Placebo Controlled Trial of Bosentan in Scleroderma Patients

• ClinicalTrials.gov Identifier: NCT00377455
• Recruitment Status: Terminated
• First Posted: September 18, 2006
• Results First Posted: July 20, 2011
• Last Update Posted: May 24, 2018
• Sponsor: Georgetown University
• Collaborator: Actelion
• Information provided by (Responsible Party): Virginia Steen, MD, Georgetown University

Study Description

Brief Summary:

The purpose of this study is to determine whether the drug Bosentan improves exercise tolerance in scleroderma patients.

Condition or disease	Intervention/treatment	Phase
Systemic Scleroderma; Pulmonary Hypertension	Drug: Bosentan; Drug: Placebo	Phase 2

Detailed Description:

Pulmonary hypertension (PAH) is a common and usually fatal form of lung disease in systemic sclerosis (SSc). Multiple drugs have been approved for the treatment of New York Heart Association (NYHA)Class III/IV PAH in scleroderma. Bosentan is an endothelin-1 antagonist which showed significant improvement in distance walked during 12 week clinical trials in PAH patients (7). Therapy for asymptomatic systemic sclerosis patients diagnosed incidentally with PAH (World Health Organization (WHO) Functional Class I) remains controversial. We hypothesize that asymptomatic or minimally symptomatic patients with systemic sclerosis and normal resting pulmonary artery pressures who demonstrate an abnormal rise in pulmonary artery systolic pressure with stress Doppler echocardiography testing represent a subset of patients who already have pulmonary vascular disease and who are at risk for the development of severe PAH. We further hypothesize that early identification and treatment of such patients may retard the progression of that disease.

Hypotheses:

1. Stress echocardiography identifies early pulmonary vascular disease by detecting exercise-induced pulmonary hypertension in patients with systemic sclerosis.
2. Treatment of exercise-induced PAH with Bosentan will lead to improved exercise endurance in patients with systemic sclerosis.

Subjects will be recruited from those patients who have had an abnormal exercise test as part of an earlier study, Exercise Echocardiograms in Scleroderma (IRB# 03-363).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Placebo Controlled Trial of Bosentan vs Placebo in NYHA Class I/II Scleroderma Patients With Exercise Induced Pulmonary Hypertension
• Study Start Date: September 2006
• Actual Primary Completion Date: September 2009
• Actual Study Completion Date: March 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Bosentan	Drug: Bosentan; 62.5 mg by mouth (PO) twice daily (Bid) for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks
Placebo Comparator: Placebo	Drug: Placebo; 62.5 mg PO Bid for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks

Outcome Measures

Primary Outcome Measures :

1. Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol. [ Time Frame: This will be determined after 16 weeks on the study medication. ]
   The total exercise time measured using the exercise echocardiogram is evaluated with the standard Bruce Stress Protocol, and this will be determined after 16 weeks on the study medication.

Secondary Outcome Measures :

1. 6-minute Walk Distance [ Time Frame: 16 weeks ]
   The distance walked during a 6-minute walk test.
2. Brain Natriuretic Peptide (BNP) Level [ Time Frame: 16 weeks ]
   Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level
3. Endothelin-1(ET-1) Level [ Time Frame: 16 weeks ]
   From saved serum to determine Endothelian-1 (ET-1) levels in patients
4. Quality of Life (QOL) [ Time Frame: 16 weeks ]
   QOL is measured using the Short Form 36 Health Survey (SF-36, which measures health on eight dimensions: general health perception, physical and social functioning, role limitations by physical or emotional problems, mental health, vitality, and bodily pain. For each dimension items are coded, summed, and transformed on to a scale from 0 (worst health) to 100 (best health).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• SSc patients > 18 with NYHA functional Class I/II symptoms, informed consent, and who are willing to participate in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) long term study (Georgetown IRB 04-227)

• Right heart catheterization with

  1. Normal Mean Pulmonary Arterial Pressure (PAP) at rest
  2. Mean PAP > 30 with exercise
  3. Wedge Pressure < 18

• Entry criteria for participating in the exercise echocardiogram study (Georegtown IRB 03-363)

  1. Diffusing Capacity (DLCO) <60 with a Forced Vital Capacity (FVC) >60%, or
  2. FVC/DLCO > 1.6, or
  3. a resting Pulmonary Arterial Systolic Pressure (PASP)> 40mmHg

Exclusion Criteria:

• Established resting pulmonary hypertension
• Congestive heart failure
• Diastolic dysfunction
• Pregnancy
• Inability to adequately walk/exercise
• Severe liver disease

Contacts and Locations

Locations

United States, Connecticut

University of Connecticut

Farmington, Connecticut, United States, 06030

United States, District of Columbia

Georgetown University Medical Center

Washington, District of Columbia, United States, 20007

Sponsors and Collaborators

Georgetown University

Actelion

Investigators

• Principal Investigator: Virginia D Steen, MD; Georgetown University

More Information

Publications:

Stupi AM, Steen VD, Owens GR, Barnes EL, Rodnan GP, Medsger TA Jr. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum. 1986 Apr;29(4):515-24.

Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol. 1990 May;21(5):467-74. Review.

al-Sabbagh MR, Steen VD, Zee BC, Nalesnik M, Trostle DC, Bedetti CD, Medsger TA Jr. Pulmonary arterial histology and morphometry in systemic sclerosis: a case-control autopsy study. J Rheumatol. 1989 Aug;16(8):1038-42.

MacGregor AJ, Canavan R, Knight C, Denton CP, Davar J, Coghlan J, Black CM. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford). 2001 Apr;40(4):453-9.

Grünig E, Janssen B, Mereles D, Barth U, Borst MM, Vogt IR, Fischer C, Olschewski H, Kuecherer HF, Kübler W. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation. 2000 Sep 5;102(10):1145-50.

Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003 Feb;48(2):516-22.

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896-903. Erratum in: N Engl J Med 2002 Apr 18;346(16):1258.

• Responsible Party: Virginia Steen, MD, Professor of Medicine, Georgetown University
• ClinicalTrials.gov Identifier: NCT00377455
• Other Study ID Numbers: IRB 06-043; Bosentan ( Other Identifier: Georgetown University )
• First Posted: September 18, 2006
• Results First Posted: July 20, 2011
• Last Update Posted: May 24, 2018
• Last Verified: April 2018

Keywords provided by Virginia Steen, MD, Georgetown University:

scleroderma; systemic sclerosis; bosentan; pulmonary hypertension; PHAROS; PHROS; exercise echocardiogram

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Connective Tissue Diseases; Skin Diseases; Bosentan; Antihypertensive Agents; Endothelin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action