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

• ClinicalTrials.gov Identifier: NCT01028651
• Recruitment Status: Completed
• First Posted: December 9, 2009
• Results First Posted: February 24, 2017
• Last Update Posted: February 24, 2017
• Sponsor: United Therapeutics
• Collaborators: University of California, Los Angeles; Brigham and Women's Hospital; University of Texas; Emory University
• Information provided by (Responsible Party): United Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Portopulmonary Hypertension; Pulmonary Arterial Hypertension; Pulmonary Hypertension	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 Design

• Study Type: Observational
• Actual Enrollment: 13 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: An Open-Label Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension
• Study Start Date: January 2011
• Actual Primary Completion Date: April 2013
• Actual Study Completion Date: April 2013

Groups and Cohorts

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 Name: Remodulin

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24. [ Time Frame: 24 Weeks ]
   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).

Secondary Outcome Measures :

1. Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 [ Time Frame: 24 weeks ]
   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.
2. Change in Heart Rate at Rest From Baseline to Week 24 [ Time Frame: 24 weeks ]
   The change in heart rate was evaluated at rest from Baseline to Week 24.
3. Change in Cardiac Output at Rest From Baseline to Week 24 [ Time Frame: 24 weeks ]
   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.
4. Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24 [ Time Frame: 24 weeks ]
   The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24.
5. Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24 [ Time Frame: 24 weeks ]
   The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24.
6. Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24. [ Time Frame: Baseline and 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.
7. Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 [ Time Frame: Baseline and 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.
8. Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24 [ Time Frame: Baseline and 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.
9. Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24 [ Time Frame: Baseline and 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.
10. Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24 [ Time Frame: Baseline and 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.
11. Change in Quality of Life From Baseline to Weeks 12 and 24 [ Time Frame: Baseline and 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.
12. Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24 [ Time Frame: Baseline to Weeks 12 and 24 ]
    NT-proBNP was assessed at Baseline, Weeks 12 and 24.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

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

Criteria

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.

Contacts and Locations

Locations

United States, California

University of California, Los Angeles

Los Angeles, California, United States, 90024

United States, Georgia

Emory Univeristy

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Texas

University of Texas, Southwestern Medical Center

Dallas, Texas, United States, 75235

Sponsors and Collaborators

United Therapeutics

University of California, Los Angeles

Brigham and Women's Hospital

University of Texas

Emory University

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

More Information

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT01028651
• Other Study ID Numbers: RIV-PH-414
• First Posted: December 9, 2009
• Results First Posted: February 24, 2017
• Last Update Posted: February 24, 2017
• Last Verified: January 2017

Keywords provided by United Therapeutics:

PAH; Pulmonary Hypertension; Remodulin; Treprostinil; Quality of Life

Additional relevant MeSH terms:

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