Clinical trial NCT02579603: Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2015-10-19
Enrollment: 105
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4
timeFrame: baseline, prior to intake of study medication on week 2 and week 4
measure: Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone
timeFrame: Prior to intake of study medication on week 2 and week 4
Other outcomes:
Locations:
city: Danbury
country: United States
facility: Western CT Medical Group, P.C.
state: Connecticut
city: New Orleans
country: United States
facility: Tulane University Hospital and Clinic
state: Louisiana
city: Minneapolis
country: United States
facility: Minnesota Lung Center
state: Minnesota
city: Chesterfield
country: United States
facility: The Lung Research Center, LLC
state: Missouri
city: Charleston
country: United States
facility: Lowcountry Lung and Crit Care
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Concordia Hospital
state: Manitoba
city: Bobigny
country: France
facility: HOP Avicenne
city: Brest
country: France
facility: HOP de la Cavale Blanche
city: Bron cedex
country: France
facility: HOP Louis Pradel
city: Lille
country: France
facility: HOP Calmette
city: Nice
country: France
facility: HOP Pasteur
city: Paris
country: France
facility: HOP Bichat
city: Rennes
country: France
facility: HOP Pontchaillou
city: Donaustauf
country: Germany
facility: Klinik Donaustauf
city: Essen
country: Germany
facility: Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH
city: Heidelberg
country: Germany
facility: Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg
city: Catania
country: Italy
facility: A.O.U. Policlinico Vittorio Emanuele
city: Milano
country: Italy
facility: Osp. S. Giuseppe Fatebenefratelli
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, Wiebe S, Stansen W, Quaresma M, Stowasser S, Wuyts WA; INJOURNEY Trial Investigators. Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial. Am J Respir Crit Care Med. 2018 Feb 1;197(3):356-363. doi: 10.1164/rccm.201706-1301OC.