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

• ClinicalTrials.gov Identifier: NCT01224210
• Recruitment Status: Completed
• First Posted: October 19, 2010
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• 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 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.

Condition or disease	Intervention/treatment	Phase
Portopulmonary Hypertension	Drug: Ambrisentan	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• 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
• Actual Study Start Date: March 2010
• Actual Primary Completion Date: October 2016
• Actual Study Completion Date: March 2020

Arms and Interventions

Arm

Intervention/treatment

Ambrisentan (24 Weeks), Extension (4 Weeks); 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 Pulmonary Vascular Resistance [ Time Frame: from baseline to Week 24 ]
   Change in Pulmonary Vascular Resistance from baseline to Week 24 for all patients (using cardiac output [CO] measured by the thermodilution method and reported as percent difference from baseline).
2. 6 Minute Walk Distance [ Time Frame: Change from baseline to Week 24 ]
   Change from baseline in 6 Minute Walk Distance to Week 24 for all patients. (difference measured in meters).

Eligibility Criteria

• 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

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

• Principal Investigator: Ioana Preston, MD; Tufts Medical Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Preston IR, Burger CD, Bartolome S, Safdar Z, Krowka M, Sood N, Ford HJ, Battarjee WF, Chakinala MM, Gomberg-Maitland M, Hill NS. Ambrisentan in portopulmonary hypertension: A multicenter, open-label trial. J Heart Lung Transplant. 2020 May;39(5):464-472. doi: 10.1016/j.healun.2019.12.008. Epub 2020 Jan 21.

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT01224210
• Other Study ID Numbers: Ambrisentan Portopulm Study
• First Posted: October 19, 2010
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: 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:

Hypertension, Pulmonary; Hypertension; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Ambrisentan; Antihypertensive Agents