Combination Therapy in Pulmonary Arterial Hypertension (COMPASS 3)

COMPASS 3: An Open-label, Multi-Center Study Employing a Targeted 6-Minute Walk Test (6-MWT) Distance Threshold Approach to Guide Bosentan-Based Therapy and to Assess the Utility of Magnetic Resonance Imaging (MRI) on Cardiac Remodeling

An open label, non-comparative study design is appropriate for this Phase 4 study designed to assess whether a core therapy of bosentan, either as monotherapy or with the addition of sildenafil, enables patients with pulmonary arterial hypertension (PAH) to achieve a 6-minute walk distance (6 MWD) of ≥380 meters after 28 weeks of therapy This design is also appropriate to pioneer the utility of cardiac MRI in assessing improved functional capacity in PAH and exploring its correlation with other parameters.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Bosentan; Drug: Sildenafil

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Hospital at Birmingham
    • Mobile, Alabama, United States, 36617
      • University of South Alabama
  • California
    • Los Angeles, California, United States, 90095
      • UCLA - David Geffen School of Medicine
  • Delaware
    • Newark, Delaware, United States, 19713
      • Lung Health and Sleep Enhancement Center, LLC
  • Florida
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital (Bay Area Chest Physicians, P.A.)
    • Jacksonville, Florida, United States, 32258
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Decatur, Georgia, United States, 30030
      • Atlanta Institute for Medical Research, Inc.
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentukiana Pulmonary Associates
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital-BACH Cardiology
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Buffalo, New York, United States, 14203
      • Buffalo General Hospital / Kaleida Health
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center-Davis Heart and Lung Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Presbyterian
    • Pittsburgh, Pennsylvania, United States, 15213
      • Allegheny General Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine and the Methodist Hospital
  • Utah
    • Provo, Utah, United States, 84604
      • Central Utah Clinic, PC
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin-Frodtert Memorial Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study-mandated procedures.
2. Males or females ≥ 12 years of age (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception).

3. Symptomatic patients with the following types of PAH belonging to World Health Organization (WHO) Pulmonary Hypertension Classification Group I:

   • Idiopathic (IPAH)
   • Familial (FPAH)

   • Associated with PAH (APAH):

     • Collagen vascular disease
     • Drugs and toxins

4. Patients naïve to treatment with advanced PAH therapies (i.e., endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors or prostacyclins) with a right heart catheterization (RHC) showing all of the following:

   • Mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg
   • Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mm Hg when PCWP is not accurately obtained
   • Pulmonary vascular resistance ≥ 3 Wood units
5. 6-MWT distance ≥ 150 meters and < 360 meters.

Exclusion Criteria:

1. Patients with Pulmonary Hypertension (PH) belonging to WHO Classification Group II-V.
2. Patients with PAH (WHO PH Classification Group I) other than that listed in the Inclusion Criteria.
3. Pregnant and/or nursing.
4. Women of childbearing potential not using a reliable method of contraception.
5. Patients with known human immunodeficiency virus (HIV) infection.
6. Patients with significant vasoreactivity during right heart catheterization (i.e., a fall in mPAP to < 40 mm Hg with a decrease of ≥ 10 mm Hg and with a normal cardiac index ≥ 2.5 l/min.m^2).
7. Patients with restrictive lung disease (i.e., total lung capacity (TLC) < 60% of normal predicted value).
8. Patients with obstructive lung disease (i.e., forced expiratory volume/ forced vital capacity (FEV1/FVC) < 0.5).
9. Patients with impaired left ventricular function (LVEF <50%) or diastolic dysfunction.
10. Patients with portal hypertension, cirrhosis, moderate to severe liver impairment (Child-Pugh Class B or C), or liver enzymes (Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) > 3.0 times the upper limit of normal range.
11. Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A, tacrolimus) sirolimus, everolimus up to 1 week prior to Baseline (Day 1).
12. Patients currently receiving or predicted to require treatment, during the course of the study, with nitrates, protease inhibitors, or alpha-blockers.
13. Patients with a hemoglobin concentration < 75 % of the lower limit of the normal range or < 8.5 g/dL.
14. Patients currently receiving or predicted to require treatment with a prostanoid during the course of the study.
15. Patients with systolic blood pressure < 85 mm Hg.
16. Patients with body weight < 40 kg.
17. Patients who have received any investigational product within 90 days prior to Baseline.
18. Patients who previously received any advanced therapy for PAH (e.g., ERAs, PDE-5 inhibitors or prostacyclins).
19. Patients with hypersensitivity to sildenafil or any excipients of its formulation.
20. Patients with any contraindication to sildenafil treatment (i.e., nitrates).
21. Patients with any recent medical condition limiting the ability to comply with the study requirements (i.e., stroke, myocardial infarction).
22. Patients with unstable PAH whose disease state would prohibit the completion of study procedures, in the opinion of the investigator.
23. Patients unable to complete a MRI scan (e.g., claustrophobia).
24. Patients with permanent cardiac pacemakers, automatic internal cardioverter defibrillators (AICD's), neurostimulators, hearing aides, and other implanted metallic devices that are contraindicated during a MRI study.
25. Patients with conditions that would interfere with proper cardiac gating during MRI, such as atrial fibrillation or multiple premature ventricular contractions (PVCs)/premature atrial contractions (PACs).
26. Patients with conditions that prevent compliance with the protocol or the ability to adhere to therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; Oral bosentan 62.5 mg twice daily (BID) first 4 weeks, followed by 24 weeks of 125 mg BID if the 62.5 mg BID dose was well tolerated, with the addition of sildenafil 20 mg thrice daily (TID) in patients who do not reach the 6-MWT distance threshold at Week 16	Drug: Bosentan; Oral bosentan 62.5 mg BID first 4 weeks followed by 24 weeks of 125 mg BID if the 62.5 mg BID dose was well tolerated; Drug: Sildenafil; Oral sildenafil 20 mg TID in patients who do not reach the 6-MWT distance threshold at Week 16

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Reaching a 6-Minute Walk Test (6MWT) Distance ≥ 380 Meters	The 6MWT is a non encouraged test, which measures the walking distance covered over a 6 minute period	at 16 weeks and at 28 weeks of a stepped approach to therapy

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• Benza RL, Raina A, Gupta H, Murali S, Burden A, Zastrow MS, Park MH, Simon MA. Bosentan-based, treat-to-target therapy in patients with pulmonary arterial hypertension: results from the COMPASS-3 study. Pulm Circ. 2018 Jan-Mar;8(1):2045893217741480. doi: 10.1177/2045893217741480. Epub 2017 Oct 24.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: February 7, 2007
• First Submitted That Met QC Criteria: February 8, 2007
• First Posted (Estimated): February 9, 2007

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: sildenafil; combination therapy; pulmonary arterial hypertension; bosentan; Compass 3
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Vasodilator Agents; Urological Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Antihypertensive Agents; Endothelin Receptor Antagonists; Sildenafil Citrate; Bosentan
• Other Study ID Numbers: AC-052-419