Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension

A Multinational, Multicentre, Randomized, Double-blind Study To Assess The Efficacy And Safety Of Oral Sildenafil 20mg Tid Or Placebo When Added To Bosentan In The Treatment Of Subjects, Aged 18 Years And Above, With Pulmonary Arterial Hypertension (Pah)

To assess the efficacy and safety of sildenafil when added to patients with PAH who are taking bosentan as all or part of their background therapy.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincents Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • The Prince Charles Hospital
• Czechia
  • Praha 2, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze
  • Praha 4, Czechia, 140 21
    • Institut Klinické a Experimentální Medicíny, Klinika Kardiologie
• France
  • Lille, France, 59037
    • Hôpital Claude Huriez
  • Lille, France, 59037
    • Clinique des Maladies Respiratoires
  • Vandoeuvre Les Nancy, France, 54511
    • Hopital Adules Brabois
• Germany
  • Berlin, Germany, 12683
    • Unfallkrankenhaus Berlin, Klinik fuer Innere Medizin
  • Coburg, Germany, 96450
    • II. Medizinische Klinik, Kardiologie, Angiologie und Pneumologie
  • Essen, Germany, 45122
    • Universitaetsklinikum Essen, Zentrum fuer Innere Medizin, Klinik fuer Kardiologie
  • Giessen, Germany, 35392
    • Universitaetsklinikum Giessen und Marburg GmbH, Standort Giessen
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Homburg, Germany, 66421
    • Universitaetsklinikum des Saarlandes, Innere Medizin V
  • Leipzig, Germany, 04103
    • Medizinische Klinik und Poliklinik I, Universitaetsklinikum Leipzig
  • Muenchen, Germany, 81377
    • Med. Klinik u. Poliklinik I der LMU Muenchen, Klinikum Grosshadern
  • Nuernberg, Germany, 90402
    • Praxis fuer Innere Medizin, Kardiologie und Angiologie
  • Wuerzburg, Germany, 97067
    • Missionsaerztliche Klinik Wuerzburg, Gemeinnuetzige Gesellschaft mbH
• Greece
  • Athens
    • Haidari, Athens, Greece, 12462
      • Attikon Hospital
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Petach Tikva, Israel, 49100
    • Rabin Medical Centre
• Italy
  • Napoli, Italy, 80131
    • Cardiologia, Azienda Ospedaliera Monaldi, Seconda Università di Napoli
  • Roma, Italy, 00161
    • Unita' di Ipertensione Polmonare, Dipartimento di Scienze Respiratorie e Cardiovascolari
• Taiwan
  • Taipei, Taiwan, 100
    • Department of Surgery, National Taiwan University Hospital
• United Kingdom
  • Cambridgeshire
    • Papworth Everard, Cambridgeshire, United Kingdom, CB23 3RE
      • PVDU
• United States
  • California
    • Los Angeles, California, United States, 90073
      • West Los Angeles VA Healthcare, Pulmonary Hypertension Program
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • Diagnostics Research Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects aged 18 and over above with PAH and for which bosentan therapy is indicated according to national license
• Subjects with a mean pulmonary artery pressure of >25mmHg and a pulmonary artery wedge pressure of <15mmHg at rest via right heart catheterization within 3 years prior to randomization.
• Subjects whose baseline 6 Minute Walk Test distance is >100m and < 450m.

Exclusion Criteria:

• PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria
• Subjects whose 6 Minute Walk Test may be limited by conditions other than PAH related dyspnoea or fatigue eg. claudication from vascular insufficiency or arthritis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: Bosentan; Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil); Other: Placebo; Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil); Drug: Bosentan; Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase
Experimental: Active	Drug: Bosentan; Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil); Drug: Bosentan; Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase; Drug: Sildenafil Citrate; Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12	6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF	WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.	Week 12
Clinical Worsening Events	No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.	Week 12
Change From Baseline in Borg Dyspnea Score at Week 12	Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]); (very slight);; (slight breathlessness);; (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum).	Week 12
One Year Survival Probability From the Start of Sildenafil Treatment.	The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.	One year from the time of starting sildenafil
One Year Survival From the Start of Sildenafil Treatment.	The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.	One year from the time of starting sildenafil

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

General Publications

• Vizza CD, Jansa P, Teal S, Dombi T, Zhou D. Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord. 2017 Sep 6;17(1):239. doi: 10.1186/s12872-017-0674-3.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: May 5, 2006
• First Submitted That Met QC Criteria: May 5, 2006
• First Posted (Estimate): May 9, 2006

Study Record Updates

• Last Update Posted (Actual): February 1, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Sildenafil Citrate; Bosentan
• Other Study ID Numbers: A1481243; 2006-001464-23 (EudraCT Number); PATHWAYS (Other Identifier: Alias Study Number)