Efficacy and Safety of Combination Ambrisentan and Tadalafil in Patients With Portopulmonary Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of the combination of ambrisentan and tadalafil in reducing mPAP to below 35mmHg in patients with moderate to severe Portopulmonary Hypertension (POPH) as a means to candidacy for liver transplantation.

Detailed Description
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The outcome of liver transplantation (LT) in the presence of moderate to severe POPH is significantly poor with a 50% reported mortality rate in LT recipients having a mean pulmonary artery pressure (mPAP) >35 mmHg and 100% when the mPAP is greater than 50 mmHg; therefore, making moderate to severe POPH a contraindication to liver transplants. Those recipients with significant pulmonary artery pressure (PAP) may be denied the opportunity for transplant unless the mPAP is brought below 35 mmHg with medical treatment. This study will test the efficacy & safety of the combination of using ambrisentan and tadalfil in reducing the Pulmonary Arterial Pressure to below 35 mmHg in patients with moderate to severe POPH as a means to candidacy for liver transplantation.

Official Title
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Investigator Sponsored Research Proposal : Efficacy and Safety of Combination Ambrisentan and TadaLafil in PATiEnts With PortoPulmonary Hypertension (ESCALATE-PPH)

Conditions
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Portopulmonary Hypertension, Pulmonary Hypertension, Cirrhosis, Liver

Intervention / Treatment
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* Drug: Ambrisentan Pill
* Drug: Tadalafil Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Child-Pugh Class Class A & B Cirrhosis mPAP ≥35mmHg Pulmonary Capillary Wedge Pressure (PWCP) <15mmHg on Right Heart Catheterization's (RHCs) mPAP > 50mmHg will be considered eligible unless they are World Health Organization (WHO) Functional Class IV Exclusion Criteria: End stage renal disease on hemodialysis (ESRD on HD) Renal dysfunction and GFR < 30 AST, ALT > 5 times the upper limit of normal Total bilirubin ≥ 6.0 INR > 2 Initially, Child-Pugh Class C patients will be excluded; however, after the first 5 patients are included, if there is no signal of worsening liver function, the protocol may be amended to include patients with Class C cirrhosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Combination Therapy<br>Qualifying participants will begin combination therapy with ambrisentan pill 5 mg daily and tadalafil pill 20 mg. After one week of therapy, patients will increase tadalafil pill to 40 mg daily and continue ambrisentan pill 5 mg daily. On day 15, patients will increase ambrisentan pill to 10 mg daily and continue at 40 mg of tadalafil pill daily. | Drug: Ambrisentan Pill<br>* Will be administered as stated in Arm/Group Descriptions<br>* Other names: Letairis;Drug: Tadalafil Pill<br>* Will be administered as stated in Arm/Group Descriptions<br>* Other names: Adcirca;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in mPAP to 35mmHg | A Right Heart Catheterization will be performed in order to see if there's a reduction in mPAP to less than 35mmHg from baseline | 2 months post initiation of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure | Systemic Blood pressure | 2 months post therapy | 
| mPAP Reduction | Percent reduction in mPAP will be assessed and measured from baseline via RHC | 2 months post initiation of therapy | 
| Post-Transplant Survival Outcome: Alive or Dead at 30 days | Post-transplant survival comparing subjects with or without history of POPH | Post-op Day 1 and 30 | 
| Kidney function evaluation through measurement of Creatinine levels (mg/dL) | Comprehensive metabolic panel will be completed at 2 months post therapy to assess kidney function | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Liver Function test measured by AST (iu/L) | AST will be done to monitor and measure the degree of cirrhosis on the liver as well as the overall function of the liver | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Liver Function test measured by ALT (iu/L) | ALT test will be done to monitor and measure the degree of cirrhosis on the liver as well as the overall function of the liver | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Liver Function test measured by Bilirubin (mg/dL) | Bilirubin test will be done to monitor and measure the degree of cirrhosis on the liver as well as the overall function of the liver | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Liver Function test measured by INR | INR test will be done to monitor and measure the degree of cirrhosis on the liver as well as the overall function of the liver | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Right Ventricular (RV) Size in centimeters | To measure Right Ventricular Size in centimeters | Baseline, 1-month, 6-month and 12 months post therapy, 1 month post transplant | 
| Right Ventricular (RV) Qualitative Systolic Function: assessment that is categorized as normal, mildly depressed, moderately depressed or severely depressed | To measure Right Ventricular Qualitative Systolic Function assessment that is categorized as normal, mildly depressed, moderately depressed or severely depressed | Baseline, 1-month, 6-month and 12 months post therapy, 1 month post transplant | 
| Right Ventricular (RV) Function in centimeters | Tricuspid Annular Plane Systolic Excursion (TAPSE) measured in centimeters | Baseline, 1-month, 6-month and 12 months post therapy and 1-month post transplant | 
| Biomarker of Right ventricular failure | serum BNP | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| New York Heart Association Functional class | NYHA FC will be assessed by clinician at baseline and each subsequent visit | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant | 
| Change in 6 Minute Walk Distance | 6 Minute walk will be performed at baseline and each study visit | baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 months/end of treatment, 1 month post transplant |