Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial (Portopulm)

• Sponsor: Tufts Medical Center
• Collaborator: Gilead Sciences
• Information provided by (Responsible Party): Tufts Medical Center

Study Description

Brief 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 6MWD and in PVR 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.

Condition or disease	Intervention/treatment	Phase
Portopulmonary Hypertension	Drug: Ambrisentan	Not Applicable

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial
Study Start Date :	March 2010
Actual Primary Completion Date :	October 2016
Estimated Study Completion Date :	October 2018

Arms and Interventions

Arm

Intervention/treatment

Ambrisentan; Open Label Ambrisentan

Drug: Ambrisentan; 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.; Other Name: Letairis

Outcome Measures

Primary Outcome Measures :

1. Change in PVR [ Time Frame: from baseline to Week 24 ]
   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).

Secondary Outcome Measures :

1. 6 Minute Walk Distance [ Time Frame: Change from baseline to Week 24 ]
   Change from baseline in 6MWD at Week 24 for all patients. (difference measured in meters).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Locations

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United States, California
UCSD Medical Center
La Jolla, California, United States, 92093
United States, Florida
Mayo Clinic Florida
Jacksonville, Florida, United States, 32224
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
The Ohio State University Medical Center
Columbus, Ohio, United States, 43221
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390

Sponsors and Collaborators

Tufts Medical Center

Gilead Sciences

Investigators

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Principal Investigator:	Ioana Preston, MD	Tufts Medical Center

More Information

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Responsible Party:	Tufts Medical Center
ClinicalTrials.gov Identifier:	NCT01224210 History of Changes
Other Study ID Numbers:	Ambrisentan Portopulm Study
First Posted:	October 19, 2010
Last Update Posted:	April 24, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Tufts Medical Center:

portopulmonary hypertension; portal hypertension; esophageal or gastric varices; right heart catheterization; transpulmonary gradient	Endothelin Receptor Antagonist; Ambrisentan; Letairis; pulmonary hemodynamics

Additional relevant MeSH terms:

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Hypertension; Hypertension, Pulmonary; Vascular Diseases; Cardiovascular Diseases; Lung Diseases	Respiratory Tract Diseases; Ambrisentan; Endothelin Receptor Antagonists; Antihypertensive Agents; Molecular Mechanisms of Pharmacological Action