Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment

NCT ID: NCT02802345

Last Updated: 2019-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 274 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2018-04-13

Brief Summary

To assess efficacy and safety of concomitant treatment with nintedanib and sildenafil in Idiopathic Pulmonary Fibrosis (IPF) patients with advanced lung function impairment.

Conditions

Idiopathic Pulmonary Fibrosis

Study Design

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

Study Groups

Nintedanib + placebo matching sildenafil

Group Type: EXPERIMENTAL

Nintedanib

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Nintedanib + Sildenafil

Group Type: ACTIVE_COMPARATOR

Nintedanib

Intervention Type: DRUG

Sildenafil

Intervention Type: DRUG

Interventions

Nintedanib

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Sildenafil

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written informed consent consistent with International Conference on Harmonization-Good Clinical Practice and local laws, signed prior to any study procedures being performed (including any required washout);
• Male or female patients aged >= 40 years at visit 1;
• A clinical diagnosis of IPF within the last 6 years before visit 1, based upon the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American thoracic Association 2011 guideline [P11-07084];
• Combination of high-resolution computed tomography (HRCT) pattern, and if available, surgical lung biopsy pattern consistent with a diagnosis of IPF as assessed by the investigator based on a HRCT scan performed within 18 months of visit 1;
• Carbon Monoxide Diffusion Capacity (corrected for Hb) less or equal to 35% predicted of normal at visit 1.

Exclusion Criteria

• Previous enrolment in this trial;
• Alanine Transaminase, Aspartate Transaminase > 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 Forced Expiratory Volume in 1 second/Forced Vital Capacity <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, direct thrombin inhibitors, heparin, hirudin, etc.) 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 activated partial thromboplastin time (aPTT) > 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;
• Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula at visit 1;
• Presence of aortic stenosis (AS) per investigator judgement at visit 1;
• Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25% per investigator judgement at visit 1;
• Presence of idiopathic hypertrophic subaortic stenosis (IHSS) per investigator judgement at visit 1;
• Second-degree or third-degree atrioventricular (AV) block on electrocardiogram (ECG) per investigator judgement at visit 1;
• Hypotension (systolic blood pressure [SBP] < 100 mm Hg or diastolic blood pressure [DBP] < 50 mm Hg) (symptomatic orthostatic hypotension) at visit 1;
• Uncontrolled systemic hypertension (SBP > 180 mmHg; or DBP > 100 mmHg) at visit 1;
• Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, leukemia) that may predispose to priapism;
• Retinitis pigmentosa;
• History of vision loss;
• History of nonarteritic ischemic optic neuropathy;
• Veno-occlusive disease;
• History of acute IPF exacerbation or respiratory infection within 8 weeks of visit 2.
• Treatment with nitrates, n-acetylcysteine, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids as well as any investigational drug within 4 weeks of visit 2;
• Treatment with prostaglandins (e.g., epoprostenol, treprostinil), endothelin-1 antagonists (e.g., bosentan, sitaxsentan, ambrisentan), phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) or a stimulator of guanylatcyclase (e.g.,riociguat) within 4 weeks of visit 2;
• Treatment with potent cytochrome CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir within 4 weeks of visit 2;
• Supplementation with L-arginine and concurrent use of grapefruit juice or St John's wort within 4 weeks of visit 2;
• Treatment with the reduced dose of nintedanib (100 mg bid) within 4 weeks of visit 2; 27. Permanent discontinuation of nintedanib in the past due to adverse events considered drug-related;
• Known hypersensitivity or intolerance to nintedanib, sildenafil, galactose, peanut or soya or any other components of the study medication;
• 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;

• 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

University of Alabama at Birmingham

Birmingham, Alabama, United States

Pulmonary Assoc of Stamford

Stamford, Connecticut, United States

University of Florida College of Medicine

Jacksonville, Florida, United States

University of Chicago

Chicago, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Michigan Clinical Research Unit

Ann Arbor, Michigan, United States

Minnesota Lung Center

Minneapolis, Minnesota, United States

The Lung Research Center, LLC

Chesterfield, Missouri, United States

NewYork-Presbyterian/Weill Cornell Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Clinical Research Solutions

Dayton, Ohio, United States

Mercy Respiratory Specialist

Toledo, Ohio, United States

The Oregon Clinic

Portland, Oregon, United States

Lowcountry Lung and Crit Care

Charleston, South Carolina, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Pulmonary Associates of Richmond, Inc.

Richmond, Virginia, United States

Royal Prince Alfred Hospital

Camperdown, Sydney, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Ziekenhuis Netwerk Antwerpen (ZNA) - Campus Middelheim

Antwerp, , Belgium

ULB Hopital Erasme

Brussels, , Belgium

UZ Leuven

Leuven, , Belgium

University of Alberta Hospital (University of Alberta)

Edmonton, Alberta, Canada

St. Paul's Hospital

Vancouver, British Columbia, Canada

QEII Health Sciences Centre (Dalhousie University)

Halifax, Nova Scotia, Canada

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Toronto General Hospital

Toronto, Ontario, Canada

HOP Louis Pradel

Bron, , France

HOP Calmette

Lille, , France

HOP Nord

Marseille, , France

HOP Arnaud de Villeneuve

Montpellier, , France

HOP Pasteur

Nice, , France

HOP Européen G. Pompidou

Paris, , France

HOP Bichat

Paris, , France

HOP Pontchaillou

Rennes, , France

Fachkrankenhaus Coswig GmbH

Coswig, , Germany

Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH

Essen, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Universitätsklinikum Gießen und Marburg GmbH

Giessen, , Germany

Universitätsmedizin Greifswald

Greifswald, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Lungenfachklinik Immenhausen

Immenhausen, , Germany

Wissenschaftliches Institut Bethanien

Solingen, , Germany

Sanjivani Superspeciality Hospital Pvt. Ltd.

Ahmedabad, , India

Care Institute Of Medical Sciences

Ahmedabad, , India

Sri Bala Medical Centre & Hospitals

Coimbatore, , India

Fortis Hospital

Kolkata, , India

Jehangir Clinical Development Centre Pvt. Ltd.

Pune, , India

Osp. Clin. SS. Anunziata

Chieti Scalo, , Italy

Ospedale Colonnello D Avanzo

Foggia, , Italy

Ospedale "G.B. Morgagni - L. Pierantoni" ausl forli

Forlì, , Italy

Osp. S. Giuseppe Fatebenefratelli

Milan, , Italy

Università di Modena e Reggio Emilia

Modena, , Italy

Azienda Ospedaliera Universitaria di Padova

Padua, , Italy

Az. Ospedaliera Universitaria Polic.Tor Vergata

Roma, , Italy

Policlinico Gemelli

Roma, , Italy

A.O.U. Senese Policlinico Santa Maria alle Scotte

Siena, , Italy

Ospedale Riuniti di Ancona

Torrette Di Ancona (Ancona), , Italy

Tosei General Hospital

Aichi, Seto, , Japan

Kurume University Hospital

Fukuoka, Kurume, , Japan

Ogaki Municipal Hospital

Gifu, Ogaki, , Japan

National Hospital Organization Himeji Medical Center

Hyogo, Himeji, , Japan

Ibarakihigashi National Hospial

Ibaraki, Naka-gun, , Japan

Kanagawa Cardiovascular and Respiratory Center

Kanagawa, Yokohama, , Japan

National Hospital Organization Kinki-Chuo Chest Medical Center

Osaka, Sakai, , Japan

Nippon Medical School Hospital

Tokyo, Bunkyo-ku, , Japan

Toho University Omori Medical Center

Tokyo, Ota-ku, , Japan

Nuevo Hospital Civil de Guadalajara DR. JUAN I. MENCHACA

Guadalajara, , Mexico

Centro Respiratorio de Mexico

México, , Mexico

Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas

México, , Mexico

Centro de Prevención y Rehabilitación de Enfermedades Pulmon

Monterrey, , Mexico

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Universitari de Girona Doctor Josep Trueta

Girona, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Quirónsalud Madrid

Pozuelo de Alarcón, , Spain

Hospital General Universitario de Valencia

Valencia, , Spain

Southmead Hospital

Bristol, , United Kingdom

Papworth Hospital

Cambridge, , United Kingdom

Ninewells Hospital & Medical School

Dundee, Scotland, , United Kingdom

Queen Elizabeth University Hospital

Glasgow, , United Kingdom

Northern General Hospital

Sheffield, , United Kingdom

South Tyneside District Hospital

Tyne and Wear, , United Kingdom

Countries

United States; Australia; Belgium; Canada; France; Germany; India; Italy; Japan; Mexico; South Korea; Spain; United Kingdom

References

Richeldi L, Kolb M, Jouneau S, Wuyts WA, Schinzel B, Stowasser S, Quaresma M, Raghu G. Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis. BMC Pulm Med. 2020 Jan 8;20(1):3. doi: 10.1186/s12890-019-1030-4.

Reference Type: DERIVED

PMID: 31914963 (View on PubMed)

Behr J, Kolb M, Song JW, Luppi F, Schinzel B, Stowasser S, Quaresma M, Martinez FJ. Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. A Prespecified Subgroup Analysis of a Double-Blind Randomized Clinical Trial (INSTAGE). Am J Respir Crit Care Med. 2019 Dec 15;200(12):1505-1512. doi: 10.1164/rccm.201903-0488OC.

Reference Type: DERIVED

PMID: 31365829 (View on PubMed)

Kolb M, Raghu G, Wells AU, Behr J, Richeldi L, Schinzel B, Quaresma M, Stowasser S, Martinez FJ; INSTAGE Investigators. Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 Nov 1;379(18):1722-1731. doi: 10.1056/NEJMoa1811737. Epub 2018 Sep 15.

Reference Type: DERIVED

PMID: 30220235 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-002619-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1199.36

Identifier Type: -

Identifier Source: org_study_id