Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
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.
Interventions
DRUGNintedanib
Nintedanib 150mg bid
DRUGPirfenidone
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | baseline, prior to intake of study medication on week 2 and week 4 | Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline (Visit 3), Week 2 (Visit 4) and Week 4 (Visit 5) |
| Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone | Prior to intake of study medication on week 2 and week 4 | Predose plasma concentrations at steady state (Cpre,ss) of pirfenidone at Week 2 (Visit 4) and Week 4 (Visit 5) |
Countries
Canada, France, Germany, Italy, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily). | 51 |
| Nintedanib + Pirfenidone Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily. | 53 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Not treated | 1 | 0 |
| Overall Study | Other than stated | 1 | 0 |
Baseline characteristics
| Characteristic | Nintedanib | Nintedanib + Pirfenidone | Total |
|---|---|---|---|
| Age, Continuous | 68.9 Years STANDARD_DEVIATION 6.8 | 68.9 Years STANDARD_DEVIATION 6.6 | 68.9 Years STANDARD_DEVIATION 6.6 |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 44 Participants | 42 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 51 | 46 / 53 |
| serious Total, serious adverse events | 5 / 51 | 2 / 53 |
Outcome results
Primary
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).
Time frame: Baseline to week 12
Population: Treated set : The treated set (104 patients) consisted of all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of randomised investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12 | 52.9 percentage of participants |
| Nintedanib + Pirfenidone | Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12 | 69.8 percentage of participants |
Secondary
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)
Time frame: baseline, prior to intake of study medication on week 2 and week 4
Population: Pharmacokinetic Set (PKS): This analysis set included all patients who had been treated with study medication and who provided evaluable data for at least 1 PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | Week 4 | 5.92 ng/mL | Geometric Coefficient of Variation 73.5 |
| Nintedanib | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | baseline | 7.08 ng/mL | Geometric Coefficient of Variation 56 |
| Nintedanib | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | Week 2 | 7.25 ng/mL | Geometric Coefficient of Variation 52.7 |
| Nintedanib + Pirfenidone | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | baseline | 7.65 ng/mL | Geometric Coefficient of Variation 72.5 |
| Nintedanib + Pirfenidone | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | Week 2 | 8.17 ng/mL | Geometric Coefficient of Variation 69.8 |
| Nintedanib + Pirfenidone | Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4 | Week 4 | 7.13 ng/mL | Geometric Coefficient of Variation 63.9 |
Secondary
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)
Time frame: Prior to intake of study medication on week 2 and week 4
Population: PKS set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib | Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone | Week 2 | 1120 ng/mL | Geometric Coefficient of Variation 122 |
| Nintedanib | Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone | Week 4 | 1220 ng/mL | Geometric Coefficient of Variation 90.7 |