Portopulm: Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial

• Sponsor: Tufts Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01224210
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 30
• Locations: 6
• Arm: 1
• Actual Duration (Months): 120
• Patients Per Site: 5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an Open Label, Multicenter, pilot clinical trial to assess the efficacy and safety of an oral selective Endothelin Receptor Antagonist (ambrisentan) in patients with portopulmonary hypertension.

Preliminary evidence suggests that ambrisentan is safe and effective in patients with portopulmonary hypertension. The goal of therapy for these patients is to improve symptoms of dyspnea and to improve pulmonary hemodynamics to a mean pulmonary artery pressure <35 mm Hg in order to make patients eligible for liver transplantation. Therefore, the primary endpoints for this study will include 6 minute walk distance (6MWD) and pulmonary vascular resistance (PVR).

Eligible subjects will receive 5 mg ambrisentan once-daily for the first 4 weeks. After the initial 4-week period, investigators will increase study drug dose to 10 mg once daily (both 5 mg and 10 mg doses are FDA approved). If 10 mg is not tolerated in the opinion of investigator, then the investigator may decrease the dose back to 5 mg once daily. Primary outcome is a change in both the 6 Minute Walk Distance and in Pulmonary Vascular Resistance from baseline to Week 24. Subjects will be monitored with liver function tests (LFT) every 2 weeks for the first 8 weeks, then every 4 weeks thereafter. These safety laboratory tests may be performed at a local phlebotomy laboratory or at the Investigator clinic. In addition, the Investigator will assess each subject for safety and efficacy at Week 4, Week 12, and Week 24. Following Week 24, subjects will be assessed for safety and efficacy every 12 weeks. Patients will be followed for a total of 1 year. After 1 year, if the Investigator feels that continuing the treatment will be beneficial to the patients, they will be provided with ambrisentan by Gilead Pharmaceuticals, free of charge.

Condition or Disease	Intervention/Treatment	Phase
Portopulmonary Hypertension	Drug: Ambrisentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial
• Actual Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Mar 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Other: Ambrisentan (24 Weeks), Extension (4 Weeks) Open Label Ambrisentan

Drug: Ambrisentan; Ambrisentan once-daily in the morning with or without food. The adult dose selected for this study will be 5 mg for the first 4 weeks. After the initial 4 weeks the dose will be increased to 10mg (available doses are 5, and 10 mg) based on tolerance safety. Subjects will remain on 10mg until they complete the study. Dose adjustments may be made based on side effects.; Other Names: Letairis

Outcome Measures

Primary Outcome Measures

1. Change in Pulmonary Vascular Resistance [from baseline to Week 24]

   Change in Pulmonary Vascular Resistance from baseline to Week 24 for all patients (using cardiac output [CO] measured by the thermodilution method and reported as percent difference from baseline).

2. 6 Minute Walk Distance [Change from baseline to Week 24]

   Change from baseline in 6 Minute Walk Distance to Week 24 for all patients. (difference measured in meters).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects need to fulfill all of the following 4 criteria:

1. Evidence of portal hypertension (by hemodynamic measurement, or by Doppler flow of portal circulation, or by clinical evidence of portal hypertension such as esophageal or gastric varices, as evidenced by prior upper endoscopy).

2. Evidence of pulmonary arterial hypertension by right heart catheterization (all three criteria need to be present) Right heart catheterization may have been performed up to 30 days prior to screening

• Mean PAP (pulmonary artery pressure) >25 mm Hg, and

• PVR (pulmonary vascular resistance) >240 dynes/s/cm5, and

• TPG (transpulmonary gradient = meanPAP -PAWP) >12 mm Hg

1. Baseline AST, ALT < 5 times the upper limit of normal, total Bili < 3.0 mg/dl, and mild liver impairment with Child -Pugh class A or B

2. Ages 18 years and above

Exclusion Criteria:

1. Presence of any other etiology of pulmonary arterial hypertension (HIV, connective tissue disease, sickle cell, left heart failure, chronic thromboembolic PH, etc)

2. Treatment with prostacyclins, other ERAs, or PDE5 inhibitors within 30 days of enrollment.

3. Moribund state or anticipated death within 1 month.

4. AST or ALT ≥ 5 times upper limit of normal

5. Total bilirubin ≥ 3.0 mg/dl

6. Significant lung disease (obstructive lung disease with FEV1 < 1L, or FEV1/FVC <50%; or restrictive lung disease with Total Lung Capacity < 60% predicted). PFTs may have been performed up to 6 months prior to enrollment.

7. Pregnancy

8. Age <18 years

9. Child -Pugh class C

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD Medical Center	La Jolla	California	United States	92093
2	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
3	Tufts Medical Center	Boston	Massachusetts	United States	02111
4	University of North Carolina	Chapel Hill	North Carolina	United States	27599
5	The Ohio State University Medical Center	Columbus	Ohio	United States	43221
6	UT Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• Tufts Medical Center
• Gilead Sciences

Investigators

• Principal Investigator: Ioana Preston, MD, Tufts Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT01224210
• Other Study ID Numbers: Ambrisentan Portopulm Study
• First Posted: Oct 19, 2010
• Last Update Posted: Jan 12, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Tufts Medical Center: portopulmonary hypertension; portal hypertension; esophageal or gastric varices; right heart catheterization; transpulmonary gradient; Endothelin Receptor Antagonist; Ambrisentan; Letairis; pulmonary hemodynamics
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Ambrisentan

Study Results

Participant Flow

Arm/Group Title	Ambrisentan (24 Weeks), Extension (4 Weeks)
Arm/Group Description	Treatment-naive Group 1 Pulmonary Arterial Hypertension patients with Porto-pulmonary Hypertension with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks).
Period Title: Overall Study
STARTED	30
COMPLETED	23
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Ambrisentan (24 Weeks), Extension (4 Weeks)
Arm/Group Description	Long-term extension of 24-28 weeks of ambrisentan.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (5)
Sex: Female, Male (Count of Participants)
Female	18 60%
Male	12 40%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	19 63.3%
pulmonary vascular resistance (HRU/Wood units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [HRU/Wood units]	7.1 (5)

Outcome Measures

1. Primary Outcome

Title	Change in Pulmonary Vascular Resistance
Description	Change in Pulmonary Vascular Resistance from baseline to Week 24 for all patients (using cardiac output [CO] measured by the thermodilution method and reported as percent difference from baseline).
Time Frame	from baseline to Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan
Arm/Group Description	Open Label Ambrisentan Ambrisentan: Ambrisentan once-daily in the morning with or without food. The adult dose selected for this study will be 5 mg for the first 4 weeks. After the initial 4 weeks the dose will be increased to 10mg (available doses are 5, and 10 mg) based on tolerance safety. Subjects will remain on 10mg until they complete the study. Dose adjustments may be made based on side effects.
Measure Participants	30
Mean (Standard Deviation) [percent difference from baseline]	7.1 (5)

2. Primary Outcome

Title	6 Minute Walk Distance
Description	Change from baseline in 6 Minute Walk Distance to Week 24 for all patients. (difference measured in meters).
Time Frame	Change from baseline to Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 PAH With PoPH
Arm/Group Description	Treatment-naive Group 1 PAH patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks).
Measure Participants	30
Baseline	314 (94)
Week 24	336 (108)

Adverse Events

Arm/Group Title	Ambrisentan (24 Weeks), Extension (4 Weeks)
Arm/Group Description	Treatment-naive Group 1 Pulmonary Arterial Hypertension patients with Porto-pulmonary Hypertension with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks).
All Cause Mortality
	Ambrisentan (24 Weeks), Extension (4 Weeks)
	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)
Serious Adverse Events
	Ambrisentan (24 Weeks), Extension (4 Weeks)
	Affected / at Risk (%)	# Events
Total	14/30 (46.7%)
Musculoskeletal and connective tissue disorders
Headache	3/30 (10%)	3
Respiratory, thoracic and mediastinal disorders
Edema	11/30 (36.7%)	11
Other (Not Including Serious) Adverse Events
	Ambrisentan (24 Weeks), Extension (4 Weeks)
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Blood and lymphatic system disorders
Leg Edema	1/30 (3.3%)	1

Limitations/Caveats

Standardization of the 6 Minute Walk Test

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.