Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial
Condition: Portopulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension
Intervention: Ambrisentan
Intervention description: Ambrisentan once-daily in the morning with or without food. The adult dose selected for this study will be 5 mg for the first 4 weeks. After the initial 4 weeks the dose will be increased to 10mg (available doses are 5, and 10 mg) based on tolerance safety. Subjects will remain on 10mg until they complete the study. Dose adjustments may be made based on side effects.
Intervention MeSH terms: Ambrisentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: portopulmonary hypertension; portal hypertension; esophageal or gastric varices; right heart catheterization; transpulmonary gradient; Endothelin Receptor Antagonist; Ambrisentan; Letairis; pulmonary hemodynamics

Summary:

      This is an Open Label, Multicenter, pilot clinical trial to assess the efficacy and safety of
      an oral selective Endothelin Receptor Antagonist (ambrisentan) in patients with
      portopulmonary hypertension.

      Preliminary evidence suggests that ambrisentan is safe and effective in patients with
      portopulmonary hypertension. The goal of therapy for these patients is to improve symptoms of
      dyspnea and to improve pulmonary hemodynamics to a mean pulmonary artery pressure <35 mm Hg
      in order to make patients eligible for liver transplantation. Therefore, the primary
      endpoints for this study will include 6 minute walk distance (6MWD) and pulmonary vascular
      resistance (PVR).

      Eligible subjects will receive 5 mg ambrisentan once-daily for the first 4 weeks. After the
      initial 4-week period, investigators will increase study drug dose to 10 mg once daily (both
      5 mg and 10 mg doses are FDA approved). If 10 mg is not tolerated in the opinion of
      investigator, then the investigator may decrease the dose back to 5 mg once daily. Primary
      outcome is a change in both the 6 Minute Walk Distance and in Pulmonary Vascular Resistance
      from baseline to Week 24. Subjects will be monitored with liver function tests (LFT) every 2
      weeks for the first 8 weeks, then every 4 weeks thereafter. These safety laboratory tests may
      be performed at a local phlebotomy laboratory or at the Investigator clinic. In addition, the
      Investigator will assess each subject for safety and efficacy at Week 4, Week 12, and Week
      24. Following Week 24, subjects will be assessed for safety and efficacy every 12 weeks.
      Patients will be followed for a total of 1 year. After 1 year, if the Investigator feels that
      continuing the treatment will be beneficial to the patients, they will be provided with
      ambrisentan by Gilead Pharmaceuticals, free of charge.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects need to fulfill all of the following 4 criteria:

          1. Evidence of portal hypertension (by hemodynamic measurement, or by Doppler flow of
             portal circulation, or by clinical evidence of portal hypertension such as esophageal
             or gastric varices, as evidenced by prior upper endoscopy).

          2. Evidence of pulmonary arterial hypertension by right heart catheterization (all three
             criteria need to be present) Right heart catheterization may have been performed up to
             30 days prior to screening

               -  Mean PAP (pulmonary artery pressure) >25 mm Hg, and

               -  PVR (pulmonary vascular resistance) >240 dynes/s/cm5, and

               -  TPG (transpulmonary gradient = meanPAP -PAWP) >12 mm Hg

          3. Baseline AST, ALT < 5 times the upper limit of normal, total Bili < 3.0 mg/dl, and
             mild liver impairment with Child -Pugh class A or B

          4. Ages 18 years and above

        Exclusion Criteria:

          1. Presence of any other etiology of pulmonary arterial hypertension (HIV, connective
             tissue disease, sickle cell, left heart failure, chronic thromboembolic PH, etc)

          2. Treatment with prostacyclins, other ERAs, or PDE5 inhibitors within 30 days of
             enrollment.

          3. Moribund state or anticipated death within 1 month.

          4. AST or ALT ≥ 5 times upper limit of normal

          5. Total bilirubin ≥ 3.0 mg/dl

          6. Significant lung disease (obstructive lung disease with FEV1 < 1L, or FEV1/FVC <50%;
             or restrictive lung disease with Total Lung Capacity < 60% predicted). PFTs may have
             been performed up to 6 months prior to enrollment.

          7. Pregnancy

          8. Age <18 years

          9. Child -Pugh class C