Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF

Inclusion criteria:

• Written informed consent consistent with ICH-GCP(The International Conference onHarmonisation of Technical Requirements for Registration of Pharmaceuticals for HumanUse- Good clinical practice) and local laws, signed prior to any study proceduresbeing performed (including any required washout)

• Male or female patients aged greater than or equal to 40 years at visit 1

• Idiopathic Pulmonary Fibrosis (IPF) diagnosis, based upon the ATS (American ThoracicSociety)/ERS (European Respiratory Society)/JRS (Japanese Respiratory Society)/ALAT (Latin American Thoracic Association) 2011 guideline and confirmed by the investigatorbased on chest high resolution computed tomography (HRCT) scan performed within 12months of visit 1

• FVC (Forced vital capacity) greater than or equal to 50% of predicted normal at visit 1

Exclusion criteria:

• ALT (Alanine transaminase), AST (Aspartate aminotransferase)> 1.5 fold upper limit ofnormal (ULN) at visit 1

• Total bilirubin > 1.5 fold ULN at visit 1

• Relevant airways obstruction (i.e. pre-bronchodilator FEV1 (Forced Expiratory Volumein one second)/FVC <0.7) at visit 1

• History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 month of visit 1

• Bleeding Risk: Known genetic predisposition to bleeding, Patients who requirefibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists,dabigatran, heparin, hirudin etc) or high dose antiplatelet therapy, History ofhaemorrhagic central nervous system event within 12 months prior to visit 1, Historyof haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or majorinjury or surgery within 3 months prior to visit 1, International normalised ratio (INR) > 2 at visit 1, Prothrombin time and partial thromboplastin time (PTT) > 150% ofinstitutional ULN at visit 1

• Planned major surgery during the trial participation, including lungtransplantation,major abdominal or major intestinal surgery.

• History of thrombotic event (including stroke and transient ischemic attack) within 12months of visit 1

• Severe renal impairment (Creatinine clearance <30 mL/min calculated by Cockcroft-Gaultformula at visit 1) or end-stage renal disease requiring dialysis

• Treatment with NAC (n-acetylcysteine), prednisone >15 mg daily or >30 mg every 2 daysOR equivalent dose of other oral corticosteroids and/or fluvoxamine within 2 weeks ofvisit 2

• Treatment with azathioprine, cyclophosphamide, cyclosporine as well as any otherinvestigational drug within 8 weeks of visit 2

• Previous treatment with pirfenidone

• Permanent discontinuation of nintedanib in the past due to Adverse Events considereddrug-related

• Known hypersensitivity to nintedanib, pirfenidone, peanut or soya or to any of theexcipients

• A disease or condition which in the opinion of the investigator may interfere withtesting procedures or put the patient at risk when participating in this trial

• Alcohol or drug abuse which in the opinion of the treating physician would interferewith treatment

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial

• Women of childbearing potential not willing or able to use highly effective methods ofbirth control per ICH M3 (R2) that result in a low failure rate of less than 1% peryear when used consistently and correctly5 for 28 days prior to and 3 months afternintedanib administration

• Patients not able to understand and follow study procedures including completion ofself administered questionnaires without help

• Patients who require dose reduction and/or temporary interruption during the run-inperiod with nintedanib 150 mg bid

• Patients with underlying chronic liver disease (Child Pugh A, B or C hepaticimpairment)