Clinical trial NCT02788474: Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2016-06-02
Enrollment: 347
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: 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.


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;
* Further exclusion criteria apply.

Primary outcomes:
measure: The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12.
timeFrame: baseline and 12 weeks
Secondary outcomes:
measure: Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52
timeFrame: 52 weeks
measure: The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12
timeFrame: baseline and 12 weeks
measure: The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12
timeFrame: baseline and 12 weeks
Other outcomes:
Locations:
city: Jasper
country: United States
facility: Jasper Summit Research, LLC
state: Alabama
city: Danbury
country: United States
facility: Western Connecticut Medical Group
state: Connecticut
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine
state: Florida
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: Dayton
country: United States
facility: Clinical Research Solutions
state: Ohio
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond, Inc.
state: Virginia
city: Camperdown, Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Concord
country: Australia
facility: Concord General Repatriation Hospital -Ambulatory Care Unit
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Bruxelles
country: Belgium
facility: ULB Hopital Erasme
city: Edegem
country: Belgium
facility: Edegem - UNIV UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Yvoir
country: Belgium
facility: Yvoir - UNIV UCL de Mont-Godinne
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
city: Plzen
country: Czechia
facility: University Hospital Plzen, Plzen-Bory
city: Praha 4
country: Czechia
facility: Thomayer Hospital
city: Praha
country: Czechia
facility: University Hospital Na Bulovce, Prague
city: Usti nad Labem
country: Czechia
facility: Masaryk Hospital, Usti nad Labem
city: Helsinki
country: Finland
facility: HYKS Keuhkosairauksien
city: Kuopio
country: Finland
facility: KYS, Keuhkosairauksien
city: Oulu
country: Finland
facility: OYS, sisätautien klinikka
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: TYKS, Keuhkosairauksien klinikka, Turku
city: Brest
country: France
facility: HOP de la Cavale Blanche
city: Bron
country: France
facility: HOP Louis Pradel
city: Paris
country: France
facility: HOP Européen G. Pompidou
city: Reims Cedex
country: France
facility: HOP Maison Blanche
city: Rennes
country: France
facility: HOP Pontchaillou
city: Strasbourg
country: France
facility: HOP Civil
city: Tours
country: France
facility: HOP Bretonneau
city: Bamberg
country: Germany
facility: CIMS Studienzentrum Bamberg GmbH
city: Berlin
country: Germany
facility: Helios Klinikum Emil von Behring
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Grosshansdorf
country: Germany
facility: Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg
city: Immenhausen
country: Germany
facility: Lungenfachklinik Immenhausen
city: München
country: Germany
facility: Klinikum der Universität München - Campus Großhadern
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Budapest
country: Hungary
facility: Semmelweis University
city: Deszk
country: Hungary
facility: Csongrad County's Hosp.
city: Farkasgyepu
country: Hungary
facility: Pulmonology Institute of Veszprem County, Farkasgyepu
city: Miskolc
country: Hungary
facility: BAZ County Central Hospital and University Teaching Hospital
city: Aichi, Seto
country: Japan
facility: Tosei General Hospital
city: Fukuoka, Kurume
country: Japan
facility: Kurume University Hospital
city: Ibaraki, Naka-gun
country: Japan
facility: Ibarakihigashi National Hospial
city: Kanagawa, Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
city: Osaka, Osakasayama
country: Japan
facility: Kindai University Hospital
city: Osaka, Sakai
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
city: Tokushima, Tokushima
country: Japan
facility: Tokushima University Hospital
city: Tokyo, Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo, Ota-ku
country: Japan
facility: Toho University Omori Medical Center
city: Tokyo, Shinjuku-ku
country: Japan
facility: Global Health and Medicine Ctr
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Bydgoszcz
country: Poland
facility: Our Doctor Clinical Trial Center, Department in Bydgoszcz
city: Katowice
country: Poland
facility: Non-pub.Health Care NZOZ Profilaktyka W. Pierzchala,Katowice
city: Krakow
country: Poland
facility: Univ. Hospital in Krakow,Pulmonology Clinical Dept
city: Krakow
country: Poland
facility: John Paul II Cracovian Hosp
city: Lodz
country: Poland
facility: Norbert Barlicki University Clinical Hospital No.1, Lodz
city: Torun
country: Poland
facility: Practice of Internists "Nasz Lekarz", Torun
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Galdakao
country: Spain
facility: Hospital de Galdakao
city: L'Hospitalet Llobregat (bcn)
country: Spain
facility: Hospital de Bellvitge
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Majadahonda (Madrid)
country: Spain
facility: Hospital Puerta de Hierro
city: Pozuelo de Alarcón
country: Spain
facility: Hospital Quirónsalud Madrid
city: Sabadell
country: Spain
facility: CS Parc Taulí
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Valencia
country: Spain
facility: Hospital Dr. Peset
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.