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Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00514683
Recruitment Status : Completed
First Posted : August 10, 2007
Results First Posted : January 6, 2015
Last Update Posted : January 6, 2015
Sponsor:
Information provided by:
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE August 9, 2007
First Posted Date  ICMJE August 10, 2007
Results First Submitted Date  ICMJE November 14, 2014
Results First Posted Date  ICMJE January 6, 2015
Last Update Posted Date January 6, 2015
Study Start Date  ICMJE August 2007
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2015)
Rate of Decline in FVC [ Time Frame: Baseline until 52 weeks ]
Rate of decline in Forced Vital Capacity (FVC) evaluated from baseline until 52 weeks of treatment. The means presents actually the adjusted rate based on a MMRM with fixed terms for treatment*time, gender*height, gender*age and random terms for patient effect, patient*time.
Original Primary Outcome Measures  ICMJE
 (submitted: August 9, 2007)
The primary endpoint is the rate of decline in FVC (expressed in mL per year), evaluated from baseline until 12 month of treatment, compared to placebo.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2015)
  • Absolute Change From Baseline in FVC%Pred [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in percentage of predicted Forced Vital Capacity (FVC%pred) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline and region.
  • Absolute Change From Baseline in FVC [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in percentage of absolute Forced Vital Capacity (FVC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline and region.
  • Relative Change From Baseline in FVC%Pred [ Time Frame: Baseline and 52 weeks ]
    Percent change from baseline in percentage of predicted Forced Vital Capacity (FVC%pred) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline and region.
  • Relative Change From Baseline in FVC [ Time Frame: Baseline and 52 weeks ]
    Percent change from baseline in absolute Forced Vital Capacity (FVC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline and region
  • Number of Participants With Change From Baseline in FVC by Categories [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in percentage of Forced Vital Capacity (FVC) at 52 weeks in below mentioned categories:
    1. Decrease > 10% or 200mL
    2. Change within <= 10% or <=200 mL
    3. Increase > 10% or 200mL
  • Survival (All Causes of Death and Lung-transplant Free) [ Time Frame: 52 weeks ]
    Survival (all causes of death and lung-transplant free) at 52 weeks, based on overall mortality and on-treatment survival. Failure means participants with event and Censored means participants with no event.
  • Absolute Change From Baseline in SpO2 at Rest [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in oxygen saturation (SpO2) at rest. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in SpO2 at Rest by Categories [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in oxygen saturation (SpO2) at rest by below mentioned categories: SpO2 (non-invasive) at 52 weeks:
    1. Decrease > 4% SpO2
    2. Change within +/- 4% SpO2
    3. Increase > 4% SpO2
  • Absolute Change From Baseline in PaO2 [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Arterial oxygen partial pressure (PaO2) at week 52. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in P(A-a)O2 [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Alveolo-arterial oxygen gradient (P(A-a)O2) at week 52. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in PaCO2 [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Arterial carbon dioxyde partial pressure (PaCO2) at week 52. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in PaO2 by Categories [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Arterial oxygen partial pressure (PaO2) by below mentioned categories:
    1. Decrease > 4 mmHg
    2. Change within +/- 4 mmHg
    3. Increase > 4 mmHg
  • Absolute Change From Baseline in P(A-a) O2 by Categories [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Alveolo-arterial oxygen gradient (P(A-a) O2) by below mentioned categories:
    1. Decrease > 4 mmHg
    2. Change within +/- 4 mmHg
    3. Increase > 4 mmHg
  • Absolute Change From Baseline in DLCO [ Time Frame: Baseline and 52 weeks ]
    Absolute change from Baseline in Diffusing capacity of the lung for carbon monoxide (DLCO) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in DLCO by Categories [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Diffusing capacity of the lung for carbon monoxide (DLCO) by below mentioned categories:
    1. Decrease > 15% or > 1
    2. Change <= 15% or <= 1
    3. Increase > 15% or > 1
  • Absolute Change From Baseline in Distance Walk (6-MWT) [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in distance walk (6-MWT) at 52 weeks. The 6-Minutes Walk Test (6-MWT) was conducted according to the American Thoracic Society (ATS) Criteria. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in Dyspnoea Rating on Borg Scale Before Exercise (6-MWT) [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Dyspnoea rating before exercise (6-MWT) at 52 weeks based on Borg scale as mentioned below : 0: Nothing at all, 0.5: Very, very slight (just noticable), 1: Very slight, 2: Slight (light), 3: Moderate, 4: Somewhat severe, 5: Severe (heavy), 6, 7:Very severe, 8, 9, 10: Very, very severe (Maximal). The 6-Minutes Walk Test (6-MWT) was conducted according to the ATS Criteria. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in Dyspnoea Rating on Borg Scale After Exercise (6-MWT) [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Dyspnoea rating after exercise (6-MWT) at 52 weeks based on Borg scale as mentioned below : 0: Nothing at all, 0.5: Very, very slight (just noticable), 1: Very slight, 2: Slight (light), 3: Moderate, 4: Somewhat severe, 5: Severe (heavy), 6, 7:Very severe, 8, 9, 10: Very, very severe (Maximal). The 6-Minutes Walk Test (6-MWT) was conducted according to the ATS Criteria. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Absolute Change From Baseline in MRC Dyspnea Scale by Categories [ Time Frame: Baseline and 52 weeks ]
    Absolute change from baseline in Medical Research Council (MRC) dyspnea scale by below mentioned categories:
    1. Decrease
    2. No Change
    3. Increase
  • Absolute Change From Baseline in FEV1/FVC [ Time Frame: Baseline and 52 weeks ]
    Change from baseline of percentage of FVC expelled in the first second of a forced expiration (FEV1/FVC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in SGRQ Total Score [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Saint George's Respiratory Questionnaire (SGRQ) total score. Total score is defined as sum of the three domain scores symptoms, activities and impacts. Scores range from 0 to 100, with higher scores indicating worst possible health status. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in SGRQ Domain Score Symptoms [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Saint George's Respiratory Questionnaire (SGRQ) domain score symptoms. Scores range from 0 to 100, with higher scores indicating more limitations. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in SGRQ Domain Score Impacts [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Saint George's Respiratory Questionnaire (SGRQ) domain score impacts. Scores range from 0 to 100, with higher scores indicating worst possible health status. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Domain Score Activities [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Saint George's Respiratory Questionnaire (SGRQ) domain score activities. Scores range from 0 to 100, with higher scores indicating worst possible health status. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • St George's Respiratory Questionnaire (SGRQ) Responder [ Time Frame: 52 weeks ]
    St George's Respiratory Questionnaire (SGRQ) responder (<= -4 points change) (%) at 52 weeks-worst case
  • Change From Baseline in TLC [ Time Frame: Baseline and 52 weeks ]
    Change from Baseline in Total Lung Capacity (TLC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in RV [ Time Frame: Baseline and 52 weeks ]
    Change from Baseline in Residual volume (RV) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in TGV [ Time Frame: Baseline and 52 weeks ]
    Change from Baseline in Thoracic gas volume (TGV) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in VC [ Time Frame: Baseline and 52 weeks ]
    Change from baseline in Vital capacity (VC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Change From Baseline in IC [ Time Frame: Baseline and 52 weeks ]
    Change from Baseline in Inspiratory Capacity (IC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.
  • Number of Patients With at Least One IPF Exacerbation [ Time Frame: 52 weeks ]
    Number of patients with at least one Idiopathic Pulmonary Fibrosis (IPF) exacerbation at 52 weeks
  • Occurrences of IPF Exacerbations Per Patient Per Year [ Time Frame: 52 weeks ]
    Occurrences of Idiopathic Pulmonary Fibrosis (IPF) exacerbations per patient per year at 52 weeks
  • Time to First Occurrence of IPF Exacerbation [ Time Frame: 52 weeks ]
    This endpoint is called time to first occurrence of IPF exacerbation however it was actually analysed as the proportion of patients having occurrence of Idiopathic Pulmonary Fibrosis (IPF) exacerbation at 52 weeks. Failure means participants with event and Censored means participants with no event.
  • Survival (Death Due to Respiratory Cause, and Lung-transplant Free) [ Time Frame: 52 weeks ]
    Survival (death due to respiratory cause, and lung-transplant free) at 52 weeks. Failure means participants with event and Censored means participants with no event.
  • Time to Progression [ Time Frame: 52 weeks ]
    Time to progression. Progression was defined as at least one of the following: 5mmHg increase in the alveolo-arterial pressure difference in oxygen (P(A-a)O2), 10% decrease in FVC (FVC(baseline)-FVC(progression) >= 10%) or Death. Failure means participants with event and Censored means participants with no event.
  • Pre-dose Plasma Concentration of Nintedanib in Plasma at Steady State on Day 365 (Cpre,ss,365) and Day 729 (Cpre,ss,729). [ Time Frame: day 365 and day 729 ]
    Cpre,ss,729 represents the pre-dose plasma concentration of nintedanib in plasma at steady state on Day 729 and Cpre,ss,365 represents the pre-dose plasma concentration of nintedanib in plasma at steady state on Day 365. At day 365, values only for Nintedanib 50 qd group are presented as no values reported for other groups and at day 729, values are presented for all group except for Nintedanib 50 qd group as no values reported for it.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis
Official Title  ICMJE A 12 Month, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of BIBF 1120 Administered at Oral Doses of 50 mg qd, 50 mg Bid, 100 mg Bid and 150 mg Bid on Forced Vital Capacity Decline During One Year, in Patients With Idiopathic Pulmonary Fibrosis, With Optional Active Treatment Extension Until Last Patient Out.
Brief Summary

The general purpose of this trial is to investigate the efficacy and safety of 4 dose strategies of BIBF 1120 treatment for 12 months, compared to placebo in patients with idiopathic pulmonary fibrosis.

The primary objective of this study is to demonstrate whether at least one dose strategy is superior to placebo in patients with IPF, in modifying the rate of decline of Forced Vital Capacity (FVC).

As a secondary objective, additional parameters will be assessed in order to differentiate between dose strategies on the basis of safety and efficacy

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Fibrosis
Intervention  ICMJE
  • Drug: low dose BIBF1120 once daily
    low dose BIBF1120 once daily
  • Drug: low dose BIBF 1120 twice daily
    low dose BIBF 1120 twice daily
  • Drug: intermediate dose BIBF 1120 twice daily
    intermediate dose BIBF 1120 twice daily
  • Drug: high dose BIBF 1120 twice daily
    high dose BIBF 1120 twice daily
  • Drug: placebo
    placebo
Study Arms  ICMJE
  • Experimental: dose 1
    low dose BIBF1120 once daily
    Intervention: Drug: low dose BIBF1120 once daily
  • Experimental: dose 2
    low dose BIBF 1120 twice daily
    Intervention: Drug: low dose BIBF 1120 twice daily
  • Experimental: dose 3
    intermediate dose BIBF 1120 twice daily
    Intervention: Drug: intermediate dose BIBF 1120 twice daily
  • Experimental: dose 4
    high dose BIBF 1120 twice daily
    Intervention: Drug: high dose BIBF 1120 twice daily
  • Placebo Comparator: placebo
    placebo
    Intervention: Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 24, 2009)
432
Original Enrollment  ICMJE
 (submitted: August 9, 2007)
400
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patient >40 years
  2. Written informed consent signed prior to entry into the study
  3. IPF diagnosed (according to ATS / ERS criteria) less than 5 years prior to screening visit.
  4. HRCT within 12 months of randomisation and biopsy (the latter if needed to fulfil ATS/ERS criteria) centrally reviewed and consistent with diagnosis.
  5. FVC>50 % of predicted value

    Predicted normal values will be calculated according to ESCS (R94-1408):

    Males :

    FVC predicted (L) = 5.76 x height (meters)- 0.026 x age (years) -4.34

    Females :

    FVC predicted (L) = 4.43 x height (meters)- 0.026 x age (years) -2.89

  6. Single breath DLCO (corrected for Hb) 30 - 79% inclusive of predicted .

    Different sites may use different prediction formulas, based on the method used to measure DLco. In any case, the method used must be in compliance with the ATS/ERS guideline on DLCO measurements (R06-2002), and the prediction formula appropriate for that method. Raw data (gas mixture, equation used for prediction of normal, further adjustments made if so) must be traced.

    Adjustment for haemoglobin (R06-2002):

    Males :

    DLCO predicted for Hb = DLCO predicted x (1.7Hb/[10.22+Hb])

    Females :

    DLCO predicted for Hb = DLCO predicted x (1.7Hb/[9.38+Hb]) where Hb is expressed in g/dL-1

  7. PaO2 >= 55 mmHg (sea level to 1500 m) or 50 mmHg (above 1500 m) room air

Exclusion Criteria:

  1. AST, ALT > 1.5 x ULN ;
  2. Bilirubin > 1.5 x ULN
  3. Relevant airways obstruction
  4. Continuous oxygen supplementation at randomisation (defined as > 15 hours supplemental oxygen per day).
  5. Active infection at screening or randomisation.
  6. Neutrophils < 1500 / mm3
  7. International normalised ratio (INR) > 1.5 and/or Partial thromboplastin time (PTT) > 1.5 x ULN ;
  8. Platelets < 100 000 /mL
  9. Haemoglobin < 9.0 g/dL
  10. In the opinion of the Investigator, patient is likely to have lung transplantation during study
  11. Life expectancy for disease other than IPF < 2.5 years (Investigator assessment).
  12. Other disease that may interfere with testing procedures or in judgement of Investigator may interfere with trial participation or may put the patient at risk when participating to this trial.

    • Myocardial infarction during the previous 6 months
    • Unstable angina during the previous month
  13. Other investigational therapy received within 8 weeks prior to screening visit.
  14. Pregnant women or women who are breast feeding or of child bearing potential not using a highly effective method of birth control for at least one month prior to enrolment.
  15. Sexually active males not committing to using condoms during the course of the study (except if their partner is not of childbearing potential).
  16. Known or suspected active alcohol or drug abuse.
  17. Bleeding risk : Known inherited predisposition to bleeding, patients who require full-dose anticoagulation, Patients who require full-dose antiplatelet therapy, History of hemorrhagic CNS event within 12 months prior to screening , Any of the following within 3 months prior to screening : Gross / frank haemoptysis or haematuria, Active gastro-intestinal bleeding or ulcers, Major injury or surgery
  18. Thrombotic risk
  19. Surgical procedures planned to occur during trial period.
  20. Coagulopathy
  21. Uncontrolled systemic arterial hypertension
  22. known hypersensitivity to lactose or any component of the study medication
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Bulgaria,   Canada,   Chile,   China,   Czech Republic,   France,   Germany,   Greece,   Hungary,   Ireland,   Italy,   Korea, Republic of,   Mexico,   Netherlands,   Portugal,   Russian Federation,   South Africa,   Spain,   Taiwan,   Turkey,   United Kingdom
Removed Location Countries El Salvador
 
Administrative Information
NCT Number  ICMJE NCT00514683
Other Study ID Numbers  ICMJE 1199.30
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date January 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP