Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD)

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.