Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment

Inclusion criteria

• Written informed consent consistent with International Conference on Harmonization-Good Clinical Practice and local laws, signed prior to any study procedures being performed (including any required washout);
• Male or female patients aged >= 40 years at visit 1;
• A clinical diagnosis of IPF within the last 6 years before visit 1, based upon the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American thoracic Association 2011 guideline [P11-07084];
• Combination of high-resolution computed tomography (HRCT) pattern, and if available, surgical lung biopsy pattern consistent with a diagnosis of IPF as assessed by the investigator based on a HRCT scan performed within 18 months of visit 1;
• Carbon Monoxide Diffusion Capacity (corrected for Hb) less or equal to 35% predicted of normal at visit 1.

Exclusion criteria

• Previous enrolment in this trial;
• Alanine Transaminase, Aspartate Transaminase > 1.5 fold upper limit of normal (ULN) at visit 1;
• Total bilirubin > 1.5 fold ULN at visit 1;
• Relevant airways obstruction (i.e. pre-bronchodilator Forced Expiratory Volume in 1 second/Forced Vital Capacity <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 require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelet therapy;
• History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1;
• History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1;
• International normalised ratio (INR) > 2 at visit 1;
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) > 150% of institutional ULN at visit 1;
• Planned major surgery during the trial participation, including lung transplantation, major abdominal or major intestinal surgery;
• History of thrombotic event (including stroke and transient ischemic attack) within 12 months of visit 1;
• Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula at visit 1;
• Presence of aortic stenosis (AS) per investigator judgement at visit 1;
• Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25% per investigator judgement at visit 1;
• Presence of idiopathic hypertrophic subaortic stenosis (IHSS) per investigator judgement at visit 1;
• Second-degree or third-degree atrioventricular (AV) block on electrocardiogram (ECG) per investigator judgement at visit 1;
• Hypotension (systolic blood pressure [SBP] < 100 mm Hg or diastolic blood pressure [DBP] < 50 mm Hg) (symptomatic orthostatic hypotension) at visit 1;
• Uncontrolled systemic hypertension (SBP > 180 mmHg; or DBP > 100 mmHg) at visit 1;
• Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, leukemia) that may predispose to priapism;
• Retinitis pigmentosa;
• History of vision loss;
• History of nonarteritic ischemic optic neuropathy;
• Veno-occlusive disease;
• History of acute IPF exacerbation or respiratory infection within 8 weeks of visit 2.
• Treatment with nitrates, n-acetylcysteine, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids as well as any investigational drug within 4 weeks of visit 2;
• Treatment with prostaglandins (e.g., epoprostenol, treprostinil), endothelin-1 antagonists (e.g., bosentan, sitaxsentan, ambrisentan), phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) or a stimulator of guanylatcyclase (e.g.,riociguat) within 4 weeks of visit 2;
• Treatment with potent cytochrome CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir within 4 weeks of visit 2;
• Supplementation with L-arginine and concurrent use of grapefruit juice or St John's wort within 4 weeks of visit 2;
• Treatment with the reduced dose of nintedanib (100 mg bid) within 4 weeks of visit 2; 27. Permanent discontinuation of nintedanib in the past due to adverse events considered drug-related;
• Known hypersensitivity or intolerance to nintedanib, sildenafil, galactose, peanut or soya or any other components of the study medication;
• A disease or condition which in the opinion of the investigator may interfere with testing 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 interfere with treatment;
• Further exclusion criteria apply.