A Study to Compare the Amount of Nintedanib and Pirfenidone in the Blood When Nintedanib and Pirfenidone Are Given Separately or in Combination

Study Overview
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Brief Summary
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The primary objective of this study is to investigate the effect of steady state pirfenidone on the pharmacokinetics of nintedanib and its metabolites following oral administration of 2403 mg/day pirfenidone and to investigate the effect of steady state nintedanib on the pharmacokinetics of pirfenidone at steady state following oral administration of 150 mg bid nintedanib. There will be two cohorts of patients; the first one will consist of patients not treated with pirfenidone or nintedanib, while the second one will consist of patients on pirfenidone treatment.

Official Title
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Investigation of Drug-drug Interaction Between Nintedanib and Pirfenidone in Patients With IPF (an Open Label, Multiple-dose, Two Group Study)

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: Any patients diagnosed with IPF and who comply with eligibility requirements may qualify for participation in the trial. Written informed consent consistent with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) 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 IPF diagnosis, based upon the American Thoracic Society (ATS)/European Respiratory Society(ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) 2011 guideline and chest high-resolution computed tomography (HRCT) scan. Force Vital Capacity (FVC) >=50% of predicted normal at Visit 1 Diffusing capacity of the Lung for Carbon monoxide (DLCO) (corrected for Hb [visit 1]): 30%-79% predicted of normal at visit 2. (test can be performed at visits 1 or 2, or during the screening period) Currently treated with pirfenidone at full dose (this is only for patients going into Group 2). Exclusion criteria: Alanine transaminase (ALT), Aspartate aminotransferase (AST) >1.5 fold upper limit of normal (ULN) at visit 1. Total bilirubin >1.5 fold ULN at visit 1. Underlying chronic liver disease (Child Pugh A, B, or C hepatic impairment) Relevant airways obstruction (i.e. pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/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 (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 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 n-acetylcysteine, prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids 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 in the past three months prior to Visit 2 (Group 1 only). Previous treatment with nintedanib in the past 14 days prior to Visit 2. Permanent discontinuation of nintedanib or pirfenidone in the past due to adverse events considered drug-related. Known hypersensitivity to nintedanib, pirfenidone or their excipients; or to peanut or soya. 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 using highly effective methods of birth control per ICH M3, note 3, highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier contraceptives (e.g. male condom or diaphragm) are acceptable if used in combination with spermicides (e.g. foam, gel). Contraception must be used for 28 days prior to and 3 months after nintedanib and pirfenidone administration. Patients not able to understand and follow study procedures including completion of diaries without help. Current smoker (vaping and e-cigarettes are acceptable)

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment naïve<br>Treatment naïve to pirfenidone | Drug: nintedanib<br> <br> Drug: pirfenidone<br> <br> |
| Experimental: Pirfenidone-treated<br>Treatment before with pirfenidone | Drug: nintedanib<br> <br> Drug: pirfenidone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment naïve, Area Under the Concentration-time Curve of the Nintedanib in Plasma Over the Time Interval 0 to the Last Quantifiable Data Point (AUC0-tz). | AUC0-tz , area under the concentration-time curve of nintedanib in plasma over the time interval from 0 to the last quantifiable concentration. Standard error mentioned in the Method of Dispersion is actually a Geometric Standard Error. | Blood samples were collected at pre-dose and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00 and 10:00 hours post dose. | 
| Treatment naïve, Maximum Measured Concentration of Nintedanib in Plasma After Single Dose Administration (Cmax). | Cmax, maximum measured concentration of nintedanib in plasma. Standard error mentioned in the Method of Dispersion is actually a Geometric Standard Error. | Blood samples were collected at pre-dose and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00 and 10:00 hours post dose. | 
| Pirfenidone-treated, Area Under the Concentration-time Curve of Pirfenidone in Plasma Over a Dosing Interval at Steady State (AUCτ,ss) | AUCτ,ss, area under the concentration-time curve of pirfenidone in plasma over a dosing interval at steady state. Standard error mentioned in the Method of Dispersion is actually a Geometric Standard Error. | Blood samples were collected at pre-dose and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00 and 10:00 hours post dose. | 
| Pirfenidone-treated, Maximum Measured Concentration of Pirfenidone in Plasma at Steady State (Cmax,ss) | Cmax,ss, maximum measured concentration of pirfenidone in plasma at steady state. Standard error mentioned in the Method of Dispersion is actually a Geometric Standard Error. | Blood samples were collected at pre-dose and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00 and 10:00 hours post dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment naïve, Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | AUC0-∞, area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity. Standard error mentioned in the Method of Dispersion is actually a Geometric Standard Error. | Blood samples were collected at pre-dose and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00 and 10:00 hours post dose. |