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

December 17, 2018 updated by: Boehringer Ingelheim

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
274

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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 Hopital 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
        • Universitätsklinikum 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 Cosió 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 Quirónsalud 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12
Time Frame: Baseline and 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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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
Time Frame: Baseline and 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
Time Frame: Baseline and 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
Time Frame: Baseline and 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
Time Frame: Baseline and 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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Boehringer Ingelheim

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 30, 2016

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 19, 2017

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 13, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 14, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 14, 2016

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 16, 2016

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 11, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 17, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 1199.36
  • 2015-002619-14 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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