efficacy and safety of nintedanib co-administered with sildenafil in idiopathic pulmonary fibrosis patients with advanced lung function impairment

Conditions: Idiopathic Pulmonary Fibrosis

Summary: to assess efficacy and safety of concomitant treatment with nintedanib and sildenafil in idiopathic pulmonary fibrosis (ipf) patients with advanced lung function impairment.


Eligibility criteria:
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.