Clinical trial NCT00926627: Safety and Efficacy Study of Bosentan in Progressive Pulmonary Sarcoidosis
Official title: A Prospective Randomized, Double Blind, Placebo-controlled, Safety and Efficacy Study of Bosentan as add-on Therapy in Progressive Pulmonary Sarcoidosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sarcoidosis
Pulmonary Hypertension
Keywords: endothelin receptor antagonist
bosentan
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2009-06-23
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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)
timeFrame: 6 months
Secondary outcomes:
measure: Assess safety and tolerability of bosentan in progressive pulmonary sarcoidosis
timeFrame: 6 months
measure: To evaluate the efficacy of bosentan treatment in the subgroups of patents with and without sarcoidosis-associated pulmonary hypertension.
timeFrame: 6 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: General Hospital Vienna
city: Vienna
country: Austria
facility: Wilhelminenspital Wien
Study officials:
affiliation: Medical University of Vienna
name: Daniel Doberer, MD, MSc
role: STUDY_DIRECTOR
References: