Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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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

Official Title
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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.

Conditions
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Pulmonary Fibrosis

Intervention / Treatment
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* Drug: low dose BIBF1120 once daily
* Drug: low dose BIBF 1120 twice daily
* Drug: intermediate dose BIBF 1120 twice daily
* Drug: high dose BIBF 1120 twice daily
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient >40 years Written informed consent signed prior to entry into the study IPF diagnosed (according to ATS / ERS criteria) less than 5 years prior to screening visit. HRCT within 12 months of randomisation and biopsy (the latter if needed to fulfil ATS/ERS criteria) centrally reviewed and consistent with diagnosis. 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 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 PaO2 >= 55 mmHg (sea level to 1500 m) or 50 mmHg (above 1500 m) room air Exclusion Criteria: AST, ALT > 1.5 x ULN ; Bilirubin > 1.5 x ULN Relevant airways obstruction Continuous oxygen supplementation at randomisation (defined as > 15 hours supplemental oxygen per day). Active infection at screening or randomisation. Neutrophils < 1500 / mm3 International normalised ratio (INR) > 1.5 and/or Partial thromboplastin time (PTT) > 1.5 x ULN ; Platelets < 100 000 /mL Haemoglobin < 9.0 g/dL In the opinion of the Investigator, patient is likely to have lung transplantation during study Life expectancy for disease other than IPF < 2.5 years (Investigator assessment). 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 Other investigational therapy received within 8 weeks prior to screening visit. 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. Sexually active males not committing to using condoms during the course of the study (except if their partner is not of childbearing potential). Known or suspected active alcohol or drug abuse. 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 Thrombotic risk Surgical procedures planned to occur during trial period. Coagulopathy Uncontrolled systemic arterial hypertension known hypersensitivity to lactose or any component of the study medication

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dose 1<br>low dose BIBF1120 once daily | Drug: low dose BIBF1120 once daily<br>* low dose BIBF1120 once daily<br>|
| Experimental: dose 2<br>low dose BIBF 1120 twice daily | Drug: low dose BIBF 1120 twice daily<br>* low dose BIBF 1120 twice daily<br>|
| Experimental: dose 3<br>intermediate dose BIBF 1120 twice daily | Drug: intermediate dose BIBF 1120 twice daily<br>* intermediate dose BIBF 1120 twice daily<br>|
| Experimental: dose 4<br>high dose BIBF 1120 twice daily | Drug: high dose BIBF 1120 twice daily<br>* high dose BIBF 1120 twice daily<br>|
| Placebo Comparator: placebo<br>placebo | Drug: placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline until 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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 | 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: Decrease > 10% or 200mL Change within <= 10% or <=200 mL Increase > 10% or 200mL | 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. | 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. | 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: Decrease > 4% SpO2 Change within +/- 4% SpO2 Increase > 4% SpO2 | 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. | 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. | 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. | 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: Decrease > 4 mmHg Change within +/- 4 mmHg Increase > 4 mmHg | 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: Decrease > 4 mmHg Change within +/- 4 mmHg Increase > 4 mmHg | 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. | 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: Decrease > 15% or > 1 Change <= 15% or <= 1 Increase > 15% or > 1 | 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. | 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. | 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. | 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: Decrease No Change Increase | 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. | 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. | 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. | 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. | 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. | 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 | 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. | 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. | 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. | 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. | 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. | 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 | 52 weeks | 
| Occurrences of IPF Exacerbations Per Patient Per Year | Occurrences of Idiopathic Pulmonary Fibrosis (IPF) exacerbations per patient per year at 52 weeks | 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. | 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. | 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. | 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. | day 365 and day 729 |