Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment

A 12-week, Double Blind, Randomised, Placebo Controlled, Parallel Group Trial Followed by a Single Active Arm Phase of 40 Weeks Evaluating the Effect of Oral Nintedanib 150 mg Twice Daily on Change in Biomarkers of Extracellular Matrix (ECM) Turnover in Patients With Idiopathic Pulmonary Fibrosis (IPF) and Limited Forced Vital Capacity (FVC) Impairment.

Identifying biomarkers to predict the clinical course and benefits of therapy early in the course of the disease remains one of the most urgent and relevant challenges to improve overall patient management, to prevent treatment delay or overtreatment. This study is conducted to examine the effect of nintedanib treatment on change in biomarkers indicative of extracellular matrix turnover which have been shown recently to correlate with disease progression. This study further aims to confirm the association of biomarker course during the first three months of treatment and disease progression.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: placebo; Drug: nintedanib

• Study Type: Interventional
• Enrollment (Actual): 347
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Concord, New South Wales, Australia, 2139
      • Concord General Repatriation Hospital -Ambulatory Care Unit
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
• Belgium
  • Bruxelles, Belgium, 1070
    • ULB Hopital Erasme
  • Edegem, Belgium, 2650
    • Edegem - UNIV UZ Antwerpen
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire de Liège
  • Yvoir, Belgium, 5530
    • Yvoir - UNIV UCL de Mont-Godinne
• Czechia
  • Olomouc, Czechia, 779 00
    • University Hospital Olomouc
  • Plzen, Czechia, 30599
    • University Hospital Plzen, Plzen-Bory
  • Praha, Czechia, 180 81
    • University Hospital Na Bulovce, Prague
  • Praha 4, Czechia, 14059
    • Thomayer Hospital
  • Usti nad Labem, Czechia, 401 13
    • Masaryk Hospital, Usti nad Labem
• Finland
  • Helsinki, Finland, 00290
    • HYKS Keuhkosairauksien
  • Kuopio, Finland, 70210
    • KYS, Keuhkosairauksien
  • Oulu, Finland, 90220
    • OYS, sisätautien klinikka
  • Tampere, Finland, FI-33520
    • Tampere University Hospital
  • Turku, Finland, 20520
    • TYKS, Keuhkosairauksien klinikka, Turku
• France
  • Brest, France, 29609
    • HOP de la Cavale Blanche
  • Bron, France, 69677
    • HOP Louis Pradel
  • Paris, France, 75015
    • HOP Européen G. Pompidou
  • Reims Cedex, France, 51092
    • HOP Maison Blanche
  • Rennes, France, 35033
    • HOP Pontchaillou
  • Strasbourg, France, 67091
    • HOP Civil
  • Tours, France, 37044
    • HOP Bretonneau
• Germany
  • Bamberg, Germany, 96049
    • CIMS Studienzentrum Bamberg GmbH
  • Berlin, Germany, 14165
    • Helios Klinikum Emil Von Behring
  • Gießen, Germany, 35392
    • Universitätsklinikum Gießen und Marburg GmbH
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Grosshansdorf, Germany, 22927
    • Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany, 69126
    • Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg
  • Immenhausen, Germany, 34376
    • Lungenfachklinik Immenhausen
  • München, Germany, 81377
    • Klinikum der Universität München - Campus Grosshadern
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
• Hungary
  • Budapest, Hungary, 1125
    • Semmelweis University
  • Deszk, Hungary, 6772
    • Csongrad County's Hosp.
  • Farkasgyepu, Hungary, 8582
    • Pulmonology Institute of Veszprem County, Farkasgyepu
  • Miskolc, Hungary, 3526
    • BAZ County Central Hospital and University Teaching Hospital
• Japan
  • Aichi, Seto, Japan, 489-8642
    • Tosei General Hospital
  • Fukuoka, Kurume, Japan, 830-0011
    • Kurume University Hospital
  • Ibaraki, Naka-gun, Japan, 319-1113
    • Ibarakihigashi National Hospial
  • Kanagawa, Yokohama, Japan, 236-0051
    • Kanagawa Cardiovascular and Respiratory Center
  • Osaka, Osakasayama, Japan, 589-8511
    • Kindai University Hospital
  • Osaka, Sakai, Japan, 591-8555
    • National Hospital Organization Kinki-Chuo Chest Medical Center
  • Tokushima, Tokushima, Japan, 770-8503
    • Tokushima University Hospital
  • Tokyo, Bunkyo-ku, Japan, 113-8603
    • Nippon Medical School Hospital
  • Tokyo, Ota-ku, Japan, 143-8541
    • Toho University Omori Medical Center
  • Tokyo, Shinjuku-ku, Japan, 162-8655
    • Global Health and Medicine Ctr
• Korea, Republic of
  • Seongnam, Korea, Republic of, 13620
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
• Poland
  • Bydgoszcz, Poland, 85065
    • Our Doctor Clinical Trial Center, Department in Bydgoszcz
  • Katowice, Poland, 40-752
    • Non-pub.Health Care NZOZ Profilaktyka W. Pierzchala,Katowice
  • Krakow, Poland, 31-066
    • Univ. Hospital in Krakow,Pulmonology Clinical Dept
  • Krakow, Poland, 31-202
    • John Paul II Cracovian Hosp
  • Lodz, Poland, 90-153
    • Norbert Barlicki University Clinical Hospital No.1, Lodz
  • Torun, Poland, 87-100
    • Practice of Internists "Nasz Lekarz", Torun
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau
  • Galdakao, Spain, 48960
    • Hospital de Galdakao
  • L'Hospitalet Llobregat (bcn), Spain, 08907
    • Hospital De Bellvitge
  • Madrid, Spain, 28040
    • Fundación Jiménez Díaz
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28006
    • Hospital La Princesa
  • Majadahonda (Madrid), Spain, 28220
    • Hospital Puerta de Hierro
  • Pozuelo de Alarcón, Spain, 28223
    • Hospital Quirónsalud Madrid
  • Sabadell, Spain, 08208
    • CS Parc Taulí
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocío
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
  • Valencia, Spain, 46017
    • Hospital Dr. Peset
• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Southmead Hospital
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter Hospital
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital
• United States
  • Alabama
    • Jasper, Alabama, United States, 35501
      • Jasper Summit Research, LLC
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Western Connecticut Medical Group
  • Florida
    • Clearwater, Florida, United States, 33765
      • St. Francis Medical Institute
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minnesota Lung Center
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Lung Research Center, LLC
  • Ohio
    • Dayton, Ohio, United States, 45409
      • Clinical Research Solutions
  • Virginia
    • Richmond, Virginia, United States, 23225
      • Pulmonary Associates of Richmond, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Written informed consent consistent with International Conference on Harmonisation Good Clinical Practice and local laws, signed prior to participation in the trial including any study related procedures being performed;
• Male or female patients aged >=40 years at Visit 1;
• A clinical diagnosis of Idiopathic pulmonary fibrosis (IPF) within the last 3 years from visit 0, based upon the American Thoracic Society/ European Respiratory Society /Japanese Respiratory Society/ Latin American Thoracic Association 2011 guideline;
• Chest high resolution computed tomography (HRCT) scan performed within 18 months of Visit 0;
• Combination of HRCT pattern, and surgical lung biopsy pattern (the latter if available) as assessed by central review are consistent with the diagnosis of Idiopathic pulmonary fibrosis;
• Forced vital capacity (FVC) >=80% of predicted normal at Visit 1.

Exclusion criteria:

• Alanine transaminase, Aspartate aminotransferase > 1.5 fold upper limit of normal (ULN) at Visit 1;
• Total bilirubin > 1.5 fold ULN at Visit 1;
• Patients with 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 / Forced vital capacity < 0.70;
• 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 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 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;
• Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula at Visit 1;
• Treatment with nintedanib, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, any other investigational drug, n-acetylcysteine, prednisone/prednisolone >15 mg daily or >30 mg every 2 days OR use of other systemic corticosteroids as well as any investigational drugs within 4 weeks of Visit 2;
• Known hypersensitivity to nintedanib, peanut, soya or to any other components of the study medication;
• Prior discontinuation of nintedanib treatment due to intolerability/ adverse events considered drug related;
• 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 the treatment and would affect patient's ability to participate in this trial;
• Patients not able to understand and follow any study procedures such as but not limited to home spirometry, including completion of self-administered questionnaires without help;
• Women who are pregnant, nursing, who plan to become pregnant while in the trial or female patients with positive pregnancy (ß-HCG) test at Visit 1 and/or Visit 2;
• Women of childbearing potential4 not willing or able to use highly effective methods of birth control per International Conference on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.
• Patients with acute IPF exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period;
• Patients who are or have been participating in another trial with investigational drug/s within one month prior to Visit 1 and patients who have previously been enrolled in this trial;
• Further exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: placebo
Experimental: nintedanib	Drug: nintedanib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12.	The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time.	baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52	For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry. This is a key secondary endpoint of the trial. This outcome measure is "percentage of patients with disease progression" and CRPM is included in the various models as a factor/covariate, and that this outcome measure, the percentage of progressors are displayed under "Measured values"	52 weeks
The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12	The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.	baseline and 12 weeks
The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12	The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time.	baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

General Publications

• Glaspole I, Bonella F, Bargagli E, Glassberg MK, Caro F, Stansen W, Quaresma M, Orsatti L, Bendstrup E. Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities. Respir Res. 2021 Apr 26;22(1):125. doi: 10.1186/s12931-021-01695-y.
• Noth I, Cottin V, Chaudhuri N, Corte TJ, Johannson KA, Wijsenbeek M, Jouneau S, Michael A, Quaresma M, Rohr KB, Russell AM, Stowasser S, Maher TM; INMARK trial investigators. Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial. Eur Respir J. 2021 Jul 8;58(1):2001518. doi: 10.1183/13993003.01518-2020. Print 2021 Jul.
• Maher TM, Stowasser S, Nishioka Y, White ES, Cottin V, Noth I, Selman M, Rohr KB, Michael A, Ittrich C, Diefenbach C, Jenkins RG; INMARK trial investigators. Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study. Lancet Respir Med. 2019 Sep;7(9):771-779. doi: 10.1016/S2213-2600(19)30255-3. Epub 2019 Jul 17.
• Maher TM, Stowasser S, Nishioka Y, White ES, Cottin V, Noth I, Selman M, Blahova Z, Wachtlin D, Diefenbach C, Jenkins RG. Investigating the effects of nintedanib on biomarkers of extracellular matrix turnover in patients with IPF: design of the randomised placebo-controlled INMARK(R)trial. BMJ Open Respir Res. 2018 Aug 20;5(1):e000325. doi: 10.1136/bmjresp-2018-000325. eCollection 2018.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2016
• Primary Completion (Actual): August 4, 2017
• Study Completion (Actual): June 8, 2018

Study Registration Dates

• First Submitted: May 27, 2016
• First Submitted That Met QC Criteria: May 27, 2016
• First Posted (Estimated): June 2, 2016

Study Record Updates

• Last Update Posted (Actual): December 21, 2023
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1199.227; 2015-003148-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

• IPD Sharing Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.
• IPD Sharing Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR