
  • 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])
• 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 Sponsor: University of California, San Francisco

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 November 19, 2008

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