Safety and Efficacy Study of Bosentan in Progressive Pulmonary Sarcoidosis (BOPSAC)

• Assess safety and tolerability of bosentan in progressive pulmonary sarcoidosis [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• To evaluate the efficacy of bosentan treatment in the subgroups of patents with and without sarcoidosis-associated pulmonary hypertension. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

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.

• Sarcoidosis
• Pulmonary Hypertension

• 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)
• Drug: placebo
  identical preparation as the study drug, but without the active substance, administered b.i.d.

• Placebo Comparator: Placebo
  placebo b.i.d.
  Intervention: Drug: placebo
• Experimental: Bosentan
  62.5 mg/125 mg bosentan b.i.d.
  Intervention: Drug: bosentan

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.