Clinical trial NCT00377455: Placebo Controlled Trial of Bosentan in Scleroderma Patients
Official title: Placebo Controlled Trial of Bosentan vs Placebo in NYHA Class I/II Scleroderma Patients With Exercise Induced Pulmonary Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Systemic Scleroderma
Pulmonary Hypertension
Keywords: scleroderma
systemic sclerosis
bosentan
pulmonary hypertension
PHAROS
PHROS
exercise echocardiogram
Lead sponsor: Georgetown University
Sponsor class: OTHER
Collaborators: name: Actelion
First posted: 2006-09-18
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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).

Eligibility 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

Primary outcomes:
measure: Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol.
timeFrame: This will be determined after 16 weeks on the study medication.
Secondary outcomes:
measure: 6-minute Walk Distance
timeFrame: 16 weeks
measure: Brain Natriuretic Peptide (BNP) Level
timeFrame: 16 weeks
measure: Endothelin-1(ET-1) Level
timeFrame: 16 weeks
measure: Quality of Life (QOL)
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Farmington
country: United States
facility: University of Connecticut
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
Study officials:
affiliation: Georgetown University
name: Virginia D Steen, MD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1002/art.1780290409.
citation: Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol. 1990 May;21(5):467-74. doi: 10.1016/0046-8177(90)90002-m.
citation: 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.
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. doi: 10.1093/rheumatology/40.4.453.
citation: Grunig E, Janssen B, Mereles D, Barth U, Borst MM, Vogt IR, Fischer C, Olschewski H, Kuecherer HF, Kubler W. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation. 2000 Sep 5;102(10):1145-50. doi: 10.1161/01.cir.102.10.1145.
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. doi: 10.1002/art.10775.
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. doi: 10.1056/NEJMoa012212.