Placebo Controlled Trial of Bosentan in Scleroderma Patients

Pulmonary Hypertension Clinical Trial

Official title:

Placebo Controlled Trial of Bosentan vs Placebo in NYHA Class I/II Scleroderma Patients With Exercise Induced Pulmonary Hypertension

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00377455
• Other study ID #: IRB 06-043
• Secondary ID: Bosentan
• Status: Terminated
• Phase: Phase 2
• Start date: September 2006
• Est. completion date: March 2010

Study information

• Verified date: April 2018
• Source: Georgetown University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: March 2010
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension
• Scleroderma, Diffuse
• Scleroderma, Localized
• Scleroderma, Systemic
• Systemic Scleroderma

Intervention

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
62.5 mg PO Bid for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks

Locations

Country	Name	City	State
United States	University of Connecticut	Farmington	Connecticut
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Georgetown University	Actelion

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol.	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.	This will be determined after 16 weeks on the study medication.
Secondary	6-minute Walk Distance	The distance walked during a 6-minute walk test.	16 weeks
Secondary	Brain Natriuretic Peptide (BNP) Level	Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level	16 weeks
Secondary	Endothelin-1(ET-1) Level	From saved serum to determine Endothelian-1 (ET-1) levels in patients	16 weeks
Secondary	Quality of Life (QOL)	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).	16 weeks