Placebo Controlled Trial of Bosentan in Scleroderma Patients

• Sponsor: Georgetown University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00377455
• Collaborator: Actelion (Industry)
• Enrollment: 5
• Locations: 2
• Arms: 2
• Duration (Months): 42
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Sep 1, 2006
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Mar 1, 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. [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 [16 weeks]

   The distance walked during a 6-minute walk test.

2. Brain Natriuretic Peptide (BNP) Level [16 weeks]

   Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level

3. Endothelin-1(ET-1) Level [16 weeks]

   From saved serum to determine Endothelian-1 (ET-1) levels in patients

4. Quality of Life (QOL) [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	University of Connecticut	Farmington	Connecticut	United States	06030
2	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Virginia Steen, MD, Professor of Medicine, Georgetown University
• ClinicalTrials.gov Identifier: NCT00377455
• Other Study ID Numbers: IRB 06-043; Bosentan
• First Posted: Sep 18, 2006
• Last Update Posted: May 24, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Virginia Steen, MD, Professor of Medicine, 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; Bosentan

Study Results

Participant Flow

Arm/Group Title	Bosentan and Placebo Arms
Arm/Group Description	This group consists of subjects on both arms of the study - bosentan and placebo
Period Title: Overall Study
STARTED	5
COMPLETED	4
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Bosentan and Placebo Arms
Arm/Group Description	This group consists of subjects on both arms of the study - bosentan and placebo
Overall Participants	5
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	5 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol.
Description	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.
Time Frame	This will be determined after 16 weeks on the study medication.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bosentan/Placebo
Arm/Group Description	Outcomes not available, due to early termination of study
Measure Participants	0

2. Secondary Outcome

Title	6-minute Walk Distance
Description	The distance walked during a 6-minute walk test.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Outcomes not available, due to early termination of study

Arm/Group Title	Bosentan/Placebo
Arm/Group Description	Outcomes not available, due to early termination of study
Measure Participants	0

3. Secondary Outcome

Title	Brain Natriuretic Peptide (BNP) Level
Description	Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Outcomes not available, due to early termination of study

Arm/Group Title	Bosentan/Placebo
Arm/Group Description	Outcomes not available, due to early termination of study
Measure Participants	0

4. Secondary Outcome

Title	Endothelin-1(ET-1) Level
Description	From saved serum to determine Endothelian-1 (ET-1) levels in patients
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Outcomes not available, due to early termination of study

Arm/Group Title	Bosentan/Placebo
Arm/Group Description	Outcomes not available, due to early termination of study
Measure Participants	0

5. Secondary Outcome

Title	Quality of Life (QOL)
Description	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).
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Outcomes not available, due to early termination of study

Arm/Group Title	Bosentan/Placebo
Arm/Group Description	Outcomes not available, due to early termination of study
Measure Participants	0

Adverse Events

Adverse Event Reporting Description	Serious or Other (non-serious) Adverse Events were collected/assessed, but none observed
Arm/Group Title	Bosentan and Placebo Arms
Arm/Group Description	This group consists of subjects on both arms of the study - bosentan and placebo
All Cause Mortality
	Bosentan and Placebo Arms
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bosentan and Placebo Arms
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	Bosentan and Placebo Arms
	Affected / at Risk (%)	# Events
Total	0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.