AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE ARM STUDY OF THE SAFETY AND TOLERABILITY OF PIRFENIDONE (ESBRIET®) IN COMBINATION WITH NINTEDANIB (OFEV®) IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) is a devastating orphan disease of unknown
etiology characterized by progressively decreasing lung volume, worsening
dyspnea, and diminishing exercise capacity is recognized by the American
Thoracic Society (ATS), European Respiratory Society (ERS), Japanese
Respiratory Society (JRS), and Latin American Thoracic Association (LATA) as a
distinct form of chronic fibrosing interstitial pneumonia. IPF occurs primarily
in older adults, is limited to the lungs, and is defined by a radiologic and
histopathologic pattern of usual interstitial pneumonia (UIP); it is the most
common of the UIPs.

IPF typically begins insidiously, with exertional dyspnea and nonproductive
cough; the clinical course is unpredictable and ranges from slow and
progressive respiratory decline to abrupt and accelerated deterioration. IPF is
irreversible and ultimately fatal, with progressive disability and morbidity
due to respiratory insufficiency. The diagnosis of IPF carries a bleak
prognosis, with an estimated median survival after diagnosis of only 2.5 to 5
years

Although the pathogenesis of IPF remains incompletely understood, the current
view is that a series of microinjuries to the alveolar epithelium results in
release of profibrotic mediators, causing fibroblast and myofibroblast
proliferation, organization into fibroblastic foci, and excessive collagen
deposition and accumulation.

Primary Safety Objective
* Proportion of patients who complete 24 weeks of combination treatment on
pirfenidone at a dose of 1602*2403 mg/d and nintedanib at a dose of 200*300
mg/d

Secondary Safety Objective
* Proportion of patients who discontinue pirfenidone, nintedanib, or both study
treatments because of adverse events before the Week 24 Visit
* Total number of patient days of combination treatment with pirfenidone at a
dose of 1602*2403 mg/d and nintedanib at a dose of 200*300 mg/d
* Total number of days from the initiation of combination treatment to
discontinuation of pirfenidone, nintedanib, or both study treatments
* Frequency and timing of Adverse (AE) and Serious Adverse Events (SAEs)

For futher objectives see protocol section 2.2 and 2.3

This is a multicenter, international, open-label, single-arm safety and
tolerability study of pirfenidone/nintedanib combination treatment in patients
with IPF who have been on a stable dose of pirfenidone with demonstrated
tolerability. In this study, a stable pirfenidone dose will be defined as 1602*
2403 mg/d (801 mg BID or TID). Up to approximately 60 clinical centers in the
US, Europe, and Canada are expected to enroll up to approximately 80 patients.

See further protocol section 3.1

Patients will receive next to their treatment with pirfenidone a treatment of
24 weeks with nintedanib. Patients will be asked to complete a questionnaire at
the beginning and the end of the study. During the whole study the patient is
asked to complete a diary with adverse events, used medication and time and
dose of the study medication.

As both study drugs have gastrointestinal side effects, it is expected that the
frequency of these side effects will increase, i.e. nausea, diarrhoea, vomiting
and resulting weight loss.

These expected side effects, can however, vary from mild to very serious and
may vary from person to person. Everyone taking part in the study will be
watched carefully for any side effects.

For more side effects see section 9 and appendix II if the patient information