Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment
Condition: Idiopathic Pulmonary Fibrosis
MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis
Intervention: Nintedanib; Placebo; Sildenafil
Intervention MeSH terms: Nintedanib; Sildenafil Citrate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 274.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

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.