Safety and Efficacy Study of Bosentan in Progressive Pulmonary Sarcoidosis

Study Overview
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Brief Summary
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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.

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

Conditions
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Sarcoidosis, Pulmonary Hypertension

Intervention / Treatment
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* Drug: bosentan
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo b.i.d. | Drug: placebo<br>* identical preparation as the study drug, but without the active substance, administered b.i.d.<br>|
| Experimental: Bosentan<br>62.5 mg/125 mg bosentan b.i.d. | Drug: bosentan<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endothelin receptor antagonist, bosentan