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Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment

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ClinicalTrials.gov Identifier: NCT02788474
Recruitment Status : Completed
First Posted : June 2, 2016
Results First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Description
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Brief Summary:
Identifying biomarkers to predict the clinical course and benefits of therapy early in the course of the disease remains one of the most urgent and relevant challenges to improve overall patient management, to prevent treatment delay or overtreatment. This study is conducted to examine the effect of nintedanib treatment on change in biomarkers indicative of extracellular matrix turnover which have been shown recently to correlate with disease progression. This study further aims to confirm the association of biomarker course during the first three months of treatment and disease progression.

Condition or disease Intervention/treatment Phase
Idiopathic Pulmonary Fibrosis Drug: nintedanib Drug: placebo Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 347 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A 12-week, Double Blind, Randomised, Placebo Controlled, Parallel Group Trial Followed by a Single Active Arm Phase of 40 Weeks Evaluating the Effect of Oral Nintedanib 150 mg Twice Daily on Change in Biomarkers of Extracellular Matrix (ECM) Turnover in Patients With Idiopathic Pulmonary Fibrosis (IPF) and Limited Forced Vital Capacity (FVC) Impairment.
Actual Study Start Date : June 9, 2016
Actual Primary Completion Date : August 4, 2017
Actual Study Completion Date : June 8, 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: placebo Drug: placebo
Experimental: nintedanib Drug: nintedanib


Outcome Measures
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Primary Outcome Measures :
  1. The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12. [ Time Frame: baseline and 12 weeks ]
    The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time.


Secondary Outcome Measures :
  1. Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52 [ Time Frame: 52 weeks ]

    For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry.

    This is a key secondary endpoint of the trial. This outcome measure is "percentage of patients with disease progression" and CRPM is included in the various models as a factor/covariate, and that this outcome measure, the percentage of progressors are displayed under "Measured values"


  2. The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12 [ Time Frame: baseline and 12 weeks ]

    The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented.

    The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.


  3. The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12 [ Time Frame: baseline and 12 weeks ]

    The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented.

    The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time.



Eligibility Criteria
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Ages Eligible for Study:   40 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 Good Clinical Practice and local laws, signed prior to participation in the trial including any study related procedures being performed;
  • Male or female patients aged >=40 years at Visit 1;
  • A clinical diagnosis of Idiopathic pulmonary fibrosis (IPF) within the last 3 years from visit 0, based upon the American Thoracic Society/ European Respiratory Society /Japanese Respiratory Society/ Latin American Thoracic Association 2011 guideline;
  • Chest high resolution computed tomography (HRCT) scan performed within 18 months of Visit 0;
  • Combination of HRCT pattern, and surgical lung biopsy pattern (the latter if available) as assessed by central review are consistent with the diagnosis of Idiopathic pulmonary fibrosis;
  • Forced vital capacity (FVC) >=80% of predicted normal at Visit 1.

Exclusion criteria:

  • Alanine transaminase, Aspartate aminotransferase > 1.5 fold upper limit of normal (ULN) at Visit 1;
  • Total bilirubin > 1.5 fold ULN at Visit 1;
  • Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment);
  • Relevant airways obstruction, i.e. pre-bronchodilator Forced expiratory volume in 1 second / Forced vital capacity < 0.70;
  • 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 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 partial thromboplastin time (PTT) > 150% of 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;
  • Treatment with nintedanib, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, any other investigational drug, n-acetylcysteine, prednisone/prednisolone >15 mg daily or >30 mg every 2 days OR use of other systemic corticosteroids as well as any investigational drugs within 4 weeks of Visit 2;
  • Known hypersensitivity to nintedanib, peanut, soya or to any other components of the study medication;
  • Prior discontinuation of nintedanib treatment due to intolerability/ adverse events considered drug related;
  • 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 the treatment and would affect patient's ability to participate in this trial;
  • Patients not able to understand and follow any study procedures such as but not limited to home spirometry, including completion of self-administered questionnaires without help;
  • Women who are pregnant, nursing, who plan to become pregnant while in the trial or female patients with positive pregnancy (ß-HCG) test at Visit 1 and/or Visit 2;
  • Women of childbearing potential4 not willing or able to use highly effective methods of birth control per International Conference on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.
  • Patients with acute IPF exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period;
  • Patients who are or have been participating in another trial with investigational drug/s within one month prior to Visit 1 and patients who have previously been enrolled in this trial;
  • Further exclusion criteria apply.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02788474


Locations
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Sponsors and Collaborators
Boehringer Ingelheim
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] July 9, 2018
Statistical Analysis Plan  [PDF] July 19, 2018

More Information
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Additional Information:

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

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02788474    
Other Study ID Numbers: 1199.227
2015-003148-38 ( EudraCT Number )
First Posted: June 2, 2016    Key Record Dates
Results First Posted: August 6, 2019
Last Update Posted: August 6, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Fibrosis
Pathologic Processes
Lung Diseases, Interstitial
Lung Diseases
 Respiratory Tract Diseases
Nintedanib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action