A Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension

An Open-Label Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension

This was a multicenter, prospective, observational, open-label study. Patients meeting inclusion/exclusion criteria received treatment with treprostinil as recommended by their treating physicians and were followed according to standard of care. This observational study collected clinical data and biologic specimens from patients who were treated for portopulmonary hypertension (PoPH), with a goal of achieving hemodynamic parameters appropriate for orthotopic liver transplantation candidacy, including mean pulmonary arterial pressure (mPAP) less than 35 mmHg and pulmonary vascular resistance (PVR) less than 3 Wood-units (WU) at Week 24 in patients with severe PoPH.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Pulmonary Hypertension; Portopulmonary Hypertension
• Intervention / Treatment: Drug: Treprostinil

Detailed Description

Treprostinil is approved as a continuous subcutaneous (SC) or intravenous (IV) infusion by the FDA for the treatment of WHO group I PAH with New York Heart Association (NYHA) Functional Class II, III or IV symptomatology. To date, treprostinil has not been studied in the setting of PoPH; however, it is commonly prescribed in this setting. This was an observational, open-label, multicenter study which documented the safety and efficacy profile of this agent in PoPH to facilitate orthotopic liver transplantation (OLT).

• Study Type: Observational
• Enrollment (Actual): 13

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90024
      • University of California, Los Angeles
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Univeristy
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas, Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Subjects were recruited from 4 liver transplantation centers in the US, referred for portopulmonary hypertension.

Description

Inclusion Criteria:

• Patients must:

  1. Had portal hypertension.
  2. Be otherwise suitable candidates for OLT.
  3. Had severe pulmonary arterial hypertension (PAH) defined as a resting mean pulmonary arterial pressure (mPAP) >35 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood Units (WU) by right heart catheterization (RHC) performed as part of standard of care evaluation within 90 days of enrollment.
  4. Treprostinil therapy must be recommended by the treating physician per standard of care.
  5. Be NYHA Functional Class II, III, or IV.
  6. Had pulmonary capillary wedge (PCW) pressure ≤18 mmHg and transpulmonary gradient (TPG) ≥15 mmHg.

Exclusion Criteria:

• Patients must not:

  1. Had received any any investigational therapy as part of a clinical trial for any indication within 30 days prior to enrollment.
  2. Had a change in dose of treatment for PAH (bosentan [Tracleer], ambrisentan [Letairis], tadalafil [Adcirca], or sildenafil [Revatio]), within 30 days prior to enrollment. That is, subjects may have been treated with any of these agents provided the dose was stable for at least 30 days prior to enrollment.
  3. Had renal failure requiring hemodialysis.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Portopulmonary hypertension

Drug: Treprostinil; Remodulin is supplied in concentrations of 1, 2.5 , 5, and 10 mg/mL and can be administered as supplied or diluted for intravenous (IV) infusion prior to administration. Remodulin is indicated for subcutaneous (SC) or IV use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central IV line if the SC route is not tolerated. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625 ng/kg/min.; Other Names: Remodulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24.	The primary efficacy endpoint was the number of subjects who achieved a mean pulmonary arterial pressure (mPAP) less than 35 mmHg and a pulmonary vascular resistance (PVR) less than 3 Wood units (WU) at Week 24 in patients with severe portopulmonary hypertension (PoPH).	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24	The change in hemodynamic parameters (including systolic pulmonary arterial pressure [PAPs], diastolic pulmonary arterial pressure [PAPd], mean pulmonary arterial pressure [mPAP], and transpulmonary gradient [TPG]) was evaluated at rest from Baseline to Week 24. The median change in hemodynamic parameters from Baseline to Week 24 via right-heart catheterization (RHC) is presented.	24 weeks
Change in Heart Rate at Rest From Baseline to Week 24	The change in heart rate was evaluated at rest from Baseline to Week 24.	24 weeks
Change in Cardiac Output at Rest From Baseline to Week 24	The change in cardiac output was evaluated at rest from Baseline to Week 24. The median change in cardiac output from Baseline to Week 24 is presented.	24 weeks
Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24	The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24.	24 weeks
Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24	The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24.	24 weeks
Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24.	The 6-Minute Walk Test was conducted at Screening, Baseline prior to starting study drug and at least 24 hours after the Screening test, and during the Treatment Phase at Weeks 12 and 24.	Baseline and Weeks 12 and 24
Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.	Baseline and Weeks 12 and 24
Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.	Baseline and Weeks 12 and 24
Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.	Baseline and Weeks 12 and 24
Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.	Baseline and Weeks 12 and 24
Change in Quality of Life From Baseline to Weeks 12 and 24	The 36-item Short Form Survey (SF-36) is a health related quality of life instrument, which measures dimensions of physical and social roles and functioning, mental health, vitality, and pain. Items are scored on a 0 to 100 range so that the lowest scores represent the highest disability. The quality of life assessment was conducted at Baseline and Weeks 12 and 24 and the change from Baseline to Weeks 12 and 24 is presented.	Baseline and Weeks 12 and 24
Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24	NT-proBNP was assessed at Baseline, Weeks 12 and 24.	Baseline to Weeks 12 and 24

Collaborators and Investigators

• Sponsor: United Therapeutics
• Collaborators: University of California, Los Angeles; Emory University; Brigham and Women's Hospital; University of Texas
• Investigators: Study Director: Rajan Saggar, MD, University of California, Los Angeles; Study Director: Micah Fisher, MD, Emory University; Study Director: Aaron Waxman, MD, PhD, Brigham and Women's Hospital; Study Director: Sonja Bartolome, MD, UT Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: December 8, 2009
• First Submitted That Met QC Criteria: December 8, 2009
• First Posted (Estimate): December 9, 2009

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: January 5, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Quality of Life; Pulmonary Hypertension; PAH; Treprostinil; Remodulin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: RIV-PH-414