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

Idiopathic Pulmonary Fibrosis Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02788474
• Other study ID #: 1199.227
• Secondary ID: 2015-003148-38
• Status: Completed
• Phase: Phase 4
• Start date: June 9, 2016
• Est. completion date: June 8, 2018

Study information

• Verified date: December 2023
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 347
• Est. completion date: June 8, 2018
• Est. primary completion date: August 4, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• nintedanib

• placebo

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown, Sydney	New South Wales
Australia	Concord General Repatriation Hospital -Ambulatory Care Unit	Concord	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Belgium	ULB Hopital Erasme	Bruxelles
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
Czechia	University Hospital Olomouc	Olomouc
Czechia	University Hospital Plzen, Plzen-Bory	Plzen
Czechia	University Hospital Na Bulovce, Prague	Praha
Czechia	Thomayer Hospital	Praha 4
Czechia	Masaryk Hospital, Usti nad Labem	Usti nad Labem
Finland	HYKS Keuhkosairauksien	Helsinki
Finland	KYS, Keuhkosairauksien	Kuopio
Finland	OYS, sisätautien klinikka	Oulu
Finland	Tampere University Hospital	Tampere
Finland	TYKS, Keuhkosairauksien klinikka, Turku	Turku
France	HOP de la Cavale Blanche	Brest
France	HOP Louis Pradel	Bron
France	HOP Européen G. Pompidou	Paris
France	HOP Maison Blanche	Reims Cedex
France	HOP Pontchaillou	Rennes
France	HOP Civil	Strasbourg
France	HOP Bretonneau	Tours
Germany	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	Hannover
Germany	Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg	Heidelberg
Germany	Lungenfachklinik Immenhausen	Immenhausen
Germany	Klinikum der Universität München - Campus Großhadern	München
Germany	Universitätsklinikum Münster	Münster
Hungary	Semmelweis University	Budapest
Hungary	Csongrad County's Hosp.	Deszk
Hungary	Pulmonology Institute of Veszprem County, Farkasgyepu	Farkasgyepu
Hungary	BAZ County Central Hospital and University Teaching Hospital	Miskolc
Japan	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
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Our Doctor Clinical Trial Center, Department in Bydgoszcz	Bydgoszcz
Poland	Non-pub.Health Care NZOZ Profilaktyka W. Pierzchala,Katowice	Katowice
Poland	John Paul II Cracovian Hosp	Krakow
Poland	Univ. Hospital in Krakow,Pulmonology Clinical Dept	Krakow
Poland	Norbert Barlicki University Clinical Hospital No.1, Lodz	Lodz
Poland	Practice of Internists "Nasz Lekarz", Torun	Torun
Spain	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	Fundación Jiménez Díaz	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital La Princesa	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	Sevilla
Spain	Hospital Clínico de Valencia	Valencia
Spain	Hospital Dr. Peset	Valencia
United Kingdom	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 States	The Lung Research Center, LLC	Chesterfield	Missouri
United States	St. Francis Medical Institute	Clearwater	Florida
United States	Western Connecticut Medical Group	Danbury	Connecticut
United States	Clinical Research Solutions	Dayton	Ohio
United States	University of Florida College of Medicine	Jacksonville	Florida
United States	Jasper Summit Research, LLC	Jasper	Alabama
United States	Minnesota Lung Center	Minneapolis	Minnesota
United States	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  Finland,  France,  Germany,  Hungary,  Japan,  Korea, Republic of,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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