Safety and Efficacy Study of Bosentan in Progressive Pulmonary Sarcoidosis

Phase 2

Terminated

• Conditions: Sarcoidosis; Pulmonary Hypertension
• Interventions: Drug: bosentan; Drug: placebo

• Registration Number: NCT00926627
• Lead Sponsor: Daniel Doberer

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2009-04
• Study First Submitted: 2009-06-22
• Study First Submitted QC: 2009-06-22
• Study First Posted: 2009-06-23
• Primary Completion: 2010-03
• Study Completion: 2010-03
• Status Verified: 2016-09
• Last Update Submitted: 2016-09-14
• Last Update Posted: 2016-09-15

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 32

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bosentan	bosentan	62.5 mg/125 mg bosentan b.i.d.
Placebo	placebo	placebo b.i.d.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (2)

General Hospital Vienna; 🇦🇹 Vienna, Austria

Wilhelminenspital Wien; 🇦🇹 Vienna, Austria