Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan

Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan: A Prospective Single Center, Open Label, Pilot Study

The purpose of this study is to determine the clinical characteristics and hemodynamic profiles that predict exercise induced pulmonary hypertension in 15 patients with systemic sclerosis. The study also aims to determine the effectiveness of Ambrisentan for subjects with exercise induced Pulmonary Arterial Hypertension (PAH) with scleroderma

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis; Pulmonary Hypertension; Shortness of Breath
• Intervention / Treatment: Drug: Ambrisentan

Detailed Description

The current literature addresses therapies for patients with resting PAH only, diagnosed by right heart catheterization. However, the World Health Organization (WHO) also recognizes and defines exercise induced pulmonary arterial hypertension (ex-PAH), which may precede the development of resting PAH. The natural progression of PAH, especially during exercise, has not been well delineated. An exercise hemodynamic study previously showed that in normal healthy subjects the mean pulmonary pressure does not exceed 30mmHg even at maximal cardiac outputs. A prior study evaluated exercise Doppler echocardiography systemic sclerosis patients with normal resting echocardiograms, finding an abnormal response which was defined as an estimated right ventricular systolic pressure greater than 40 mmHg. In the same study, 6.6% of the patients progressed to resting PAH over the followup period of 12 months. Limited data is available regarding the prevalence of ex-PAH in systemic sclerosis using right heart catheterization.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine, University of California, Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Systemic Sclerosis diagnosed by the American College of Rheumatology consensus statement including any of the following:

   • Limited
   • Diffuse
   • Sine Scleroderma
2. Patients must be willing and able to undergo right heart catheterization with lower extremity cycle ergometry
3. Mean pulmonary artery pressure (mPAP) > 30mmHg with exercise; PCWP ≤ 15mmHg on RHC at rest
4. Men and women, ages 18 years of age or older
5. Standard adjunctive medications will be allowed concurrently in this study at the discretion of the treating pulmonologist and rheumatologist, including digoxin, diuretics, anticoagulants (e.g. warfarin), stable immunosuppression or other anti-fibrotic therapy for at least one month prior to enrollment

Exclusion Criteria:

1. Resting PAH (mPAP > 25mmHg) on right heart catheterization
2. Other known causes of PAH including prior venous thromboembolism, HIV infection, chronic liver disease with portal hypertension, left ventricular systolic dysfunction (e.g. LVEF < 40%), and congenital causes of PAH
3. Severe hepatic disease precluding the use of ambrisentan (AST/ALT ≥3x ULN).
4. Women who are pregnant or breastfeeding.
5. Concurrent therapy with a prostanoid or prostanoid analogue, PDE5 inhibitors, or enrolled in another active clinical study.
6. Use of any prostacyclin or endothelial receptor antagonist (ERA) within 30 days before study entry.
7. Bed or wheel chair bound or a baseline 6-Minute Walk distance (6MWD) less than 150 meters.
8. Childbearing capable women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period.
9. New York Heart Association (NYHA) Classification: Class IV
10. Renal dysfunction (serum creatinine >2.5mg/dL).
11. Uncontrolled sleep apnea.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ambrisentan; ambrisentan dosed at either 5mg or 10mg orally once per day	Drug: Ambrisentan; Ambrisentan 5mg or 10mg once daily; Other Names: Letairis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Exercise Pulmonary Hemodynamics From Baseline to Week 24	We defined ePH (exercise PH) as an mPAP of 30 mmHg, PCWP of 18 mm Hg, and a transpulmonary gradient (TPG) of 15 mm Hg, where TPG equals mPAP minus PCWP. We defined ePVH (exercise pulmonary venous hypertension) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg. We defined eoPH (exercise out of proportion) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg (4). Our hypothesis was that SSc patients with normal exercise physiology and ePVH have a different patho-physiology compared to patients with pulmonary vascular disease (ePH and eoPH).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Distance Walked in Six Minutes From Baseline to 24 Week	ATS guideline based assessment with known minimally clinically important difference	24 weeks
Quality of Life (QOL) Based on SF36 and HAQ-DI	Number of participants exceeding minimally important difference estimates on changes in quality of life as assessed by SF-36 (short form 36) quality of life index with mental and physical component scores, or by HAQ-DI (health assessment questionnaire disability index) limitations that may be related to musculoskeletal limitations	24 weeks
HAQ-DI (Health Assessment Questionnaire Disability Index)	Assessing limitations that may be related to musculoskeletal limitations, the HAQ-DI assesses the difficulty a participant has had in the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consists of 2-3 items in which level of difficulty is scored from 0 to 3 with 0=no difficulty, 1=some difficulty, 2=much difficulty, and 3=unable to do. The 8 domain scores are averaged into a total HAQ-DI score ranging from 0 (no disability) to 3 (completely disabled).	24 weeks
St. George's Respiratory Questionnaire	To assess overall health, daily life, and perceived well-being in patients with underlying lung disease, the SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status.	24 weeks

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: Gilead Sciences
• Investigators: Principal Investigator: Rajeev Saggar, MD, University of California, Los Angeles; Principal Investigator: Dinesh Khanna, MD, University of California, Los Angeles

Publications and helpful links

General Publications

• Saggar R, Khanna D, Shapiro S, Furst DE, Maranian P, Clements P, Abtin F, Dua S, Belperio J, Saggar R. Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study. Arthritis Rheum. 2012 Dec;64(12):4072-7. doi: 10.1002/art.34614.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2009
• Primary Completion (ACTUAL): June 1, 2010
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: January 19, 2010
• First Submitted That Met QC Criteria: January 19, 2010
• First Posted (ESTIMATE): January 20, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2020
• Last Update Submitted That Met QC Criteria: October 28, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Systemic Sclerosis; Shortness of breath; connective tissue disease
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Connective Tissue Diseases; Signs and Symptoms, Respiratory; Sclerosis; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Hypertension, Pulmonary; Dyspnea; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: 10-000567

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO