A European multi-centre, randomised, double-blind trial of pirfenidone in bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant recipients.

The EPOS trial is an investigator initiated study to look at the effect of
Pirfenidone on patients who have had a double lung transplant and who have been
diagnosed with Bronchiolitis Obliterans Syndrome (BOS).
BOS is the result of chronic rejection of the donor lungs in patients who have
had a transplant. The rejection leads to narrowing and fibrosis of the airways
which creates shortness of breath and a dry cough. There is a progressive and
irreversible decline in the FEV1 (the amount of air that can be exhaled in one
second). BOS is the leading cause of death after 1 year post transplant. The
treatment options for BOS are limited and not always effective. The usual
treatment is with drug therapy (Azithromycin) and bronchodilators (drugs to
help open up the airways). Photopheresis (treatment of the blood using
ultraviolet light) has been used to damage the immune cells to try and slow
down the rejection of the donor lungs.
Recent clinical trials in patients with Idiopathic Pulmonary Fibrosis (IPF)
have shown that Pirfenidone can be effective in increasing the lung function;
IPF is a lung condition where scarring occurs in the lung tissue leading to
difficulty in breathing. Pirfenidone is now approved for use in Europe for IPF.
BOS is similar to IPF in that the airways become narrowed due to swelling and
scarring. It is thought that Pirfenidone will help reduce the swelling and
scarring in the airways, in a similar way to IPF.
Approximately 80 patients will take part in this study at 11 lung transplant
centres across Europe. Seven countries will be involved: Denmark, Sweden,
Norway, Germany, The Netherlands, Belgium and the United Kingdom. Patients who
are regularly treated within these 11 lung transplant centres will be
considered for the EPOS study.
The study has been organized by a group of expert physicians and the sponsor of
this study is the lead physician in the University Hospital of Copenhagen.
There is no industrial sponsor for this study.

Primary objective
The primary objective is to evaluate the effect of Pirfenidone on the change in
FEV1 over 6 months in lung transplant recipients with BOS, who are treated with
Azithromycin.


Secondary objectives
The secondary objectives involve the changes seen in the different lung
function tests over the 6 months of the study. In addition, the secondary
objectives will look at the number of patients with treatment failure, with a
change in BOS grade and with any hospital admission. The rate of death or
re-transplantation will be assessed as well as the change in the health
questionnaire score.

Study Design:
Randomized double blinded, placebo controlled study. Eligible patients are to
be randomized in a 1:1 ratio to receive either Pirfenidone 2403 mg/d or the
matching placebo treatment for 6 months.

Study Procedures
All study procedures are the same as the routine tests that are done for
patients with BOS except for one health questionnaire.
Screening
Patients will be screened for the study if they have had a double lung
transplant only. Patients who have other transplants will not be eligible for
the study. The screening process will use the results of diagnostic tests that
the patient will routinely have had due to their condition and their symptoms
of BOS. These diagnostic tests will include the following:
* Chest x-ray
* Lung function tests (spirometry to measure the volume of air inhaled and
exhaled)
* ECG (measure the heart rhythm)
* Bronchoscopy with bronchoalveolar lavage (BAL) according to standard
international criteria. This is an endoscope that passes into the lungs and
saline is flushed in and out to wash the airways and check if there are
bacteria and fungi present.
* Transbronchial biopsy * a biopsy of the large airways
* Blood samples (haematology and chemistry) including liver function tests
* Drug monitoring for immuno-suppressive treatment
Patients who are eligible for the study need to be taking the currently
accepted treatment for BOS * Azithromycin.

Start of Study
Once the patient has signed the consent form, they will have a series of
diagnostic tests that are routine for BOS:
* measurement of weight,
* lung function tests
o spirometry * measure the volume of air inhaled and exhaled to determine the
FEV1
o plethysmography * lung function test to calculate how much air is left in the
lungs after exhalation
o diffusion capacity (DLco) * test to show the movement of oxygen from the air
sacs of the lungs into the blood, after inhalation.
* 6 minute walk test - a test to see the best distance that the patient can
walk in 6 minutes,
* blood tests to check the amount of blood cells, kidney function, liver
function and signs of infection.
* Female patients, who are of child bearing age, will have a pregnancy test
done, before they can enter the study.

In addition, a 2 page health questionnaire will be completed.

The patient will be randomised to receive either Pirfenidone or a placebo.
This is a double blind study, so neither the doctor nor the patient will know
which treatment they are receiving. If there are any safety concerns for a
patient during the study, there will be a possibility to unblind the study
treatment. The patient will be given a bottle of tablets to take home and will
be told to escalate the dose over the 4 weeks as shown in the table below.

Treatment Day Number of capsules
1-7 1 (three times a day with food )
8-14 2 (three times a day with food )
15 + 3 (three times a day with food )


Months 1-4
The patient will come back to the clinic every month for the first 4 months.
Their supply of the treatment will be renewed and they will have a series of
routine tests (weight measurement, spirometry, blood tests). At the 4 month
visit, you will be given enough study drug for 2 months.

Month 5
A blood test will be done to check the condition of the liver. This test may
be done at the study centre or at the family doctor or local clinic.

Month 6
The 6 month visit is the last study visit. The patient will be asked to fill
out the health questionnaire again and also to have a number of routine tests:
* measurement of weight,
* lung function tests (spirometry, plethysmography, diffusion capacity),
* chest x-ray
* 6 minute walk test
* blood tests

A chest CT scan may be arranged but only if this is routine practice for the
clinic. The next routine follow up visit will be arranged as per routine
practice. If a patient wishes to withdraw their consent or if the physician
wishes to change their treatment due to a deterioration in BOS, they will be
withdrawn from the study and will undergo the tests in the 6 month visit.

Subjects who wish to receive open label pirfenidone at the end of the 6 month
EPOS trial, will be offered treatment for 1 year. Safety blood tests will be
done once a month for the first 6 months of open label treatment and then at 3
monthly intervals. The blood results and all spirometry measurements that are
done within this 1 year open label period will be collected for a safety
analysis.

Side Effects

Severe side effects may include the following: allergic reaction (such as
swelling of the face, lips and/or tongue, difficulty breathing or wheezing);
skin reaction to sunlight (blistering and/or large amount of peeling of the
skin); signs of an infection such as a sore throat, fever, mouth ulcers or
flu-like symptoms and signs of liver problems (yellowing of the eyes or skin or
dark urine). Severe allergic reaction and difficulty in breathing are uncommon
and may affect up to 1 in a 100 people.

Very common side effects (may affect more than 1 in 10 people) include: skin
reactions, feeling sick, tiredness, diarrhoea and indigestion or stomach upset.

Common side effects (may affect up to 1 in 10 people) include: throat
infections, sinusitis (infection of the sinus) or infection of the airways
going into the lungs, bladder infections, weight loss, loss of apetite,
difficulty sleeping, dizziness, headache, changes in taste, hot flushes,
shortness of breath, cough, muscle pain, aching joints/joint pains and chest
pain.

Rare side effects (may affect up to 1 in 1000 people) -blood tests may show a
decrease in the white blood cells

Patients will be encouraged to contact someone on the study team if they
experience any side effects.

Treatment failure
Treatment failure will be considered as one of the following:
* New transplantation needed
* Death due to respiratory causes
* Stop study treatment due to need for a rescue therapy (change treatment for
worsening of BOS)


Benefits of the study
There are very few treatment options for patients with BOS. Recent clinical
trials in patients with Idiopathic Pulmonary Fibrosis (IPF) have shown that
Pirfenidone can be effective in increasing the lung function; IPF is a lung
condition where scarring occurs in the lung tissue leading to difficulty in
breathing. Pirfenidone is now approved for use in Europe for IPF.
BOS is similar to IPF in that the airways become narrowed due to swelling and
scarring. It is thought that Pirfenidone will help reduce the swelling and
scarring in the airways, in a similar way to IPF.

Safety considerations
Patients will not be included in the study if they have restarted smoking after
their lung transplant. They will also not be allowed to smoke during the study
as this can reduce the effect of the active drug. They are not allowed to
drink grapefruit juice and they need to keep the same bronchodilator (drug
administered in an inhaler) throughout the study. As Pirfenidone increases the
sensitivity to sunlight, patients will be advised to wear clothes that cover
their arms and legs and to wear sunblock if they go outside.

The Investigator*s Brochure has a section on how to treat the patient if there
are side effects. The study treatment can be stopped for up to 2 weeks, if
there are severe side effects, but the dose escalation will be repeated to
restart the study drug if there has been a 2 week break.

Female patients of child bearing ability will need to use 2 methods of
contraception during the study to avoid becoming pregnant.

An independent Data Safety Monitoring Board will be reviewing the safety
aspects of the trial during the study. In addition to this, the steering
committee will review all enrolled patients to ensure that they were eligible
for entry into the study; this information will be prepared so that each
reviewer is unaware in which centre the patients were enrolled and so that the
reviewer does not review his own patients. The steering committee will also
take on the role of the Clinical Events Committee to review all serious adverse
events; this will be done in the same way as the patient review.