Bosentan in Pulmonary Hypertension in Interstitial Lung Disease Treatment Study

NCT ID: NCT00637065

Last Updated: 2008-03-17

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2010-08-31

Brief 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).

Detailed 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.

Conditions

Pulmonary Hypertension; Interstitial Lung Disease; Idiopathic Pulmonary Fibrosis; Nonspecific Interstitial Pneumonia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Bosentan tablets (62.5mg bd for first 4 weeks, then 125mg bd as tolerated)

Group Type: ACTIVE_COMPARATOR

Bosentan

Intervention Type: DRUG

Bosentan tablets - 62.5mg bd for first 4 weeks, then 125mg bd if tolerated until trial completion.

2

Placebo tablets

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tables - identical to active drug but without the active ingredient -

Interventions

Bosentan

Bosentan tablets - 62.5mg bd for first 4 weeks, then 125mg bd if tolerated until trial completion.

Intervention Type: DRUG

Placebo

Placebo tables - identical to active drug but without the active ingredient -

Intervention Type: DRUG

Other Intervention Names

Tracleer; Placebo tablets

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Actelion

INDUSTRY

Sponsor Role: collaborator

Royal Brompton & Harefield NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Royal Brompton Hospital NHS Trust

Principal Investigators

Stephen J Wort, FRCP PhD

Role: PRINCIPAL_INVESTIGATOR

Royal Brompton Hospital, London

Athol U Wells, MD FRCP FRCR

Role: PRINCIPAL_INVESTIGATOR

Royal Brompton Hospital, London

Luke Howard, DPhil MRCP

Role: PRINCIPAL_INVESTIGATOR

Hammersmith Hospitals NHS Trust

Brendan Madden, MD MSc FRCP

Role: PRINCIPAL_INVESTIGATOR

Royal Brompton & Harefield NHS Foundation Trust

Locations

St George's Hospital

London, London, United Kingdom

Royal Brompton Hospital

London, London, United Kingdom

Hammersmith Hospital

London, London, United Kingdom

Countries

United Kingdom

Central Contacts

Stephen J Wort, MRCP PhD

Role: CONTACT

s.wort@imperial.ac.uk

0207 352 8121 ext. 8362

Athol U Wells, MD FRCP FRCR

Role: CONTACT

a.wells@rbht.nhs.uk

0207 352 8121 ext. 3354

Facility Contacts

Brendan Madden, MD MSc FRCP

Role: primary

Brendan.Madden@stgeorges.nhs.uk

0208 725 5877

Stephen J Wort, FRCP PhD

Role: primary

s.wort@imperial.ac.uk

0207 352 8121 ext. 8362

Athol U Wells, MD FRCP FRCR

Role: backup

A.Wells@rbht.nhs.uk

0207 352 8121 ext. 3354

Luke Howard, DPhil MRCP

Role: primary

luke.howard@hhnt.nhs.uk

0208 383 2330

References

Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, Foley C, Yanez-Lopez M, Babalis D, Marino P, Maher TM, Renzoni EA, Spencer L, Elliot CA, Birring SS, O'Reilly K, Gatzoulis MA, Wells AU, Wort SJ; BPHIT Study Group. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2014 Jul 15;190(2):208-17. doi: 10.1164/rccm.201403-0446OC.

Reference Type: DERIVED

PMID: 24937643 (View on PubMed)

Other Identifiers

REC number: 07/H0714/125

Identifier Type: -

Identifier Source: secondary_id

EudraCT no: 2007-001643-21

Identifier Type: -

Identifier Source: secondary_id

2007OE002B

Identifier Type: -

Identifier Source: org_study_id