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

Pulmonary Hypertension Clinical Trial

Official title:

Phase 4 Open-Label Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01028651
• Other study ID #: RIV-PH-414
• Status: Completed
• Phase: N/A
• First received: December 8, 2009
• Last updated: June 25, 2014
• Start date: November 2009
• Est. completion date: April 2013

Study information

• Verified date: June 2014
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

This is a multicenter, observational, open-label study. Patients meeting inclusion/exclusion criteria will receive treatment with treprostinil as recommended by their treating physician and will follow patients according to standard of care. This observational study proposes to collect clinical data and biologic specimens from patients who will be treated for Portopulmonary Hypertension, with a goal of achieving hemodynamic parameters acceptable for liver transplantation.

Description:

Portopulmonary hypertension (PoPH) is characterized by the presence of pulmonary arterial hypertension (PAH) in the setting of portal hypertension, and is considered the third most common cause of PAH[[1], [2]]. Approximately 2 to 6% of patients with portal hypertension demonstrate significant pulmonary hypertension based on hemodynamic observation[[3], [4], [5]]. In those patients undergoing liver transplant evaluation, the prevalence of PAH is approximately 5-6%[[4], [6], [7]]. PoPH is associated with a median survival ranging from 8 months to 2.3 years.

Among patients undergoing liver transplantation, the presence of PoPH contributes significantly to morbidity and mortality[[8], [9], [10]]. In particular, patients with PoPH who undergo OLT with mean pulmonary artery pressure (PAPm) > 35 mmHg and/or pulmonary vascular resistance (PVR) > 250 dyn/s/cm5 have > 90% risk of death posttransplant[[8]]. As such, in many transplant centers, the presence of severe PoPH ((PAPm) > 35 mmHg and/or pulmonary vascular resistance (PVR) > 250 dyn/s/cm5) is considered an absolute contraindication to OLT[[6], [11], [12]]. These patients thus have limited treatment options.

To date, pulmonary vasodilator medication use in the setting of PoPH has largely been limited to single case reports or small case series. These include intravenous (IV)/inhaled prostacyclin, sildenafil and bosentan [[15], [16], [17], [18], [19], [20], [21]]. More recently, encouraging results have been published in open label studies with the use of IV epoprostenol which was shown to improve pulmonary hemodynamics and possibly survival [[19], [21], [22]]. Specifically, in patients with severe PoPH who were referred for OLT, initiation of IV epoprostenol allowed for mPA < 35 mmHg in certain cases, allowing a successful bridge to OLT [[21], [22]].

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) Class II, III or IV symptomatology[[13], [14]]. To date, treprostinil has not been studied in the setting of PoPH; however, it is commonly prescribed in this setting. This is an observational, open-label, multi-center study will attempt to document the safety and efficacy profile of this agent in PoPH to facilitate OLT efficacy profile of this agent in PoPH to facilitate OLT.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients must:

1. Confirmed severe PoPH documented on standard of care right-heart catheterization (RHC) with a plan to initiate treprostinil therapy, as recommended by the treating physician state within 30 days.

2. Have portal hypertension.

3. Be otherwise suitable candidates for OLT.

4. Treprostinil therapy must be recommended by the treating physician per standard of care.

5. Be NYHA Class II, III, or IV

6. Have Pulmonary Capillary Wedge Pressure (PCW) < 18 mmHg AND transpulmonary gradient (TPG) = 15 mmHg Severe PAH is defined as a resting mean pulmonary artery pressure (mPA) > 25 mmHg AND pulmonary vascular resistance (PVR) = 3 wood-units by right-heart catheterization (RHC) performed as part of standard of care evaluation within 30 days of enrollment

Exclusion Criteria:

• Patients must not:

1. Be taking any investigational therapy as part of a clinical trial for any indication within 30 days of enrollment.

2. Be receiving any vasodilator treatment for pulmonary hypertension (i.e. bosentan, sitaxsentan, ambrisentan, sildenafil, tadalafil, epoprostenol, beraprost, iloprost, inhaled treprostinil) at the time of enrollment.

3. Exhibit renal failure requiring hemodialysis.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Portopulmonary Hypertension
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Intervention

Drug:
• Treprostinil sodium
Remodulin is supplied in 20 mL vials in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL and 10 mg/mL. Remodulin can be administered as supplied or diluted for intravenous infusion with Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Flolan® Sterile Diluent for Injection prior to administration. Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated, because of severe site pain or reaction. 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.

Locations

Country	Name	City	State
United States	UCLA	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin

Sponsors (7)

Lead Sponsor	Collaborator
United Therapeutics	Brigham and Women's Hospital, Emory University, University of California, Los Angeles, University of Kansas Medical Center, University of Texas, University of Wisconsin, Madison

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To estimate the probability of achieving a mPAP to less than 35 mmHg and a PVR less than 3 Wood-units in subjects with severe portopulmonary hypertension undergoing OLT treated for 24 weeks with treprostinil.		24 weeks	No
Secondary	To assess the effect of treprostinil therapy on safety, secondary efficacy endpoints and chemokine profiles.		24 weeks, and 30 day post-OLT and one year post-OLT	Yes