Nintedanib Twice Daily vs Placebo in Patients Diagnosed With Idiopathic Pulmonary Fibrosis (IPF)

A Six Month Double Blind Randomized Placebo Controlled Trial Followed by Each Arm Being Converted to Oral Nintedanib 150 mg Twice Daily Comparing the Effect on High Resolution Computerized Tomography Quantitative Lung Fibrosis Score, Lung Function, Six Minute Walk Test Distance and St. George's Respiratory Questionnaire After Six Months of Treatment in Patients With Idiopathic Pulmonary Fibrosis With Continued Evaluations Over a Period of up to Eighteen Months

This is an 6 month multi-centre, prospective, randomized, placebo controlled, double blind clinical trial followed by conversion of each arm to active nintedanib for an additional 6 months comparing the effect of nintedanib 150mg bis in die (BID twice daily) on the progression of IPF measured by using High Resolution Computerized Tomography(HRCT), lung function, functional component (6MWT), biomarkers, and PRO component (PROs) with continued treatment and assessments for up to 18 months.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 3

Contacts and Locations

Study Locations

• 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
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2K 3S8
      • Concordia 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
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS Fleurimont
• Turkey
  • Adana, Turkey, 01330
    • Cukurova Universitesi Tip Fakultesi Gog. Hast. Anabilim Dali
  • Ankara, Turkey, 06100
    • Ankara Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34098
    • Istanbul Universitesi Cerrahpasa Tip Fakultesi
  • Istanbul, Turkey, 34760
    • Yedikule Gog. Hst. EAH
  • Istanbul, Turkey, 34844
    • Sureyyapasa Gogus Hast. ve Gogus Cer. Egit. ve Aras. Has.
  • Izmir, Turkey, 35100
    • Ege Universitesi T.F.
  • Izmir, Turkey, 35110
    • Dr.Suat Seren EAH
• United States
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Western CT Medical Group, P.C.
  • Florida
    • Sarasota, Florida, United States, 34239
      • Clinical Research Center Sarasota Memorial Hosptial
  • Illinois
    • Skokie, Illinois, United States, 60076
      • Chest Medicine Clinical Services
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minnesota Lung Research
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
  • Ohio
    • Toledo, Ohio, United States, 43608
      • ID Clinical Research, LTD
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Lowcountry Lung and Crit Care
  • Texas
    • Dallas, Texas, United States, 75246
      • Annette C & Harold C Simmons Transplant Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Written Informed Consent consistent with International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and local laws signed prior to entry into the study
2. Patient aged >= 40 years at Visit 1.
3. IPF diagnosed, according to the 2011 American Thoracic Society (ATS) / European Respiratory Society (ERS) / Japanese Respiratory Society(JRS)/ Latin American Thoracic Association (ALAT)/ Latin American Thoracic Association/ Idiopathic Pulmonary Fibrosis (IPF) guidelines for diagnosis and management, within 5 years and reaffirmed applying 2011 Guidelines (P11-07084) if diagnosed >2 years and up to 5 year from Visit 1,. Diagnosis must be confirmed by chest High Resolution Computerized Tomography (HRCT) taken within 24 months of Visit 1. All HRCT results reported to be possible or inconsistent usual interstitial pneumonia (UIP) must have confirmatory pathology.
4. Carbon monoxide Diffusing capacity or Transfer factor of the lung for carbon monoxide (DLCO) (corrected for Hb): 30%-79% predicted of normal
5. Forced Vital Capacity (FVC) >= 50% predicted of normal at Visit 1 and Visit 2

Exclusion criteria:

1. AST, ALT > 1.5 fold ULN
2. Bilirubin > 1.5 fold ULN

3. Bleeding risk:

   1. Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, dabigatran, heparin, hirudin), or high dose antiplatelet therapy. Exceptions: prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 IU s.c. per day) and prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/d, or clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet therapy)
   2. History of hemorrhagic Central Nervous System (CNS) event within 12 months

   3. Any of the following within 3 months:

      • Haemoptysis or haematuria.
      • Active gastro-intestinal bleeding or ulcers.
      • Major injury or surgery.
   4. Coagulation parameters: International normalised ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 150% of institutional ULN.
4. Planned major surgery within the next 3 months, including lung transplantation, major abdominal or major intestinal surgery.

5. Thrombotic risk

   1. Known inherited predisposition to thrombosis.
   2. History of thrombotic event (including stroke and transient ischemic attacks) within 12 months
6. Current or planned usage of any investigational drug during the course of this trial
7. Previous treatment with nintedanib within a clinical trial in the previous 3 months and discontinuation of nintedanib study treatment due to an adverse event
8. Known hypersensitivity to the trial drug or its component
9. A disease or condition which in the opinion of investigator may put the patient at risk because of participation in this trial or limit the patient's ability to participate in this trial. Patients will be excluded if they require greater than 12L/min oxygen, are not ambulatory or require use of a walker or cane during the 6 Minute Titration Walk Test. Patients who cannot complete the 6 Minute Titration Walk Test are excluded from participation.
10. Alcohol or drug abuse which in the opinion of the investigator would interfere with trial participation.
11. Pregnant women or women who are breast feeding or of child bearing potential not using two effective methods of birth control (one barrier and one highly effective non-barrier) for at least 1 month prior to trial and/or not committing to using it until 3 months after end of treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nintedanib; 150 mg twice daily	Drug: Nintedanib; gelating capsule
Placebo Comparator: Placebo; twice daily dosing	Drug: Matching Placebo; twice daily dosing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change From Baseline in High Resolution Computerized Tomography (HRCT) Quantitative Lung Fibrosis (QLF) Score at 6 Months	Relative change from baseline in HRCT QLF score at 6 months was calculated as the difference of the QLF score at month 6 minus the QLF score at baseline divided by the baseline QLF score. The QLF score itself ranges from 0 to 100%, where greater values represent a greater amount of lung fibrosis and are considered a worse health status. Hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline.	Baseline and 6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Six Month Delayed Treatment Onset: Relative Change From Baseline in HRCT QLF Score at 12 Months	Relative change from baseline in HRCT QLF score at 12 months was calculated as the ratio of the QLF score at 12 months to baseline. Greater values of the QLF score represented a worse health status and hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline. Note that due to the change in study design, patients randomized to the placebo group were treated with nintedanib after completion of the first 6-month treatment period. Therefore, this new endpoint was defined to address the effect of a 6-month delayed onset of nintedanib treatment.	Baseline and 12 Months
Absolute Change in Forced Vital Capacity (FVC) From Baseline at 6 Months	Absolute change in Forced Vital Capacity (FVC) from baseline at 6 months is presented.	Baseline and 6 Months
Relative Change in FVC From Baseline at 6 Months	Relative change in FVC from baseline at 6 months is presented.	Baseline and 6 Months
Categorical Change in FVC From Baseline at 6 Months	Percentage of participants reporting categorical change in FVC from baseline at 6 months are presented.	Baseline and 6 Months
St. George's Respiratory Questionnaire (SGRQ) Total Score Change From Baseline at 6 Months	SGRQ total score change from baseline at 6 months is presented. SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status. Means provided are the adjusted means based on all analyzed patients in the model (not only patients with a baseline and measurement at month 6).	Baseline and 6 Months
6MWT Total Distance Walked Change From Baseline at 6 Months	Change in total distance covered in 6-minute walk test (6MWT) from baseline at 6 month is presented. The 6-Minutes Walk Test (6-MWT) was conducted according to the American Thoracic Society (ATS) Criteria.	Baseline and 6 Months
University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Change From Baseline at 6 Months	University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) change from baseline at 6 months is presented. Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at month 6).	Baseline and 6 Months
All-cause Mortality at 6 Months	Percentage of subjects died from all causes between 0 to 6 months are presented.	6 Months
Respiratory Hospitalizations at 6 Months	Percentage of subjects hospitalized due to respiratory problems between 0 to 6 months are presented.	6 Months
Respiratory Mortality at 6 Months	Percentage of subjects who died due to respiratory cause between 0 to 6 months are presented.	6 Months
Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbations at 6 Months	Percentage of subjects experienced first acute IPF exacerbations (based on Investigator reported adverse events) between 0 to 6 months are presented.	6 Months

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Glaspole I, Bonella F, Bargagli E, Glassberg MK, Caro F, Stansen W, Quaresma M, Orsatti L, Bendstrup E. Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities. Respir Res. 2021 Apr 26;22(1):125. doi: 10.1186/s12931-021-01695-y.

Helpful Links

• Synopsis Link

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2013
• Primary Completion (Actual): October 27, 2016
• Study Completion (Actual): October 27, 2016

Study Registration Dates

• First Submitted: November 4, 2013
• First Submitted That Met QC Criteria: November 4, 2013
• First Posted (Estimate): November 8, 2013

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1199.187