Open-label extension study in patients with Idiopathic Pulmonary Fibrosis who completed protocol AC-052-321 BUILD-3

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing
alveolitis, is a distinct clinical disorder belonging to the spectrum of
interstitial lung diseases (ILD). IPF is a progressive disease characterized by
the presence of a histological pattern of usual interstitial pneumonia (UIP) on
surgical lung biopsy.
IPF was considered a chronic inflammatory disease resulting in parenchymal
fibrosis. However, recent evidence suggests a mechanism of abnormal wound
healing, with progressive extracellular matrix accumulation, decreased
fibroblast-myoblast cell death, continuous epithelial cell apoptosis and
abnormal re-epithelialization. Progressive fibrotic tissue deposition in the
interstitial areas of the lung leads to decreased lung compliance and reduced
gas exchanges.
The onset of symptoms is usually gradual and patients complain of
non-productive cough, shortness of breath occurring first on exercise and then
at rest. Cyanosis, cor pulmonale, and peripheral edema may be observed in the
late phase of the disease.
No therapies have been shown to improve the survival or quality of life for
patients with IPF and none is registered. Current treatment is still based on
the former assumption that IPF is an inflammatory process with concurrent
remodeling of the lung by fibrosis. Consequently, it involves anti-inflammatory
therapy, including corticosteroids (e.g., prednisone, prednisolone),
immunosuppressive/cytotoxic agents (e.g., azathioprine, cyclophosphamide) or a
combination of both. However, because of the marginal benefit and serious side
effects of the current therapies, along with newer insights into the
pathogenesis of IPF, there is an important need for novel therapeutic
approaches.

To assess long-term safety and tolerability of bosentan in patients with IPF.

The trial is an open-label, prospective, non-comparative (single-arm),
multicenter study. It is an extension of the previous double-blind
placebo-controlled study (AC-052-321 / BUILD-3).
The Build-3-OL study is designed to assess the long-term safety and
tolerability of bosentan 125mg twice daily in IPF patients that have
participated in the Build-3 study.

Currently no treatment (medicine) for IPF is registered. About 600 patients
will participate. The treatment period is variable, and is dependent on the
time the patient ends the previous Build-3 study and on the time the Build-3-OL
studie will end.
After the study medication has been stoppen, the patient will be followed for
28 days for safety.

Oral bosentan
* For patients who enter BUILD 3-OL before the release of BUILD 3 study results
(i.e., study treatment in BUILD 3 unknown and must remain blinded):
* Initial dose: 62.5 mg b.i.d. for 4 weeks for all patients.
* Maintenance dose: 125 mg b.i.d. (62.5 mg b.i.d. if patient weighs < 40 kg/90
lbs).
* For patients who enter BUILD 3-OL after the release of the BUILD 3 study
results (i.e., study treatment in BUILD 3 is known):
1. For patients administered bosentan during BUILD 3:
* Patients should continue bosentan treatment at the dose they were receiving
at the end of BUILD 3.
2. For patients administered placebo during BUILD 3:
* Initial dose: 62.5 mg b.i.d. for 4 weeks.
* Maintenance dose: 125 mg b.i.d. (62.5 mg b.i.d. if patient weighs < 40 kg/90
lbs)

Visit 1= day of inclusion: there are three possibilities:
- If this visit is scheduled on the same day as the End of Study Visit of the
the preceding Build-3 study, the extra burden to the patient consists of the
informed consent procedure. The other assessments will then be carried out in
the scope of the Build-3 study.
- Visit 1 within 4 weeks of the End of Study Visit of Build-3: The following
assessments will be done: Informed Consent procedure, documenting of
IPF-specific treatment, full physical exam, bloodpressure, heart rate, weight.
-Visit 1 more than 4 weeks after End of Study Visit of Build-3:In that case
pulmonary function tests (FVC and DLco) will be performed in addition.

Every 6 months a visit to the site will be scheduled: full physical exam,
bloodpressure, heart rate and weight will be assessed. Furthermore
bloodsampling will be done to assess the liverfunction and the hemoglobine
level, and if applicalbe a pregnancy test will be performed.

Monthly in city where patient lives: Bloodsampling to assess liverfunction and
hemoglobin level. A Pregnancy test for women of childbearing potential will be
performed monthly and up to 3 months after End Of Treatment..

Risks associated with participation i.e. the use of bosentan are abnormal liver
function tests, and transient low hemoglobin levels. Therefore, all patients
will have monthly blood samples taken for LFT monitoring. Hemoglobin will be
monitored monthly up to Month 3, every 3 months thereafter up to End Of
Treatment. There is a risk of bruising or pain, at the site from where the
blood was drawn.

Every 6 months, patients will be seen at the outpatient*s department, for a
physical examination, and to take some blood samples.
See also protocol page 12, Visit and Assessment Schedule.

There is no guarantee that patients will benefit directly from this research.
Information obtained during the course of this clinical research study may
contribute to a better understanding of the disease and may be useful in
selecting medicines for future treatment. Regardless of any individual benefit,
the knowledge gained from this study may contribute to information that would
allow the use of this drug or similar drugs in later treatment for patients
suffering from IPF.