Ambrisentan in patients with Porto-pulmonary hypertension A Multicenter Open Label Trial

Study ID
STU 122012-001

Cancer Related
No

Healthy Volunteers
No

Study Sites

Contact
Namrata Banga
408/528-5497
namrata.banga@utsouthwestern.edu

Principal Investigator
Kelly Chin

Summary

This is an open Label, Multicenter, pilot clinical trial to assess the effect of ambrisentan on exercise capacity and hemodynamics in patients with porto-pulmonary 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 [Less Than]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).

Primary endpoints:
* Change in 6MWD from baseline to Week 24 for all patients (difference measured in meters).
* Change in PVR from baseline to Week 24 for all patients (using cardiac output [Co] measured by the thermodilution method and reported as percent difference from baseline).
The change in 6MWD was chosen as a surrogate, noninvasive method to evaluate submaximal exercise capacity, which is well established in PaH trials. among hemodynamic parameters, PVR would best reflect the change in the tone of small resistance pulmonary arteries. Due to possible fluctuations in volume status that may be associated with liver disease, we did not include mean pulmonary artery pressure (mPaP) as a co-primary end point.

Secondary endpoints:
* Clinical worsening (the time from initiation of ambrisentan treatment to the first occurrence of death, hospitalization for PH, a change/addition to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria) or study withdrawal due side effects
* Change in pulmonary hemodynamics
* a change from baseline in nYHa functional class
* Change in hepatic vein-inferior vena cava pressure measurements (at selected sites)
* Monotherapy treatment status, as defined by the time of initiation of ambrisentan treatment to the addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
* Failure-free treatment status, as defined by the time from initiation of ambrisentan treatment to first occurrence of death, or worsening PH.
* Long-term survival, as defined by the time of initiation of ambrisentan treatment to death.
* evaluation of edema (grade 1-4) and requirement of diuretics (increase in dose, or addition of new diuretics)
* Change in biomarkers of right heart failure and vascular inflammation: BnP and nTproBnP, and high-sensitivity (hs-) CRP.
* Safety measurements: % of subjects with an increase in aST, aLT 5 times upper limit of normal
* Genetic markers of disease


Participant Eligibility

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 (must be performed within 45 days prior to screening visit)
a. Mean PAP (pulmonary artery pressure) >25 mm Hg, and
b. PVR (pulmonary vascular resistance) >240 dynes/s/cm5, and
c. 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 xPugh class A or B

4. Ages 18 years and above