Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF

Study Overview
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Brief Summary
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This is a phase IV, twelve week, open label, randomized, parallel group study to assess safety and tolerability of combined treatment with nintedanib and pirfenidone. A secondary objective is to assess the exposure based on PK trough concentration values to nintedanib either given alone or in combination with pirfenidone and to assess the exposure of pirfenidone when combined with nintedanib.

Official Title
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A Twelve Week, Open-label, Randomised, Parallel-group Study Evaluating Safety, Tolerability and Pharmacokinetics (PK) of Oral Nintedanib in Combination With Oral Pirfenidone, Compared to Treatment With Nintedanib Alone, in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Nintedanib
* Drug: Pirfenidone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent consistent with ICH-GCP(The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use- Good clinical practice) and local laws, signed prior to any study procedures being performed (including any required washout) Male or female patients aged greater than or equal to 40 years at visit 1 Idiopathic Pulmonary Fibrosis (IPF) diagnosis, based upon the ATS (American Thoracic Society)/ERS (European Respiratory Society)/JRS (Japanese Respiratory Society)/ALAT (Latin American Thoracic Association) 2011 guideline and confirmed by the investigator based on chest high resolution computed tomography (HRCT) scan performed within 12 months of visit 1 FVC (Forced vital capacity) greater than or equal to 50% of predicted normal at visit 1 Exclusion criteria: ALT (Alanine transaminase), AST (Aspartate aminotransferase)> 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 FEV1 (Forced Expiratory Volume in one second)/FVC <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, dabigatran, heparin, hirudin etc) or high dose antiplatelet therapy, History of haemorrhagic central nervous system 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 and partial thromboplastin time (PTT) > 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 Severe renal impairment (Creatinine clearance <30 mL/min calculated by Cockcroft-Gault formula at visit 1) or end-stage renal disease requiring dialysis Treatment with NAC (n-acetylcysteine), prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids and/or fluvoxamine within 2 weeks of visit 2 Treatment with azathioprine, cyclophosphamide, cyclosporine as well as any other investigational drug within 8 weeks of visit 2 Previous treatment with pirfenidone Permanent discontinuation of nintedanib in the past due to Adverse Events considered drug-related Known hypersensitivity to nintedanib, pirfenidone, peanut or soya or to any of the excipients 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 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 correctly5 for 28 days prior to and 3 months after nintedanib administration Patients not able to understand and follow study procedures including completion of self administered questionnaires without help Patients who require dose reduction and/or temporary interruption during the run-in period with nintedanib 150 mg bid Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib<br>Nintedanib 150 mg bid | Drug: Nintedanib<br>* Nintedanib 150mg bid<br>|
| Experimental: Nintedanib and Pirfenidone<br>Nintedanib 150 mg bid combined with pirfenidone up to 801 mg tid | Drug: Nintedanib<br>* Nintedanib 150mg bid<br>Drug: Pirfenidone<br> <br> * Other names: Pirfenidone 801 mg tid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12 | Percentage of patients with on-treatment gastrointestinal (GI) Adverse events (AEs) (SOC GI disorders) from baseline to week 12. On-treatment AEs were defined as AEs with an onset from the first dose of randomised treatment up to the last dose of randomised treatment (inclusive). | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline (Visit 3), Week 2 (Visit 4) and Week 4 (Visit 5) | baseline, prior to intake of study medication on week 2 and week 4 | 
| Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone | Predose plasma concentrations at steady state (Cpre,ss) of pirfenidone at Week 2 (Visit 4) and Week 4 (Visit 5) | Prior to intake of study medication on week 2 and week 4 |