Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD) (INBUILD®)

• ClinicalTrials.gov Identifier: NCT02999178
• Recruitment Status: Completed
• First Posted: December 21, 2016
• Results First Posted: May 5, 2020
• Last Update Posted: May 5, 2020
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

The aim of the current study is to investigate the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as patients who present with features of diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging have worsened despite treatment with unapproved medications used in clinical practice to treat ILD. There is currently no efficacious treatment available for PF-ILD. Based on its efficacy and safety in Idiopathic Pulmonary Fibrosis (IPF), it is anticipated that Nintedanib will be a new treatment option for patients with PF-ILD.

Condition or disease	Intervention/treatment	Phase
Lung Diseases, Interstitial	Drug: Nintedanib; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 663 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Nintedanib Over 52 Weeks in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
• Actual Study Start Date: January 17, 2017
• Actual Primary Completion Date: April 23, 2019
• Actual Study Completion Date: August 12, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nintedanib	Drug: Nintedanib; Other Name: OVEF
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Annual Rate of Decline in Forced Vital Capacity - Overall Population [ Time Frame: Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
   Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Overall population consists of all randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only or HRCT fibrotic pattern= Other fibrotic patterns. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in the overall population is based on a random coefficient regression with fixed effects for treatment, HRCT fibrotic pattern, and baseline FVC [mL], and including treatment-by-time and baseline-by-time interactions. Within-participant errors are modelled by an unstructured variance-covariance matrix.
2. Annual Rate of Decline in Forced Vital Capacity - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
   Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only is based on a random coefficient regression with fixed effects for treatment, baseline FVC [mL], and including treatment-by-time and baseline-by-time interactions. Within-participant errors are modelled by an unstructured variance-covariance matrix.

Secondary Outcome Measures :

1. Absolute Change From Baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) Total Score at Week 52 - Overall Population [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
   King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, score of 100 representing the best health status. If missing items were >50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline in K-BILD Total score at week 52 in the overall population was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for participant. Visit was the repeated measure. Within-participant errors were modelled by unstructured variance-covariance matrix.
2. Absolute Change From Baseline in King's Brief Interstitial Lung Disease (K-BILD) Questionnaire Total Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
   King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, score of 100 representing the best health status. If missing items were >50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline in K-BILD Total score at week 52 in participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for participant. Visit was the repeated measure. Within-participant errors were modelled by unstructured variance-covariance matrix.
3. Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Overall Population [ Time Frame: From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days ]
   Time to first acute ILD exacerbation or death over 52 weeks was defined as time to first acute ILD exacerbation or death due to any cause within the first 52 weeks and was computed as earliest of date of first documented acute ILD exacerbation or death - date of first drug intake + 1. Participants alive who did not experience any ILD exacerbation event or with unknown status within the first 52 weeks were censored.
4. Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days ]
   Time to first acute ILD exacerbation or death over 52 weeks was defined as time to first acute ILD exacerbation or death due to any cause within the first 52 weeks and was computed as earliest of date of first documented acute ILD exacerbation or death - date of first drug intake + 1. Participants alive who did not experience any ILD exacerbation event or with unknown status within the first 52 weeks were censored.
5. Time to Death Over 52 Weeks - Overall Population [ Time Frame: From first drug intake until date of death or last contact date, up to 372 days ]
   Time to death over 52 weeks defined as the time from date of first drug intake until date of death from any cause for participants with known date of death (from any cause) within the first 52 weeks. Participants with no event (death from any cause) or unknown status within the first 52 weeks were censored.
6. Time to Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: From first drug intake until date of death or last contact date, up to 372 days ]
   Time to death over 52 weeks defined as the time from date of first drug intake until date of death from any cause for participants with known date of death (from any cause) within the first 52 weeks. Participants with no event (death from any cause) or unknown status within the first 52 weeks were censored.
7. Time to Death Due to Respiratory Cause Over 52 Weeks - Overall Population [ Time Frame: From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days ]
   Time to death due to respiratory cause over 52 weeks is defined as the time from date of first drug intake until date of death attributed to respiratory causes (determined by an independent Adjudication Committee) for participants with known date of death (from respiratory causes) within the first 52 weeks. Participants with no event (death from respiratory causes) or unknown status within the first 52 weeks were censored. As less than 4.95% of the total of participants in the analysis population experienced an event, only descriptive statistics were performed, as pre-specified.
8. Time to Death Due to Respiratory Cause Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days ]
   Time to death due to respiratory cause over 52 weeks is defined as the time from date of first drug intake until date of death attributed to respiratory causes (determined by an independent Adjudication Committee) for participants with known date of death (from respiratory causes) within the first 52 weeks. Participants with no event (death from respiratory causes) or unknown status within the first 52 weeks were censored. As less than 4.95% of the total of participants in the analysis population experienced an event, only descriptive statistics were performed, as pre-specified.
9. Time to Progression or Death Over 52 Weeks - Overall Population [ Time Frame: From first drug intake until date of progression or date of death or last contact date, up to 372 days ]
   Time to progression or death over 52 weeks is defined as the time from date of first drug intake to date of progression, or date of death (from any cause) if a participant died earlier. Participants with no event (progression or death from any cause) or unknown status were censored. Date of progression is defined as the date when ≥ 10% of absolute decline in FVC percent predicted compared to baseline occured for the first time. Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent.
10. Time to Progression or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: From first drug intake until date of progression or date of death or last contact date, up to 372 days ]
    Time to progression or death over 52 weeks is defined as the time from date of first drug intake to date of progression, or date of death (from any cause) if a participant died earlier. Participants with no event (progression or death from any cause) or unknown status were censored. Date of progression is defined as the date when ≥ 10% of absolute decline in FVC percent predicted compared to baseline occured for the first time. Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent.
11. Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 10 Percent at Week 52 - Overall Population [ Time Frame: Baseline and up to 52 weeks after first drug intake ]
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 10% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 10% and those participants with missing data (worst case analysis).
12. Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 10 Percent at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline and up to 52 weeks after first drug intake ]
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 10% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 10% and those participants with missing data (worst case analysis).
13. Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 5 Percent at Week 52 - Overall Population [ Time Frame: Baseline and up to 52 weeks after first drug intake ]
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 5% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those participants with missing data (worst case analysis).
14. Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 5 Percent at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline and up to 52 weeks after first drug intake ]
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 5% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those participants with missing data (worst case analysis).
15. Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 - Overall Population [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
    Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in dyspnea score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline dyspnea score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).
16. Absolute Change From Baseline in L-PF Symptoms Dyspnea Domain Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
    Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in dyspnea score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, visit, treatment-by-visit interaction, baseline dyspnea score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).
17. Absolute Change From Baseline in L-PF Symptoms Cough Domain Score at Week 52 - Overall Population [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
    Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in cough score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).
18. Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only [ Time Frame: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits) ]
    Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in cough score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Written Informed Consent consistent with International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local laws signed prior to entry into the study (and prior to any study procedure including shipment of High Resolution Computer Tomography (HRCT) to reviewer).
• Male or female patients aged >= 18 years at Visit 1.

• Patients with physician diagnosed Interstitial Lung Disease (ILD) who fulfil at least one of the following criteria for Progressive Fibrosing Interstitial Lung Disease (PF-ILD) within 24 months of screening visit (Visit 1) despite treatment with unapproved medications used in clinical practice to treat ILD, as assessed by the investigator (refer to Exclusion Criteria):

  • Clinically significant decline in Forced Vital Capacity (FVC) % pred based on a relative decline of >=10%
  • Marginal decline in FVC % pred based on a relative decline of .>=5-<10% combined with worsening of respiratory symptoms
  • Marginal decline in FVC % pred based on a relative decline of >=5-<10% combined with increasing extent of fibrotic changes on chest imaging
  • Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging [Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
• Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1 as confirmed by central readers.
• For patients with underlying Connective Tissue Disease (CTD): stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
• Carbon Monoxide Diffusion Capacity (DLCO) corrected for Haemoglobin (Hb) [visit 1] ≥ 30% and <80% predicted of normal at Visit 2
• FVC >= 45% predicted at Visit 2

Exclusion criteria:

• Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) > 1.5 x Upper Limit of Normal (ULN) at Visit 1
• Bilirubin > 1.5 x ULN at Visit 1
• Creatinine clearance <30 mL/min calculated by Cockcroft-Gault formula at Visit 1 [Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign) or the result of a temporary and reversible medical condition, once that condition is resolved].
• Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
• Previous treatment with nintedanib or pirfenidone.
• Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
• Use of any of the following medications for the treatment of Interstitial Lung Disease (ILD): azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2.

Note: Patients whose Rheumatoid Arthritis (RA)/Connective Tissue Disease (CTD) is managed by these medications should not be considered for participation in the current study unless change in RA/CTD medication is medically indicated (see Inclusion Criteria)

• Diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on American Thoracic Society (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) 2011 Guidelines.

• Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:

  • Previous clinical or echocardiographic evidence of significant right heart failure
  • History of right heart catheterization showing a cardiac index <= 2 l/min/m²
  • PAH requiring parenteral therapy with epoprostenol/treprostinil
  • Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 1).
  • In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
• Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)

• Cardiovascular diseases, any of the following:

  • Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month of Visit 1
  • Myocardial infarction within 6 months of Visit 1
  • Unstable cardiac angina within 6 months of Visit 1

• Bleeding risk, any of the following:

  • Known genetic predisposition to bleeding.

  • Patients who require

    • Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
    • High dose antiplatelet therapy. [Note: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited].
  • History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.

  • Any of the following within 3 months of Visit 1:

    • Haemoptysis or haematuria
    • Active gastro-intestinal (GI) bleeding or GI - ulcers
    • Major injury or surgery (Investigators judgment).
  • Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN at Visit 1.
• History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
• Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
• Patients with peanut allergy.
• Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
• Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
• Planned major surgical procedures.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
• Women of childbearing potential* not willing or able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly as well as one barrier method for 28 days prior to and 3 months after nintedanib administration. A list of contraception methods meeting these criteria is provided in the patient information.
• In the opinion of the Investigator, active alcohol or drug abuse.
• Patients not able to understand or follow trial procedures including completion of self-administered questionnaires without help. *A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, California

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

University of California Los Angeles

Los Angeles, California, United States, 90095

University of California Davis

Sacramento, California, United States, 95817

University of California San Francisco

San Francisco, California, United States, 94143

United States, Colorado

National Jewish Health

Denver, Colorado, United States, 80206

United States, Connecticut

Pulmonary and Sleep Specialists

Danbury, Connecticut, United States, 06810

Yale University School of Medicine

New Haven, Connecticut, United States, 06510

United States, Florida

Pulmonary and Sleep of Tampa Bay

Brandon, Florida, United States, 33511

University of Florida College of Medicine

Jacksonville, Florida, United States, 32209

University of Miami

Miami, Florida, United States, 33125

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

University of Chicago

Chicago, Illinois, United States, 60637

Loyola University Medical Center

Maywood, Illinois, United States, 60153

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Kentucky

University of Kentucky Medical Center

Lexington, Kentucky, United States, 40536

United States, Maryland

University of Maryland School of Medicine

Baltimore, Maryland, United States, 21201

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21224

Pulmonary and Critical Care Associates of Baltimore

Towson, Maryland, United States, 21286

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Michigan

Pulmonary and Critical Care Medicine

Ann Arbor, Michigan, United States, 48109

Henry Ford Health System

Detroit, Michigan, United States, 48202

Spectrum Health

Grand Rapids, Michigan, United States, 49546

United States, Minnesota

University of Minnesota Masonic Cancer Center

Minneapolis, Minnesota, United States, 55455

Mayo Clinic, Rochester

Rochester, Minnesota, United States, 55905

United States, Missouri

The Lung Research Center, LLC

Chesterfield, Missouri, United States, 63017

United States, Nebraska

Creighton University

Omaha, Nebraska, United States, 68124

United States, New Hampshire

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States, 03756

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Columbia University Medical Center-New York Presbyterian Hospital

New York, New York, United States, 10032

NewYork-Presbyterian/Weill Cornell Medical Center

New York, New York, United States, 10065

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Southeastern Research Center

Winston-Salem, North Carolina, United States, 27103

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oregon

The Oregon Clinic

Portland, Oregon, United States, 97220

The Oregon Clinic

Portland, Oregon, United States, 97225

United States, Pennsylvania

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Temple University Hospital

Oaks, Pennsylvania, United States, 19456

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

University of South Carolina

Columbia, South Carolina, United States, 29203

United States, Texas

Baylor University Medical Center

Dallas, Texas, United States, 75246

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Texas Pul & Crit Care Conslt

Fort Worth, Texas, United States, 76104

Houston Methodist Hospital

Houston, Texas, United States, 77030

Diagnostics Research Group

San Antonio, Texas, United States, 78229

Medical Arts and Research Center (MARC)

San Antonio, Texas, United States, 78229

United States, Utah

University of Utah Health Sciences Center

Salt Lake City, Utah, United States, 84108

United States, Virginia

Inova Fairfax Medical Campus

Falls Church, Virginia, United States, 22042

Pulmonary Associates of Richmond, Inc.

Richmond, Virginia, United States, 23225

Argentina

Centro Dr. Lazaro Langer S.R.L

Alberdi Sur, Argentina, X5003DCE

Centro de Investigaciones Metabólicas (CINME)

C.a.b.a, Argentina, 1056

Sanatorio Güemes

Ciudad Autónoma de Bs As, Argentina, C1180AAX

CEMER-Centro Medico De Enfermedades Respiratorias

Florida, Argentina, B1602DQD

INSARES

Mendoza, Argentina, M5500CCG

Instituto Médico de la Fundación Estudios Clínicos

Rosario, Argentina, S2000DEJ

Belgium

Centre Hospitalier Universitaire de Liège

Angleur, Belgium, 4031

ULB Hopital Erasme

Bruxelles, Belgium, 1070

UZ Leuven

Leuven, Belgium, 3000

Yvoir - UNIV UCL de Mont-Godinne

Yvoir, Belgium, 5530

Canada, Manitoba

Concordia Hospital

Winnipeg, Manitoba, Canada, R2K 3S8

Canada, Ontario

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada, L8N 4A6

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2N2

Canada, Quebec

CHUS Fleurimont

Sherbrooke, Quebec, Canada, J1H 5N4

Chile

Hospital Clínico Reg. de Concepción "Dr. G. Grant Benavente"

Concepción, Chile, 4070038

Instituto Nacional del Tórax

Providencia, Santiago De Chile, Chile, 7500000

Centro de Investigación del Maule

Talca, Chile, 3465586

China

Peking Union Medical College Hospital

Beijing, China, 100032

First Affiliated Hospital of Guangzhou Medical University

Guangzhou, China, 510120

Nanjing Drum Tower Hospital

Nanjing, China, 210008

The First Hospital of Chinese Medical University

Shenyang, China

France

HOP Avicenne

Bobigny, France, 93009

HOP Louis Pradel

Bron, France, 69500

HOP Côte de Nacre

Caen, France, 14033

HOP d'Instruction des Armées Percy

Clamart, France, 92140

HOP Calmette

Lille, France, 59037

HOP Nord

Marseille, France, 13015

HOP Arnaud de Villeneuve

Montpellier, France, 34295

HOP Pasteur

Nice, France, 06001

HOP Bichat

Paris, France, 75018

HOP Maison Blanche

Reims, France, 51092

HOP Pontchaillou

Rennes, France, 35033

HOP Civil

Strasbourg, France, 67091

HOP Bretonneau

Tours, France, 37000

Germany

Universitätsklinikum Bonn AöR

Bonn, Germany, 53105

Fachkrankenhaus Coswig GmbH

Coswig, Germany, 01640

Klinik Donaustauf

Donaustauf, Germany, 93093

Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH

Essen, Germany, 45239

Medizinische Hochschule Hannover

Hannover, Germany, 30625

Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg

Heidelberg, Germany, 69126

Wissenschaftliches Institut Bethanien

Solingen, Germany, 42699

Universitätsklinikum Tübingen

Tübingen, Germany, 72076

Petrus-Krankenhaus

Wuppertal, Germany, 42283

Italy

A.O.U. Policlinico Vittorio Emanuele

Catania, Italy, 95124

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

FORLì, Italy, 47121

Azienda Ospedaliera Policlinico di Modena

Modena, Italy, 41100

A.O. San Gerardo di Monza

Monza, Italy, 20900

Policlinico Gemelli

Roma, Italy, 00168

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

Siena, Italy, 53100

Japan

Tosei General Hospital

Aichi, Seto, Japan, 489-8642

Kurume University Hospital

Fukuoka, Kurume, Japan, 830-0011

Sapporo Medical University Hospital

Hokkaido, Sapporo, Japan, 060-8543

National Hospital Organization Himeji Medical Center

Hyogo, Himeji, Japan, 670-8520

Kobe City Medical Center General Hospital

Hyogo, Kobe, Japan, 650-0047

Ibarakihigashi National Hospial

Ibaraki, Naka-gun, Japan, 319-1113

Kanagawa Cardiovascular and Respiratory Center

Kanagawa, Yokohama, Japan, 236-0051

Saiseikai Kumamoto Hospital

Kumamoto, Kumamoto, Japan, 861-4193

Tohoku University Hospital

Miyagi, Sendai, Japan, 980-8574

Nagasaki University Hospital

Nagasaki, Nagasaki, Japan, 852-8501

National Hospital Organization Kinki-Chuo Chest Medical Center

Osaka, Sakai, Japan, 591-8555

Osaka Medical College Hospital

Osaka, Takatsuki, Japan, 569-8686

Hamamatsu University Hospital

Shizuoka, Hamamatsu, Japan, 431-3192

Jichi Medical University Hospital

Tochigi, Shimotsuke, Japan, 329-0498

Tokushima University Hospital

Tokushima, Tokushima, Japan, 770-8503

Tokyo Medical and Dental University

Tokyo, Bunkyo-ku, Japan, 113-8519

Nippon Medical School Hospital

Tokyo, Bunkyo-ku, Japan, 113-8603

Toranomon Hospital

Tokyo, Minato-ku, Japan, 105-8470

JR Tokyo General Hospital

Tokyo, Shibuya-ku, Japan, 151-8528

Global Health and Medicine Ctr

Tokyo, Shinjuku-ku, Japan, 162-8655

Korea, Republic of

The Catholic University of Korea, Bucheon St.Mary's Hospital

Bucheon, Korea, Republic of, 14647

Seoul National University Bundang Hospital

Seongnam, Korea, Republic of, 13620

Asan Medical Center

Seoul, Korea, Republic of, 05505

Poland

University Clinical Center, Gdansk

Gdansk, Poland, 80-214

Leszek Giec Upper-Silesian Med.Cent.Silesian Med.Univ.

Katowice, Poland, 40-752

Norbert Barlicki University Clinical Hospital No.1, Lodz

Lodz, Poland, 90-153

Nat.Instit.of Tuberculosis&LungDiseases,Outpat.Clin,warszawa

Warszawa, Poland, 01-138

Clinical Hospital No. 1, n.a. Prof. Szyszko from Silesian MA

Zabrze, Poland, 41-803

Russian Federation

Res.Inst.-Compl.Iss.Cardi.Dis.

Kemerovo, Russian Federation, 650002

Pulmonology Scientific Research Institute

Moscow, Russian Federation, 105077

Central Scientific Research Insitute of Tuberculosis

Moscow, Russian Federation, 107564

Moscow 1st State Med.Univ.n.a.I.M.Sechenov

Moscow, Russian Federation, 119992

Scientific Research Institute of Pulmonology

St. Petersburg, Russian Federation, 197101

Emergency Clinical Hospital n. a. N. V. Solovyev, Yaroslavl

Yaroslavl, Russian Federation, 150003

Spain

Hospital Santa Creu i Sant Pau

Barcelona, Spain, 08026

Hospital Vall d'Hebron

Barcelona, Spain, 08035

Hospital Puerta del Mar

Cádiz, Spain, 11009

Hospital de Galdakao

Galdakao, Spain, 48960

Hospital de Bellvitge

L'Hospitalet de Llobregat, Spain, 08907

Hospital La Princesa

Madrid, Spain, 28006

Hospital La Paz

Madrid, Spain, 28046

Hospital Central de Asturias

Oviedo, Spain, 33011

Hospital Son Espases

Palma de Mallorca, Spain, 07120

Hospital de Canarias

San Cristóbal de La Laguna, Spain, 38320

Hospital Virgen del Rocío

Sevilla, Spain, 41013

Hospital Politècnic La Fe

Valencia, Spain, 46026

United Kingdom

University Hospital Llandough

Cardiff, United Kingdom, CF64 2XX

Royal Infirmary of Edinburgh

Edinburgh, United Kingdom, EH16 4SA

St James's University Hospital

Leeds, United Kingdom, LS9 7TF

Royal Brompton Hospital

London, United Kingdom, SW3 6NP

Wythenshawe Hospital

Manchester, United Kingdom, M23 9LT

Royal Stoke University Hospital

Stoke-on-Trent, United Kingdom, ST4 6QG

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:

Study Protocol  [PDF] June 8, 2018

Statistical Analysis Plan  [PDF] December 14, 2018

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ogura T, Suda T, Inase N, Nishioka Y, Azuma A, Okamoto M, Takizawa A, Ito T, Rohr KB, Inoue Y. Effects of nintedanib on disease progression and safety in Japanese patients with progressive fibrosing interstitial lung diseases: Further subset analysis from the whole INBUILD trial. Respir Investig. 2022 Nov;60(6):787-797. doi: 10.1016/j.resinv.2022.06.009. Epub 2022 Aug 1.

Cottin V, Martinez FJ, Jenkins RG, Belperio JA, Kitamura H, Molina-Molina M, Tschoepe I, Coeck C, Lievens D, Costabel U. Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial. Respir Res. 2022 Apr 7;23(1):85. doi: 10.1186/s12931-022-01974-2.

Swigris JJ, Bushnell DM, Rohr K, Mueller H, Baldwin M, Inoue Y. Responsiveness and meaningful change thresholds of the Living with Pulmonary Fibrosis (L-PF) questionnaire Dyspnoea and Cough scores in patients with progressive fibrosing interstitial lung diseases. BMJ Open Respir Res. 2022 Mar;9(1):e001167. doi: 10.1136/bmjresp-2021-001167.

Inoue Y, Suda T, Kitamura H, Okamoto M, Azuma A, Inase N, Kuwana M, Makino S, Nishioka Y, Ogura T, Takizawa A, Ugai H, Stowasser S, Schlenker-Herceg R, Takeuchi T. Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial. Respir Med. 2021 Oct;187:106574. doi: 10.1016/j.rmed.2021.106574. Epub 2021 Aug 12.

Flaherty KR, Wells AU, Cottin V, Devaraj A, Inoue Y, Richeldi L, Walsh SLF, Kolb M, Koschel D, Moua T, Stowasser S, Goeldner RG, Schlenker-Herceg R, Brown KK; INBUILD Trial Investigators. Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial. Eur Respir J. 2022 Mar 17;59(3):2004538. doi: 10.1183/13993003.04538-2020. Print 2022 Mar.

Maher TM, Brown KK, Kreuter M, Devaraj A, Walsh SLF, Lancaster LH, Belloli EA, Padilla M, Behr J, Goeldner RG, Tetzlaff K, Schlenker-Herceg R, Flaherty KR; INBUILD trial investigators. Effects of nintedanib by inclusion criteria for progression of interstitial lung disease. Eur Respir J. 2022 Feb 3;59(2):2004587. doi: 10.1183/13993003.04587-2020. Print 2022 Feb.

Cottin V, Richeldi L, Rosas I, Otaola M, Song JW, Tomassetti S, Wijsenbeek M, Schmitz M, Coeck C, Stowasser S, Schlenker-Herceg R, Kolb M; INBUILD Trial Investigators. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases. Respir Res. 2021 Mar 16;22(1):84. doi: 10.1186/s12931-021-01668-1.

Brown KK, Martinez FJ, Walsh SLF, Thannickal VJ, Prasse A, Schlenker-Herceg R, Goeldner RG, Clerisme-Beaty E, Tetzlaff K, Cottin V, Wells AU. The natural history of progressive fibrosing interstitial lung diseases. Eur Respir J. 2020 Jun 25;55(6):2000085. doi: 10.1183/13993003.00085-2020. Print 2020 Jun.

Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, Moua T, Crestani B, Wuyts WA, Stowasser S, Quaresma M, Goeldner RG, Schlenker-Herceg R, Kolb M; INBUILD trial investigators. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020 May;8(5):453-460. doi: 10.1016/S2213-2600(20)30036-9. Epub 2020 Mar 5.

Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme-Beaty E, Rosenstock B, Quaresma M, Haeufel T, Goeldner RG, Schlenker-Herceg R, Brown KK; INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.

Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res. 2017 Sep 17;4(1):e000212. doi: 10.1136/bmjresp-2017-000212. eCollection 2017.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02999178
• Other Study ID Numbers: 1199.247; 2015-003360-37 ( EudraCT Number )
• First Posted: December 21, 2016
• Results First Posted: May 5, 2020
• Last Update Posted: May 5, 2020
• Last Verified: April 2020

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Interstitial; Respiratory Tract Diseases; Nintedanib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action