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

Brief Summary

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

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.

  • Study Type: Observational
  • Study Design: Observational Model: Cohort, Time Perspective: Prospective
  • Study Primary Completion Date: April 2013

Detailed Clinical Trial 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.

Interventions Used in this Clinical Trial

  • 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.

Arms, Groups and Cohorts in this Clinical Trial

  • Portopulmonary hypertension

Outcome Measures for this Clinical Trial

Primary Measures

  • 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.
    • Time Frame: 24 weeks
      Safety Issue?: No

Secondary Measures

  • To assess the effect of treprostinil therapy on safety, secondary efficacy endpoints and chemokine profiles.
    • Time Frame: 24 weeks, and 30 day post-OLT and one year post-OLT
      Safety Issue?: Yes

Criteria for Participation in this Clinical Trial

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • United Therapeutics
  • Collaborator
    • University of California, Los Angeles
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Rajan Saggar, MD, Study Director, University of California, Los Angeles
    • Michael Krowka, MD, Study Director, Mayo Clinic
    • Aaron Waxman, MD, PhD, Study Director, Brigham and Women’s Hospital
    • James Runo, MD, Study Director, University of Wisconsin, Madison

Source

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The URL of this page is:
http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01028651