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Idiopathic Pulmonary FibrosisPhase 3NCT02802345

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

A Phase 3 study testing Nintedanib and Sildenafil in people with Idiopathic Pulmonary Fibrosis, run by Boehringer Ingelheim at 85 sites in 13 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages 40 years and older
Conditions the study is for
Idiopathic Pulmonary Fibrosis
What is being tested?
Nintedanib and Sildenafil
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
274 participants
Where
85 sitesin 13 countries
Study dates
30 Jun 2016to 13 Apr 2018
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 40 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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:
Show all 36Show fewer
  • 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.

Trial locations and contacts

85 sites in 13 countries.

85 sites in 13 countries

United States17 sites

  • Michigan Clinical Research Unit

    Ann Arbor, Michigan, 48109

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • Lowcountry Lung and Crit Care

    Charleston, South Carolina, 29406

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • The Lung Research Center, LLC

    Chesterfield, Missouri, 63017

  • University of Chicago

    Chicago, Illinois, 60637

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75235

  • Clinical Research Solutions

    Dayton, Ohio, 45409

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • University of Florida College of Medicine

    Jacksonville, Florida, 32209

  • University of Kansas Medical Center

    Kansas City, Kansas, 66160

  • Minnesota Lung Center

    Minneapolis, Minnesota, 55407

  • NewYork-Presbyterian/Weill Cornell Medical Center

    New York, New York, 10065

  • The Oregon Clinic

    Portland, Oregon, 97220

  • Pulmonary Associates of Richmond, Inc.

    Richmond, Virginia, 23225

  • Pulmonary Assoc of Stamford

    Stamford, Connecticut, 06902-3633

  • Mercy Respiratory Specialist

    Toledo, Ohio, 43608

Other trials in United States

Italy10 sites

  • Osp. Clin. SS. Anunziata

    Chieti Scalo, 56100

  • Ospedale Colonnello D Avanzo

    Foggia, 71100

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

    Forlì, 47121

  • Osp. S. Giuseppe Fatebenefratelli

    Milan, 20123

  • Università di Modena e Reggio Emilia

    Modena, 41124

  • Azienda Ospedaliera Universitaria di Padova

    Padova, 35128

  • Az. Ospedaliera Universitaria Polic.Tor Vergata

    Roma, 00133

  • Policlinico Gemelli

    Roma, 00168

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

    Siena, 53100

  • Ospedale Riuniti di Ancona

    Torrette Di Ancona (Ancona), 60126

Other trials in Italy

Japan9 sites

  • Tosei General Hospital

    Aichi, Seto, 489-8642

  • Kurume University Hospital

    Fukuoka, Kurume, 830-0011

  • Ogaki Municipal Hospital

    Gifu, Ogaki, 503-8502

  • National Hospital Organization Himeji Medical Center

    Hyogo, Himeji, 670-8520

  • Ibarakihigashi National Hospial

    Ibaraki, Naka-gun, 319-1113

  • Kanagawa Cardiovascular and Respiratory Center

    Kanagawa, Yokohama, 236-0051

  • National Hospital Organization Kinki-Chuo Chest Medical Center

    Osaka, Sakai, 591-8555

  • Nippon Medical School Hospital

    Tokyo, Bunkyo-ku, 113-8603

  • Toho University Omori Medical Center

    Tokyo, Ota-ku, 143-8541

Other trials in Japan

France8 sites

  • HOP Louis Pradel

    Bron, 69677

  • HOP Calmette

    Lille, 59037

  • HOP Nord

    Marseille, 13015

  • HOP Arnaud de Villeneuve

    Montpellier, 34950

  • HOP Pasteur

    Nice, 06001

  • HOP Européen G. Pompidou

    Paris, 75015

  • HOP Bichat

    Paris, 75018

  • HOP Pontchaillou

    Rennes, 35033

Other trials in France

Germany8 sites

  • Fachkrankenhaus Coswig GmbH

    Coswig, 01640

  • Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH

    Essen, 45239

  • Universitätsklinikum Freiburg

    Freiburg im Breisgau, 79106

  • Universitätsklinikum Gießen und Marburg GmbH

    Giessen, 35392

  • Universitätsmedizin Greifswald

    Greifswald, 17475

  • Medizinische Hochschule Hannover

    Hanover, 30625

  • Lungenfachklinik Immenhausen

    Immenhausen, 34376

  • Wissenschaftliches Institut Bethanien

    Solingen, 42699

Other trials in Germany

United Kingdom6 sites

  • Southmead Hospital

    Bristol, BS10 5NB

  • Papworth Hospital

    Cambridge, CB23 3RE

  • Ninewells Hospital & Medical School

    Dundee, Scotland, DD1 9SY

  • Queen Elizabeth University Hospital

    Glasgow, G51 4TF

  • Northern General Hospital

    Sheffield, S5 7AU

  • South Tyneside District Hospital

    Tyne and Wear, NE34 0PL

Other trials in United Kingdom

Canada5 sites

  • University of Alberta Hospital (University of Alberta)

    Edmonton, Alberta, T6G 2G3

  • QEII Health Sciences Centre (Dalhousie University)

    Halifax, Nova Scotia, B3H 3A7

  • St. Joseph's Healthcare Hamilton

    Hamilton, Ontario, L8N 4A6

  • Toronto General Hospital

    Toronto, Ontario, M5G 2N2

  • St. Paul's Hospital

    Vancouver, British Columbia, V6Z 1Y6

Other trials in Canada

India5 sites

  • Sanjivani Superspeciality Hospital Pvt. Ltd.

    Ahmedabad, 380015

  • Care Institute Of Medical Sciences

    Ahmedabad, 380060

  • Sri Bala Medical Centre & Hospitals

    Coimbatore, 641045

  • Fortis Hospital

    Kolkata

  • Jehangir Clinical Development Centre Pvt. Ltd.

    Pune, 411 001

Other trials in India

Spain5 sites

  • Hospital Vall d'Hebron

    Barcelona, 08035

  • Hospital Universitari de Girona Doctor Josep Trueta

    Girona, 17007

  • Hospital Clínico San Carlos

    Madrid, 28040

  • Hospital Quirónsalud Madrid

    Pozuelo de Alarcón, 28223

  • Hospital General Universitario de Valencia

    Valencia, 46014

Other trials in Spain

Mexico4 sites

  • Nuevo Hospital Civil de Guadalajara DR. JUAN I. MENCHACA

    Guadalajara, 44340

  • Centro Respiratorio de Mexico

    México, 14050

  • Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas

    México, 14080

  • Centro de Prevención y Rehabilitación de Enfermedades Pulmon

    Monterrey, 64460

Other trials in Mexico

Australia3 sites

  • Royal Adelaide Hospital

    Adelaide, South Australia, 5000

  • Royal Prince Alfred Hospital

    Camperdown, Sydney, New South Wales, 2050

  • The Alfred Hospital

    Melbourne, Victoria, 3004

Other trials in Australia

Belgium3 sites

  • Ziekenhuis Netwerk Antwerpen (ZNA) - Campus Middelheim

    Antwerp, 2020

  • ULB Hopital Erasme

    Brussels, 1070

  • UZ Leuven

    Leuven, 3000

Other trials in Belgium

South Korea2 sites

  • Seoul National University Hospital

    Seoul, 110-744

  • Asan Medical Center

    Seoul, 138-736

Other trials in South Korea

About this study

Official title: 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.

Being tested
Nintedanib, Placebo, Sildenafil
Medical subject headings
Idiopathic Pulmonary Fibrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02802345
Study groupRoleWhat they receive
Nintedanib + placebo matching sildenafilExperimentalNot described
Receives: Drug: Nintedanib; Drug: Placebo
Nintedanib + SildenafilActive comparatorNot described
Receives: Drug: Nintedanib; Drug: Sildenafil

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline and week 12

Secondary outcomes (4)

  1. 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.

    Measured: Baseline and week 12

  2. 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.

    Measured: Baseline and week 24

  3. 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.

    Measured: Baseline and week 24

  4. 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.

    Measured: Baseline and week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jun 2016 (estimated)
  2. Study start30 Jun 2016
  3. Primary completion19 Dec 2017
  4. Study completion13 Apr 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
274 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02802345
Sponsor's protocol ID
1199.36
Other IDs
2015-002619-14, 2015
Status last verified
Dec 2018
First submitted
14 Jun 2016
Last updated
11 Jan 2019
Expanded access
Available

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.

    PubMed 31914963

  • 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.

    PubMed 31365829

  • 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.

    PubMed 30220235

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nintedanib and Sildenafil in people with Idiopathic Pulmonary Fibrosis, run by Boehringer Ingelheim at 85 sites in 13 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 85 sites in United States, Italy, Japan, France, Germany and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Jan 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12 (time frame: Baseline and week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02802345, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2019.

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