Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
Condition: Lung Diseases, Interstitial
MeSH terms: Lung Diseases; Lung Diseases, Interstitial
Intervention: Nintedanib; Placebo
Intervention MeSH terms: Nintedanib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 663.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The aim of the current study is to investigate the efficacy and safety of nintedanib over 52
      weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as
      patients who present with features of diffuse fibrosing lung disease of >10% extent on
      high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms
      or chest imaging have worsened despite treatment with unapproved medications used in clinical
      practice to treat ILD. There is currently no efficacious treatment available for PF-ILD.
      Based on its efficacy and safety in Idiopathic Pulmonary Fibrosis (IPF), it is anticipated
      that Nintedanib will be a new treatment option for patients with PF-ILD.
    

Eligibility criteria:

        Inclusion criteria:

          -  Written Informed Consent consistent with International Conference on Harmonisation
             Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local laws
             signed prior to entry into the study (and prior to any study procedure including
             shipment of High Resolution Computer Tomography (HRCT) to reviewer).

          -  Male or female patients aged >= 18 years at Visit 1.

          -  Patients with physician diagnosed Interstitial Lung Disease (ILD) who fulfil at least
             one of the following criteria for Progressive Fibrosing Interstitial Lung Disease
             (PF-ILD) within 24 months of screening visit (Visit 1) despite treatment with
             unapproved medications used in clinical practice to treat ILD, as assessed by the
             investigator (refer to Exclusion Criteria):

               -  Clinically significant decline in Forced Vital Capacity (FVC) % pred based on a
                  relative decline of >=10%

               -  Marginal decline in FVC % pred based on a relative decline of .>=5-<10% combined
                  with worsening of respiratory symptoms

               -  Marginal decline in FVC % pred based on a relative decline of >=5-<10% combined
                  with increasing extent of fibrotic changes on chest imaging

               -  Worsening of respiratory symptoms as well as increasing extent of fibrotic
                  changes on chest imaging [Note: Changes attributable to comorbidities e.g.
                  infection, heart failure must be excluded. Unapproved medications used in the
                  clinical practice to treat ILD include but are not limited to corticosteroid,
                  azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab,
                  cyclophosphamide, cyclosporine, tacrolimus].

          -  Fibrosing lung disease on HRCT, defined as reticular abnormality with traction
             bronchiectasis with or without honeycombing, with disease extent of >10%, performed
             within 12 months of Visit 1 as confirmed by central readers.

          -  For patients with underlying Connective Tissue Disease (CTD): stable CTD as defined by
             no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to
             Visit 1.

          -  Carbon Monoxide Diffusion Capacity (DLCO) corrected for Haemoglobin (Hb) [visit 1] ≥
             30% and <80% predicted of normal at Visit 2

          -  FVC >= 45% predicted at Visit 2

        Exclusion criteria:

          -  Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) > 1.5 x Upper Limit
             of Normal (ULN) at Visit 1

          -  Bilirubin > 1.5 x ULN at Visit 1

          -  Creatinine clearance <30 mL/min calculated by Cockcroft-Gault formula at Visit 1
             [Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold
             values as shown above. Visit 2 laboratory results will be available only after
             randomization. In case at Visit 2 the results do no longer satisfy the entry criteria,
             the Investigator has to decide whether it is justified that the patient remains on
             study drug. The justification for decision needs to be documented. Laboratory
             parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once)
             if it is thought to be a measurement error (i.e. there was no abnormal result of this
             test in the recent history of the patient and there is no related clinical sign) or
             the result of a temporary and reversible medical condition, once that condition is
             resolved].

          -  Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic
             impairment).

          -  Previous treatment with nintedanib or pirfenidone.

          -  Other investigational therapy received within 1 month or 6 half-lives (whichever was
             greater) prior to screening visit (Visit 1).

          -  Use of any of the following medications for the treatment of Interstitial Lung Disease
             (ILD): azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS)
             >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2,
             cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2.

        Note: Patients whose Rheumatoid Arthritis (RA)/Connective Tissue Disease (CTD) is managed
        by these medications should not be considered for participation in the current study unless
        change in RA/CTD medication is medically indicated (see Inclusion Criteria)

          -  Diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on American Thoracic Society
             (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin
             American Thoracic Association (ALAT) 2011 Guidelines.

          -  Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:

               -  Previous clinical or echocardiographic evidence of significant right heart
                  failure

               -  History of right heart catheterization showing a cardiac index <= 2 l/min/m²

               -  PAH requiring parenteral therapy with epoprostenol/treprostinil

               -  Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit
                  1).

               -  In the opinion of the Investigator, other clinically significant pulmonary
                  abnormalities.

          -  Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large
             pleural effusion)

          -  Cardiovascular diseases, any of the following:

               -  Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month
                  of Visit 1

               -  Myocardial infarction within 6 months of Visit 1

               -  Unstable cardiac angina within 6 months of Visit 1

          -  Bleeding risk, any of the following:

               -  Known genetic predisposition to bleeding.

               -  Patients who require

                    -  Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K
                       antagonists, direct thrombin inhibitors, heparin, hirudin)

                    -  High dose antiplatelet therapy. [Note: Prophylactic low dose heparin or
                       heparin flush as needed for maintenance of an indwelling intravenous device
                       (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of
                       antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or
                       clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy)
                       are not prohibited].

               -  History of haemorrhagic central nervous system (CNS) event within 12 months of
                  Visit 1.

               -  Any of the following within 3 months of Visit 1:

                    -  Haemoptysis or haematuria

                    -  Active gastro-intestinal (GI) bleeding or GI - ulcers

                    -  Major injury or surgery (Investigators judgment).

               -  Coagulation parameters: International normalized ratio (INR) >2, prolongation of
                  prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x
                  ULN at Visit 1.

          -  History of thrombotic event (including stroke and transient ischemic attack) within 12
             months of Visit 1.

          -  Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)

          -  Patients with peanut allergy.

          -  Other disease that may interfere with testing procedures or in the judgment of the
             Investigator may interfere with trial participation or may put the patient at risk
             when participating in this trial.

          -  Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).

          -  Planned major surgical procedures.

          -  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
             of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per
             year when used consistently and correctly as well as one barrier method for 28 days
             prior to and 3 months after nintedanib administration. A list of contraception methods
             meeting these criteria is provided in the patient information.

          -  In the opinion of the Investigator, active alcohol or drug abuse.

          -  Patients not able to understand or follow trial procedures including completion of
             self-administered questionnaires without help. *A woman is considered of childbearing
             potential, i.e. fertile, following menarche and until becoming post-menopausal unless
             permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral
             salpingectomy and bilateral oophorectomy.