safety and efficacy study of bosentan in progressive pulmonary sarcoidosis

Conditions: Sarcoidosis; Pulmonary Hypertension

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.


Eligibility criteria:
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.

Keywords: endothelin receptor antagonist bosentan