Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis

Boehringer Ingelheim432 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

432

Conditions

Pulmonary Fibrosis

Interventions

low dose BIBF1120 once dailyDRUG

low dose BIBF1120 once daily

low dose BIBF 1120 twice dailyDRUG

low dose BIBF 1120 twice daily

intermediate dose BIBF 1120 twice dailyDRUG

intermediate dose BIBF 1120 twice daily

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

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

Locations (92)

Outcomes

Primary Outcomes

Rate of Decline in FVC

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.

Time frame: Baseline until 52 weeks

Secondary Outcomes

Absolute Change From Baseline in FVC%Pred

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in FVC

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.

Time frame: Baseline and 52 weeks

Relative Change From Baseline in FVC%Pred

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.

Time frame: Baseline and 52 weeks

Relative Change From Baseline in FVC

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

Time frame: Baseline and 52 weeks

Number of Participants With Change From Baseline in FVC by Categories

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

Data from ClinicalTrials.gov

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high dose BIBF 1120 twice daily

1199.30.54002 Boehringer Ingelheim Investigational Site

Mendoza, Argentina

1199.30.61005 Boehringer Ingelheim Investigational Site

South Brisbane, Queensland, Australia

1199.30.61003 Boehringer Ingelheim Investigational Site

Toorak Gardens, South Australia, Australia

1199.30.61004 Boehringer Ingelheim Investigational Site

Woodville, South Australia, Australia

1199.30.61001 Royal Perth Hospital

Perth, Western Australia, Australia

1199.30.32004 Boehringer Ingelheim Investigational Site

Brussels, Belgium

1199.30.32001 Boehringer Ingelheim Investigational Site

Leuven, Belgium

1199.30.32002 Boehringer Ingelheim Investigational Site

Yvoir, Belgium

1199.30.55002 Boehringer Ingelheim Investigational Site

Porto Alegre, Brazil

1199.30.55001 Boehringer Ingelheim Investigational Site

Vila Clementino, Brazil

...and 82 more locations

Time frame: Baseline and 52 weeks

Survival (All Causes of Death and Lung-transplant Free)

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.

Time frame: 52 weeks

Absolute Change From Baseline in SpO2 at Rest

Absolute change from baseline in oxygen saturation (SpO2) at rest. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in SpO2 at Rest by Categories

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

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in PaO2

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in P(A-a)O2

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in PaCO2

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in PaO2 by Categories

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

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in P(A-a) O2 by Categories

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

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in DLCO

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in DLCO by Categories

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

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in Distance Walk (6-MWT)

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in Dyspnoea Rating on Borg Scale Before Exercise (6-MWT)

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.

Time frame: Baseline and 52 weeks

Change From Baseline in Dyspnoea Rating on Borg Scale After Exercise (6-MWT)

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.

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in MRC Dyspnea Scale by Categories

Absolute change from baseline in Medical Research Council (MRC) dyspnea scale by below mentioned categories: 1. Decrease 2. No Change 3. Increase

Time frame: Baseline and 52 weeks

Absolute Change From Baseline in FEV1/FVC

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.

Time frame: Baseline and 52 weeks

Change From Baseline in SGRQ Total Score

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.

Time frame: Baseline and 52 weeks

Change From Baseline in SGRQ Domain Score Symptoms

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.

Time frame: Baseline and 52 weeks

Change From Baseline in SGRQ Domain Score Impacts

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.

Time frame: Baseline and 52 weeks

Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Domain Score Activities

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.

Time frame: Baseline and 52 weeks

St George's Respiratory Questionnaire (SGRQ) Responder

St George's Respiratory Questionnaire (SGRQ) responder (\<= -4 points change) (%) at 52 weeks-worst case

Time frame: 52 weeks

Change From Baseline in TLC

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.

Time frame: Baseline and 52 weeks

Change From Baseline in RV

Change from Baseline in Residual volume (RV) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.

Time frame: Baseline and 52 weeks

Change From Baseline in TGV

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.

Time frame: Baseline and 52 weeks

Change From Baseline in VC

Change from baseline in Vital capacity (VC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.

Time frame: Baseline and 52 weeks

Change From Baseline in IC

Change from Baseline in Inspiratory Capacity (IC) at 52 weeks. Means were adjusted based on an ANCOVA with fixed terms for treatment, baseline, region.

Time frame: Baseline and 52 weeks

Number of Patients With at Least One IPF Exacerbation

Number of patients with at least one Idiopathic Pulmonary Fibrosis (IPF) exacerbation at 52 weeks

Time frame: 52 weeks

Occurrences of IPF Exacerbations Per Patient Per Year

Occurrences of Idiopathic Pulmonary Fibrosis (IPF) exacerbations per patient per year at 52 weeks

Time frame: 52 weeks

Time to First Occurrence of IPF Exacerbation

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.

Time frame: 52 weeks

Survival (Death Due to Respiratory Cause, and Lung-transplant Free)

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 frame: 52 weeks

Time to Progression

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.

Time frame: 52 weeks

Pre-dose Plasma Concentration of Nintedanib in Plasma at Steady State on Day 365 (Cpre,ss,365) and Day 729 (Cpre,ss,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.

Time frame: day 365 and day 729