BOPSAC: Safety and Efficacy Study of Bosentan in Progressive Pulmonary Sarcoidosis

Sponsor

Daniel Doberer (Other)

Overall Status

Terminated

CT.gov ID

NCT00926627

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Progressive pulmonary sarcoidosis occurs in up to twenty percent of patients who require persistent treatment, but available treatment options have shown considerable long-term toxicity and uncertain or unproven efficacy. In these patients, pulmonary fibrosis and pulmonary hypertension are common complications which have major prognostic impact. Endothelin-1 (ET-1) has been demonstrated to play a key role in pulmonary fibrosis and pulmonary hypertension, and a potential role in pulmonary sarcoidosis. ET-1 is a potent vasoconstrictor and can promote fibrosis, cell proliferation, and remodeling, and is pro-inflammatory. Preliminary data have shown the therapeutic potential of the endothelin receptor antagonist (ERA) bosentan in sarcoidosis associated pulmonary hypertension.

In this light, the therapeutic potential of bosentan as an add-on treatment in progressive pulmonary sarcoidosis needs to be evaluated.

Condition or Disease	Intervention/Treatment	Phase
Sarcoidosis Pulmonary Hypertension	Drug: bosentan Drug: placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Prospective Randomized, Double Blind, Placebo-controlled, Safety and Efficacy Study of Bosentan as add-on Therapy in Progressive Pulmonary Sarcoidosis

Study Start Date :

Apr 1, 2009

Actual Primary Completion Date :

Mar 1, 2010

Actual Study Completion Date :

Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo placebo b.i.d.	Drug: placebo identical preparation as the study drug, but without the active substance, administered b.i.d.
Experimental: Bosentan 62.5 mg/125 mg bosentan b.i.d.	Drug: bosentan 62.5 mg tablets b.i.d. administered orally for 4 weeks followed by the maintenance dose of 125 mg b.i.d. (62.5 mg b.i.d. if body weight < 40 kg/90 lb)

Arm

Intervention/Treatment

Placebo Comparator: Placebo

placebo b.i.d.

Drug: placebo

identical preparation as the study drug, but without the active substance, administered b.i.d.

Experimental: Bosentan

62.5 mg/125 mg bosentan b.i.d.

Drug: bosentan

62.5 mg tablets b.i.d. administered orally for 4 weeks followed by the maintenance dose of 125 mg b.i.d. (62.5 mg b.i.d. if body weight < 40 kg/90 lb)

Outcome Measures

Primary Outcome Measures

Treatment efficacy is assessed by a composite clinical score, including six parameters: Pulmonary function test (FVC and DLCO), Blood gas analysis (AaDO2), HRCT (Oberstein score), 6 minute walk test (6-MWD), Dyspnoea (ATS dyspnea scale) [6 months]

Secondary Outcome Measures

Assess safety and tolerability of bosentan in progressive pulmonary sarcoidosis [6 months]
To evaluate the efficacy of bosentan treatment in the subgroups of patents with and without sarcoidosis-associated pulmonary hypertension. [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent prior to any study-mandated procedure.
Male and female patients aged > 18 and < 70 years.
Histologically proven sarcoidosis diagnosed at least one year before screening.
Diagnosis of sarcoidosis and with evidence of pulmonary parenchymal disease on chest X-ray or CT (radiological stage II, III) with or without pulmonary hypertension. Subjects with concurrent extrapulmonary sarcoidosis are encouraged to be enrolled.
Progressive disease, defined as follows:
Deterioration in the 3-12 month period prior to screening in at least two of the following criteria:
increase in clinical symptoms (cough, shortness of breath, chest pain, fatigue or hemoptysis).
lung function: decrease of 10% in TLC, FVC or DLCO.
worsening of radiographic opacities.
Have been receiving pre-study treatment with prednisolone (or equivalent dose of corticosteroid) as a single agent (≥ 10 mg/day) or other immunosuppressants (methotrexate, azathioprine, cyclophosphamide, TNF inhibitors, etc.) within the 3-month period immediately prior to screening. Patients must be on a stable dose of these medications for > 4 weeks before starting the study medication.
AST and ALT values within three times upper limit of normal.
Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
Negative pregnancy test in female patients.
Adequate contraception in female patients of childbearing age.

Exclusion Criteria:

Known hypersensitivity to any excipients of the drug formulation or to bosentan.
Treatment with another investigational drug within 3 months prior to screening.
Pulmonary sarcoidosis:
without disease progression as defined above
with radiological stage I
with radiological stage IV (pulmonary fibrosis with evidence of honey-combing, hilar retraction, bullae and cysts)
Other cause of pulmonary disease:
Active tuberculosis (or positive Quantiferon test), fungi infection, lymphoma.
Chronic obstructive pulmonary disease, asthma, interstitial lung disease other than sarcoid-related
Anamnesis of beryllium or asbestos exposition
Previous smoking (> 10 PY), or active smoker
Previous administration of bosentan
Positive results from the hepatitis serology, except for vaccinated subjects, at screening.
Positive results from the HIV serology at screening.
Malignancy requiring chemotherapy or radiation
Uncontrolled other disease like
Chronic heart failure (NYHA III, IV)
Diabetes mellitus (blood glucose 2x per day > 250 mg/dl , HbA1c > 10 %)
Arterial hypertension (SBP > 180 mmHg)
Concomitant treatment with cyclosporine A
Concomitant treatment with tacrolimus or sirolimus
Concomitant treatment with glibenclamide
Are pregnant, nursing, or planning pregnancy during the trial or within six month period thereafter.
Have a known substance dependency (drug or alcohol within 3 years of screening).
Presumed non-compliance.
Legal incapacity or limited legal capacity at screening.