The Effects of Ambrisentan on Exercise Capacity in Fontan Patients
Condition: Single Ventricle Fontan Palliation
MeSH terms: Univentricular Heart
Intervention: Ambrisentan
Intervention MeSH terms: Ambrisentan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      Hypothesis:

      Patients with a Fontan type palliation are limited by preload, or the rate at which blood
      returns to the heart after passively traversing the pulmonary capillary bed. By decreasing
      pulmonary vascular resistance using an endothelin receptor antagonist, both ventricular
      filling pressures and volumes will increase with a simultaneous decrease in systemic
      impedance to flow and decrease in central venous pressures, leading to an improved capacity
      to increase cardiac output, and thereby an improvement in patient functional status.

      Patients who are candidates for the study will be randomized to a double-blind single
      crossover study. Therapy with either ambrisentan or placebo will be continued for 12 weeks,
      with a 2 week washout period between treatment periods. Subjects will be subjected to a VO2
      max test to evaluate exercise capacity at enrolment, and on the last day of each treatment
      period. As a component of the VO2 max testing the patient's VE, VCO2, VE/VCO2 slope,
      ventilatory anaerobic threshold (VAT), peak work, efficiency, and other physiologic
      parameters as typically obtained from cardiopulmonary testing will be assessed. In addition,
      each patient will be asked to complete an SF-36 quality of life questionnaire at enrollment,
      and on the last day of each study period.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients over 18 years of age followed at the Center for Adults with Congenital Heart
             Disease at Washington University School of Medicine or at Saint Louis Childrens
             Hospital who have had a Fontan-type of palliation with single ventricular physiology.

          2. Patients must not within the last year have been treated with an endothelin receptor
             antagonist, phosphodiesterase 5 antagonist, or prostacyclin analogue.

          3. Female patients must not be pregnant, and during the study period must be using
             effective contraception (including barrier method with spermicide, intrauterine
             device, implanon, oral contraceptives) if fertile.

          4. In the physicians opinion patients must be able to complete a VO2 max test to achieve
             an RER of >1.0

          5. In the physicians opinion patients must be socially and intellectually able to adhere
             to the treatment regimen and follow-up

          6. Patients must be intellectually able to reliably complete an SF-36 questionnaire on
             quality of life.

          7. Patients must be clinically stable for at least 3 months prior to enrolment.

          8. Patients must not have had surgery within 6 months prior to enrolment, and have no
             planned surgery for the study period.

          9. Patients must provide informed consent.

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        Exclusion Criteria:

          1. Patients under 18 years of age.

          2. Patients who are pregnant, nursing, or who in the physician's opinion are likely to
             become pregnant.

          3. Patients who are clinically unstable.

          4. Patients who have previously been treated with either an endothelin receptor
             antagonist and stopped due to adverse side effects.

          5. Patients with an AST or ALT of >3 x normal.

          6. Patients having any known contraindication to the initiation of ambrisentan.

          7. Patients with a calculated creatinine clearance of <60ml/min

          8. Patients with a serum hemoglobin concentration of <10mg/dl

          9. Patients with a poorly controlled cardiac arrhythmia

         10. Patients who are unable to provide independent informed consent.

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