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

INSTAGE: A 24-week, Double-blind, Randomized, Parallel-group Study Evaluating the Efficacy and Safety of Oral Nintedanib Co-administered With Oral Sildenafil, Compared to Treatment With Nintedanib Alone, in Patients With Idiopathic Pulmonary Fibrosis (IPF) and Advanced Lung Function Impairment

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

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: Nintedanib; Drug: Sildenafil

• Study Type: Interventional
• Enrollment (Actual): 274
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
• Belgium
  • Antwerpen, Belgium, 2020
    • Ziekenhuis Netwerk Antwerpen (ZNA) - Campus Middelheim
  • Bruxelles, Belgium, 1070
    • ULB Hôpital Erasme
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta Hospital (University of Alberta)
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QEII Health Sciences Centre (Dalhousie University)
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
• France
  • Bron cedex, France, 69677
    • HOP Louis Pradel
  • Lille, France, 59037
    • HOP Calmette
  • Marseille, France, 13015
    • HOP Nord
  • Montpellier, France, 34950
    • HOP Arnaud de Villeneuve
  • Nice, France, 06001
    • HOP Pasteur
  • Paris, France, 75018
    • HOP Bichat
  • Paris, France, 75015
    • HOP Européen G. Pompidou
  • Rennes, France, 35033
    • HOP Pontchaillou
• Germany
  • Coswig, Germany, 01640
    • Fachkrankenhaus Coswig GmbH
  • Essen, Germany, 45239
    • Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH
  • Freiburg im Breisgau, Germany, 79106
    • Universitatsklinikum Freiburg
  • Gießen, Germany, 35392
    • Universitätsklinikum Gießen und Marburg GmbH
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Immenhausen, Germany, 34376
    • Lungenfachklinik Immenhausen
  • Solingen, Germany, 42699
    • Wissenschaftliches Institut Bethanien
• India
  • Ahmedabad, India, 380060
    • Care Institute of Medical Sciences
  • Ahmedabad, India, 380015
    • Sanjivani Superspeciality Hospital Pvt. Ltd.
  • Coimbatore, India, 641045
    • Sri Bala Medical Centre & Hospitals
  • Kolkata, India
    • Fortis Hospital
  • Pune, India, 411 001
    • Jehangir Clinical Development Centre Pvt. Ltd.
• Italy
  • Chieti Scalo, Italy, 56100
    • Osp. Clin. SS. Anunziata
  • FORLì, Italy, 47121
    • Ospedale "G.B. Morgagni - L. Pierantoni" ausl forli
  • Foggia, Italy, 71100
    • Ospedale Colonnello D Avanzo
  • Milano, Italy, 20123
    • Osp. S. Giuseppe Fatebenefratelli
  • Modena, Italy, 41124
    • Università di Modena e Reggio Emilia
  • Padova, Italy, 35128
    • Azienda Ospedaliera Universitaria Di Padova
  • Roma, Italy, 00168
    • Policlinico Gemelli
  • Roma, Italy, 00133
    • Az. Ospedaliera Universitaria Polic.Tor Vergata
  • Siena, Italy, 53100
    • A.O.U. Senese Policlinico Santa Maria alle Scotte
  • Torrette Di Ancona (Ancona), Italy, 60126
    • Ospedale Riuniti di Ancona
• Japan
  • Aichi, Seto, Japan, 489-8642
    • Tosei General Hospital
  • Fukuoka, Kurume, Japan, 830-0011
    • Kurume University Hospital
  • Gifu, Ogaki, Japan, 503-8502
    • Ogaki Municipal Hospital
  • Hyogo, Himeji, Japan, 670-8520
    • National Hospital Organization Himeji Medical Center
  • Ibaraki, Naka-gun, Japan, 319-1113
    • Ibarakihigashi National Hospial
  • Kanagawa, Yokohama, Japan, 236-0051
    • Kanagawa Cardiovascular and Respiratory Center
  • Osaka, Sakai, Japan, 591-8555
    • National Hospital Organization Kinki-chuo Chest Medical Center
  • Tokyo, Bunkyo-ku, Japan, 113-8603
    • Nippon Medical School Hospital
  • Tokyo, Ota-ku, Japan, 143-8541
    • Toho University Omori Medical Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
• Mexico
  • Guadalajara, Mexico, 44340
    • Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca
  • Mexico, Mexico, 14080
    • Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
  • Monterrey, Mexico, 64460
    • Centro de Prevención y Rehabilitación de Enfermedades Pulmon
  • México, Mexico, 14050
    • Centro Respiratorio de Mexico
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Girona, Spain, 17007
    • Hospital Universitari de Girona Doctor Josep Trueta
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Pozuelo de Alarcón, Spain, 28223
    • Hospital Quironsalud Madrid
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia
• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Southmead Hospital
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital
  • Dundee, Scotland, United Kingdom, DD1 9SY
    • Ninewells Hospital & Medical School
  • Glasgow, United Kingdom, G51 4TF
    • Queen Elizabeth University Hospital
  • Sheffield, United Kingdom, S5 7AU
    • Northern General Hospital
  • Tyne And Wear, United Kingdom, NE34 0PL
    • South Tyneside District Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Connecticut
    • Stamford, Connecticut, United States, 06902-3633
      • Pulmonary Assoc of Stamford
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Clinical Research Unit
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minnesota Lung Center
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Lung Research Center, LLC
  • New York
    • New York, New York, United States, 10065
      • NewYork-Presbyterian/Weill Cornell Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Dayton, Ohio, United States, 45409
      • Clinical Research Solutions
    • Toledo, Ohio, United States, 43608
      • Mercy Respiratory Specialist
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Charleston, South Carolina, United States, 29406
      • Lowcountry Lung and Crit Care
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
  • 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
• Genders Eligible for Study: All

Description

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;
• Further exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nintedanib + placebo matching sildenafil	Drug: Placebo; Drug: Nintedanib
ACTIVE_COMPARATOR: Nintedanib + Sildenafil	Drug: Nintedanib; Drug: Sildenafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. Scores range from 0 to 100, with higher scores indicating more limitations. The mean and standard error presented are actually adjusted mean for change from baseline and its standard error.	Baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Dyspnoea Using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12	The UCSD SOBQ is a 24-item questionnaire developed to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 12
Change From Baseline in SGRQ Total Score at Week 24	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 24
Change From Baseline in Dyspnoea Using UCSD SOBQ at Week 24	The UCSD SOBQ is a 24-item questionnaire developed to to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 24
Percentage of Patients With On-treatment Serious Adverse Events (SAE) From Baseline to Week 24	Percentage of patients with on-treatment serious adverse events (SAE) from baseline to Week 24 is presented.	Baseline and week 24

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 30, 2016
• Primary Completion (ACTUAL): December 19, 2017
• Study Completion (ACTUAL): April 13, 2018

Study Registration Dates

• First Submitted: June 14, 2016
• First Submitted That Met QC Criteria: June 14, 2016
• First Posted (ESTIMATE): June 16, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 11, 2019
• Last Update Submitted That Met QC Criteria: December 17, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Nintedanib; Sildenafil Citrate
• Other Study ID Numbers: 1199.36; 2015-002619-14 (EUDRACT_NUMBER)