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

NCT ID: NCT02788474

Last Updated: 2023-12-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 347 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-09
• Study Completion Date: 2018-06-08

Brief Summary

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.

Conditions

Idiopathic Pulmonary Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

nintedanib

Group Type: EXPERIMENTAL

nintedanib

Intervention Type: DRUG

Interventions

nintedanib

Intervention Type: DRUG

placebo

Intervention Type: DRUG

Eligibility Criteria

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;

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Boehringer Ingelheim

Role: STUDY_CHAIR

Boehringer Ingelheim

Locations

Jasper Summit Research, LLC

Jasper, Alabama, United States

Western Connecticut Medical Group

Danbury, Connecticut, United States

St. Francis Medical Institute

Clearwater, Florida, United States

University of Florida College of Medicine

Jacksonville, Florida, United States

Minnesota Lung Center

Minneapolis, Minnesota, United States

The Lung Research Center, LLC

Chesterfield, Missouri, United States

Clinical Research Solutions

Dayton, Ohio, United States

Pulmonary Associates of Richmond, Inc.

Richmond, Virginia, United States

Royal Prince Alfred Hospital

Camperdown, Sydney, New South Wales, Australia

Concord General Repatriation Hospital -Ambulatory Care Unit

Concord, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

ULB Hopital Erasme

Brussels, , Belgium

Edegem - UNIV UZ Antwerpen

Edegem, , Belgium

UZ Leuven

Leuven, , Belgium

Centre Hospitalier Universitaire de Liège

Liège, , Belgium

Yvoir - UNIV UCL de Mont-Godinne

Yvoir, , Belgium

University Hospital Olomouc

Olomouc, , Czechia

University Hospital Plzen, Plzen-Bory

Pilsen, , Czechia

Thomayer Hospital

Prague, , Czechia

University Hospital Na Bulovce, Prague

Prague, , Czechia

Masaryk Hospital, Usti nad Labem

Ústí nad Labem, , Czechia

HYKS Keuhkosairauksien

Helsinki, , Finland

KYS, Keuhkosairauksien

Kuopio, , Finland

OYS, sisätautien klinikka

Oulu, , Finland

Tampere University Hospital

Tampere, , Finland

TYKS, Keuhkosairauksien klinikka, Turku

Turku, , Finland

HOP de la Cavale Blanche

Brest, , France

HOP Louis Pradel

Bron, , France

HOP Européen G. Pompidou

Paris, , France

HOP Maison Blanche

Reims, , France

HOP Pontchaillou

Rennes, , France

HOP Civil

Strasbourg, , France

HOP Bretonneau

Tours, , France

CIMS Studienzentrum Bamberg GmbH

Bamberg, , Germany

Helios Klinikum Emil von Behring

Berlin, , Germany

Universitätsklinikum Gießen und Marburg GmbH

Giessen, , Germany

Universitätsmedizin Greifswald

Greifswald, , Germany

Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH

Großhansdorf, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg

Heidelberg, , Germany

Lungenfachklinik Immenhausen

Immenhausen, , Germany

Klinikum der Universität München - Campus Großhadern

München, , Germany

Universitätsklinikum Münster

Münster, , Germany

Semmelweis University

Budapest, , Hungary

Csongrad County's Hosp.

Deszk, , Hungary

Pulmonology Institute of Veszprem County, Farkasgyepu

Farkasgyepű, , Hungary

BAZ County Central Hospital and University Teaching Hospital

Miskolc, , Hungary

Tosei General Hospital

Aichi, Seto, , Japan

Kurume University Hospital

Fukuoka, Kurume, , Japan

Ibarakihigashi National Hospial

Ibaraki, Naka-gun, , Japan

Kanagawa Cardiovascular and Respiratory Center

Kanagawa, Yokohama, , Japan

Kindai University Hospital

Osaka, Osakasayama, , Japan

National Hospital Organization Kinki-Chuo Chest Medical Center

Osaka, Sakai, , Japan

Tokushima University Hospital

Tokushima, Tokushima, , Japan

Nippon Medical School Hospital

Tokyo, Bunkyo-ku, , Japan

Toho University Omori Medical Center

Tokyo, Ota-ku, , Japan

Global Health and Medicine Ctr

Tokyo, Shinjuku-ku, , Japan

Our Doctor Clinical Trial Center, Department in Bydgoszcz

Bydgoszcz, , Poland

Non-pub.Health Care NZOZ Profilaktyka W. Pierzchala,Katowice

Katowice, , Poland

Univ. Hospital in Krakow,Pulmonology Clinical Dept

Krakow, , Poland

John Paul II Cracovian Hosp

Krakow, , Poland

Norbert Barlicki University Clinical Hospital No.1, Lodz

Lodz, , Poland

Practice of Internists "Nasz Lekarz", Torun

Torun, , Poland

Seoul National University Bundang Hospital

Seongnam, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital Clínic de Barcelona

Barcelona, , Spain

Hospital Santa Creu i Sant Pau

Barcelona, , Spain

Hospital de Galdakao

Galdakao, , Spain

Hospital de Bellvitge

L'Hospitalet Llobregat (bcn), , Spain

Hospital La Princesa

Madrid, , Spain

Fundación Jiménez Díaz

Madrid, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Puerta de Hierro

Majadahonda (Madrid), , Spain

Hospital Quirónsalud Madrid

Pozuelo de Alarcón, , Spain

CS Parc Taulí

Sabadell, , Spain

Hospital Virgen del Rocío

Seville, , Spain

Hospital Clínico de Valencia

Valencia, , Spain

Hospital Dr. Peset

Valencia, , Spain

Southmead Hospital

Bristol, , United Kingdom

Papworth Hospital

Cambridge, , United Kingdom

Royal Devon and Exeter Hospital

Exeter, , United Kingdom

Royal Brompton Hospital

London, , United Kingdom

Wythenshawe Hospital

Manchester, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

Countries

United States; Australia; Belgium; Czechia; Finland; France; Germany; Hungary; Japan; Poland; South Korea; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 33902584 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33419890 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31326319 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30167310 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-003148-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1199.227

Identifier Type: -

Identifier Source: org_study_id