Bosentan in Pulmonary Hypertension in Interstitial Lung Disease Treatment Study

Pulmonary Hypertension Clinical Trial

— B-PHIT  

Official title:

Use of the Endothelin-1 Antagonist Bosentan in Patients With Established Pulmonary Hypertension and Fibrotic Lung Disease. - A Randomised, Placebo-Controlled, Double-Blinded Study.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT00637065
• Other study ID #: 2007OE002B
• Secondary ID: REC number: 07/H
• Status: Not yet recruiting
• Phase: Phase 4
• First received: March 10, 2008
• Last updated: March 10, 2008
• Start date: April 2008
• Est. completion date: August 2010

Study information

• Verified date: March 2008
• Source: Royal Brompton & Harefield NHS Foundation Trust
• Contact: Stephen J Wort, MRCP PhD
• Phone: 0207 352 8121
• Email: s.wort[@]imperial.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Department of Health
• Study type: Interventional

Clinical Trial Summary

Over time, patients with fibrosing or interstitial lung disease (ILD) can develop high lung blood pressures (pulmonary hypertension), and this is associated with poorer prognosis and survival. It is thought that development of PH contributes to the deterioration and death of patients with ILD. Endothelin-1 (ET1) is a substance contributing to the development of both PH and ILD. Bosentan is a drug blocking the action of ET-1 by binding to its receptors. Bosentan clearly benefits patients with PH of unknown cause, or related to other diseases (such as heart conditions, or HIV) both alone and in combination with other treatments. In patients with fibrosing lung disease and PH, there have been no controlled treatment studies. Clearly it is important to evaluate the effectiveness of bosentan in these patients.

This study aims to determine the ability of bosentan to reduce high blood pressure in the lungs (pulmonary hypertension) in patients with scarring (fibrosing) lung disease. It is a placebo-controlled double blinded study for 16 weeks (and it is proposed to follow patients in a 16 week open-label phase with bosentan therapy).

Description:

• Purpose: High blood pressure in the lungs or pulmonary hypertension (PH) is a common complication of fibrosing (or interstitial, ILD) lung disease. When present, it is associated with markedly reduced prognosis and survival. Endothelin-1 (ET-1)is over-expressed in patients with PH and ILD, and is thought to play a role in the development of both conditions. Bosentan blocks the action of ET-1, and has been shown to be beneficial in patients with PH from an unknown cause, or related to other conditions (such as heart conditions, connective-tissue disease, and HIV). It is important to establish whether bosentan treatment also benefits patients with PH and ILD.

This study addresses the effectiveness of bosentan in the context of PH and ILD.

• Objective: To examine the ability of bosentan to reduce high blood pressure in the lungs in patients with fibrosing lung diseases and pulmonary hypertension.

• Design: This is a multi-centre, randomised, double-blinded, placebo-controlled study looking at the effect of bosentan in patients with fibrotic lung disease and PH.

• Methodology: Patients will be recruited from outpatient ILD and PH clinical services and will be consented prior to entering the study. We propose to study 48 patients over a 16 week period. Patients will be included in the study if they have fibrosing lung disease (specifically: idiopathic pulmonary fibrosis or idiopathic fibrosing non-specific pneumonitis) and have PH as determined by measurement on right heart catheter (mean pulmonary artery pressure >=25mmHg, pulmonary capillary wedge pressure =<15mmHg).

Patients will enter a 2 week screening period during which they will have a full medical history and examination. If they have not already had clinically important investigations ( echocardiogram, cardiac MRI, overnight oximetry) within the previous 6 weeks and CT scan within the last 3 months, these will be performed.

The patient will have a baseline 6 minute walk test, ECG (heart tracing), blood tests and pulmonary blood flow study (breath test) and lung function tests (breathing tests) and complete a quality of life questionnaire. The patient will then be randomised to bosentan or placebo (2:1)at the baseline visit. Patients will be followed every 4 weeks with physical examination, and blood tests.

At week 16, the initial investigations (including right heart catheter, lung function, pulmonary blood flow, 6-minute walk, blood tests, echocardiogram and cardiac MRI and complete a quality of life questionnaire) will be repeated.

Patients will be offered treatment with open-labelled bosentan therapy until the results of the trial become available up to a maximum of 2 years.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 48
• Est. completion date: August 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patients >=18yrs, <80yrs

2. Patients with idiopathic pulmonary fibrosis (IPF) or idiopathic fibrotic non-specific interstitial pneumonitis (NSIP) confirmed by their respiratory physician according to ATS/ERS criteria.

3. Patients with pulmonary hypertension on right heart catheter (mean pulmonary arterial pressure >=25mmHg with pulmonary artery occlusion pressure, left atrial pressure or left ventricular end-diastolic pressure <15mmHg).

4. Patients providing written informed consent.

Exclusion Criteria:

1. Patients <18, >80yrs.

2. Patients with unstable disease, or an acute exacerbation of their underlying fibrotic lung disease.

3. Patients with significant other organ co-morbidity including hepatic or renal impairment.

4. Patients with systolic BP < 85mmHg

5. Patients with other conditions that may affect the ability to perform a 6-minute walk test.

6. Patients unable to provide informed consent and comply with the patient protocol.

7. Patients receiving excluded medications (including: epoprostenol, or prostacyclin analogues, phosphodiesterase inhibitors, other endothelin receptor antagonists, drugs with potential interaction with bosentan such as glibenclamide, fluconazole, cyclosporin A, or tacrolimus, and other investigational agents).

8. Patients with planned surgical intervention during the study period.

9. Pregnant patients or women of child-bearing age, who are not using a reliable contraceptive method.

10. Patients with clinically overt ischaemic heart disease.

11. Patients with predominant emphysema on high resolution CT scan (emphysema greater in extent than interstitial changes).

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial
• Nonspecific Interstitial Pneumonia
• Pneumonia
• Pulmonary Fibrosis
• Pulmonary Hypertension

Intervention

Drug:
• Bosentan
Bosentan tablets - 62.5mg bd for first 4 weeks, then 125mg bd if tolerated until trial completion.
• Placebo
Placebo tables - identical to active drug but without the active ingredient -

Locations

Country	Name	City	State
United Kingdom	Hammersmith Hospital	London
United Kingdom	Royal Brompton Hospital	London
United Kingdom	St George's Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
Royal Brompton & Harefield NHS Foundation Trust	Actelion

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary endpoint is a fall in pulmonary vascular resistance (PVR) of 20% over 16 weeks.		16 weeks	No
Secondary	mean Pulmonary arterial Pressure		16 weeks	No
Secondary	Six minute walk distance		16 weeks	No
Secondary	Quality of life scores (Camphor questionnaire)		16 weeks	No
Secondary	Pulmonary function (DLco, FVC and PaO2)		16 weeks	No
Secondary	Pulmonary blood flow		16 weeks	No
Secondary	Right ventricular mass (Cardiac MRI)		16 weeks	No
Secondary	BNP		16 weeks	No
Secondary	Progression free survival		16 weeks	No