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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Hypertension; Sarcoidosis
• Intervention / Treatment: Drug: placebo; Drug: bosentan

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • General Hospital Vienna
  • Vienna, Austria, 1180
    • Wilhelminenspital Wien

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Daniel Doberer
• Investigators: Study Director: Daniel Doberer, MD, MSc, Medical University of Vienna

Publications and helpful links

Helpful Links

• Department of Clinical Pharmacology of the Medical University of Vienna

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: June 22, 2009
• First Submitted That Met QC Criteria: June 22, 2009
• First Posted (Estimate): June 23, 2009

Study Record Updates

• Last Update Posted (Estimate): September 15, 2016
• Last Update Submitted That Met QC Criteria: September 14, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: endothelin receptor antagonist; bosentan
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Lung Diseases; Lung Diseases, Interstitial; Hypertension; Hypertension, Pulmonary; Sarcoidosis, Pulmonary; Sarcoidosis; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: EudraCT - 2007-005117-18