Bosentan in Pulmonary Hypertension in Interstitial Lung Disease Treatment Study (B-PHIT)

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

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).

Study Overview

• Status: Unknown
• Conditions: Idiopathic Pulmonary Fibrosis; Pulmonary Hypertension; Interstitial Lung Disease; Nonspecific Interstitial Pneumonia
• Intervention / Treatment: Drug: Bosentan; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Stephen J Wort, MRCP PhD; Phone Number: 8362 0207 352 8121; Email: s.wort@imperial.ac.uk
• Study Contact Backup: Name: Athol U Wells, MD FRCP FRCR; Phone Number: 3354 0207 352 8121; Email: A.Wells@rbht.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
    • Contact: Athol U Wells, MD FRCP FRCR; Phone Number: 3354 0207 352 8121; Email: A.Wells@rbht.nhs.uk
    • Contact: Stephen J Wort, FRCP PhD; Phone Number: 8362 0207 352 8121; Email: s.wort@imperial.ac.uk
    • Principal Investigator: Stephen J Wort, FRCP PhD
    • Sub-Investigator: Athol U Wells, MD FRCP FRCR
  • London, United Kingdom, W12 OHS
    • Hammersmith Hospital
    • Contact: Luke Howard, DPhil MRCP; Phone Number: 0208 383 2330; Email: luke.howard@hhnt.nhs.uk
    • Principal Investigator: Luke Howard, DPhil MRCP
  • London, United Kingdom, SW1 O7QT
    • St George's Hospital
    • Contact: Brendan Madden, MD MSc FRCP; Phone Number: 0208 725 5877; Email: Brendan.Madden@stgeorges.nhs.uk
    • Principal Investigator: Brendan Madden, MD MSc FRCP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1; Bosentan tablets (62.5mg bd for first 4 weeks, then 125mg bd as tolerated)	Drug: Bosentan; Bosentan tablets - 62.5mg bd for first 4 weeks, then 125mg bd if tolerated until trial completion.; Other Names: Tracleer
PLACEBO_COMPARATOR: 2; Placebo tablets	Drug: Placebo; Placebo tables - identical to active drug but without the active ingredient -; Other Names: Placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint is a fall in pulmonary vascular resistance (PVR) of 20% over 16 weeks.	16 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	16 weeks
mean Pulmonary arterial Pressure	16 weeks
Six minute walk distance	16 weeks
Quality of life scores (Camphor questionnaire)	16 weeks
Pulmonary function (DLco, FVC and PaO2)	16 weeks
Pulmonary blood flow	16 weeks
Right ventricular mass (Cardiac MRI)	16 weeks
BNP	16 weeks

Collaborators and Investigators

• Sponsor: Royal Brompton & Harefield NHS Foundation Trust
• Collaborators: Actelion
• Investigators: Principal Investigator: Stephen J Wort, FRCP PhD, Royal Brompton Hospital, London; Principal Investigator: Athol U Wells, MD FRCP FRCR, Royal Brompton Hospital, London; Principal Investigator: Luke Howard, DPhil MRCP, Hammersmith Hospitals NHS Trust; Principal Investigator: Brendan Madden, MD MSc FRCP, Royal Brompton & Harefield NHS Foundation Trust

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (ANTICIPATED): April 1, 2010
• Study Completion (ANTICIPATED): August 1, 2010

Study Registration Dates

• First Submitted: March 10, 2008
• First Submitted That Met QC Criteria: March 10, 2008
• First Posted (ESTIMATE): March 17, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): March 17, 2008
• Last Update Submitted That Met QC Criteria: March 10, 2008
• Last Verified: March 1, 2008

More Information

Terms related to this study

• Keywords: Bosentan; Pulmonary hypertension; Idiopathic pulmonary fibrosis; Interstitial lung disease; Endothelin receptor antagonists; Pulmonary vascular resistance; Nonspecific interstitial pneumonia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Fibrosis; Hypertension; Lung Diseases; Pneumonia; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension, Pulmonary; Lung Diseases, Interstitial; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: 2007OE002B; REC number: 07/H0714/125; EudraCT no: 2007-001643-21