Nintedanib Twice Daily vs Placebo in Patients Diagnosed With Idiopathic Pulmonary Fibrosis (IPF)

A Six Month Double Blind Randomized Placebo Controlled Trial Followed by Each Arm Being Converted to Oral Nintedanib 150 mg Twice Daily Comparing the Effect on High Resolution Computerized Tomography Quantitative Lung Fibrosis Score, Lung Function, Six Minute Walk Test Distance and St. George's Respiratory Questionnaire After Six Months of Treatment in Patients With Idiopathic Pulmonary Fibrosis With Continued Evaluations Over a Period of up to Eighteen Months

This is an 6 month multi-centre, prospective, randomized, placebo controlled, double blind clinical trial followed by conversion of each arm to active nintedanib for an additional 6 months comparing the effect of nintedanib 150mg bis in die (BID twice daily) on the progression of IPF measured by using High Resolution Computerized Tomography(HRCT), lung function, functional component (6MWT), biomarkers, and PRO component (PROs) with continued treatment and assessments for up to 18 months.

Inclusion criteria:

1. Written Informed Consent consistent with International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and local laws signed prior to entry into the study
2. Patient aged >= 40 years at Visit 1.
3. IPF diagnosed, according to the 2011 American Thoracic Society (ATS) / European Respiratory Society (ERS) / Japanese Respiratory Society(JRS)/ Latin American Thoracic Association (ALAT)/ Latin American Thoracic Association/ Idiopathic Pulmonary Fibrosis (IPF) guidelines for diagnosis and management, within 5 years and reaffirmed applying 2011 Guidelines (P11-07084) if diagnosed >2 years and up to 5 year from Visit 1,. Diagnosis must be confirmed by chest High Resolution Computerized Tomography (HRCT) taken within 24 months of Visit 1. All HRCT results reported to be possible or inconsistent usual interstitial pneumonia (UIP) must have confirmatory pathology.
4. Carbon monoxide Diffusing capacity or Transfer factor of the lung for carbon monoxide (DLCO) (corrected for Hb): 30%-79% predicted of normal
5. Forced Vital Capacity (FVC) >= 50% predicted of normal at Visit 1 and Visit 2

Exclusion criteria:

1. AST, ALT > 1.5 fold ULN

2. Bilirubin > 1.5 fold ULN

3. Bleeding risk:

   1. Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, dabigatran, heparin, hirudin), or high dose antiplatelet therapy. Exceptions: prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 IU s.c. per day) and prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/d, or clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet therapy)

   2. History of hemorrhagic Central Nervous System (CNS) event within 12 months

   3. Any of the following within 3 months:

      • Haemoptysis or haematuria.
      • Active gastro-intestinal bleeding or ulcers.
      • Major injury or surgery.

   4. Coagulation parameters: International normalised ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 150% of institutional ULN.

4. Planned major surgery within the next 3 months, including lung transplantation, major abdominal or major intestinal surgery.

5. Thrombotic risk

   1. Known inherited predisposition to thrombosis.
   2. History of thrombotic event (including stroke and transient ischemic attacks) within 12 months

6. Current or planned usage of any investigational drug during the course of this trial

7. Previous treatment with nintedanib within a clinical trial in the previous 3 months and discontinuation of nintedanib study treatment due to an adverse event

8. Known hypersensitivity to the trial drug or its component

9. A disease or condition which in the opinion of investigator may put the patient at risk because of participation in this trial or limit the patient's ability to participate in this trial. Patients will be excluded if they require greater than 12L/min oxygen, are not ambulatory or require use of a walker or cane during the 6 Minute Titration Walk Test. Patients who cannot complete the 6 Minute Titration Walk Test are excluded from participation.

10. Alcohol or drug abuse which in the opinion of the investigator would interfere with trial participation.

11. Pregnant women or women who are breast feeding or of child bearing potential not using two effective methods of birth control (one barrier and one highly effective non-barrier) for at least 1 month prior to trial and/or not committing to using it until 3 months after end of treatment.