Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II

Study Overview
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Brief Summary
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Idiopathic Pulmonary Fibrosis (IPF) is a chronic disease of unknown cause that results in scarring of the lung and there is a high unmet medical need for effective treatment to halt lung function decline, delay or avoid exacerbation (flare-ups), and ultimately to reduce the death rate. In a large Phase 2 trial (1199.30) (NCT00514683), investigating the effects of 52 weeks of treatment with BIBF 1120 in patients with IPF, a positive effect was seen on lung function of patients treated with high dose of BIBF 1120 compared to placebo. Hence it is the purpose of this trial to investigate and confirm the efficacy and safety of BIBF 1120 at a high dose in treating patients with IPF, compared with placebo. The trial will be conducted as a prospective, randomised design with the aim to collect safety and efficacy data. Respiratory function is globally accepted for assessment of treatment effects in IPF patients. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in IPF patients.

Official Title
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A 52 Weeks, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of Oral BIBF 1120, 150 mg Twice Daily, on Annual Forced Vital Capacity Decline, in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Conditions
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Pulmonary Fibrosis

Intervention / Treatment
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* Drug: placebo
* Drug: BIBF 1120


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age >= 40 years; IPF diagnosed, according to most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Latin American Thoracic Association (ALAT) IPF guideline for diagnosis and management, within 5 years; Combination of High Resolution Computerized Tomography (HRCT) pattern, and if available surgical lung biopsy pattern, as assessed by central reviewers, are consistent with diagnosis of IPF Dlco (corrected for Hb): 30%-79% predicted of normal; 5.FVC>= 50% predicted of normal Exclusion criteria: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) > 1.5 x Upper Limit of Normal (ULN) Bilirubin > 1.5 x ULN; Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC < 0.7); Patient likely to have lung transplantation during study (being on transplantation list is acceptable for participation); Myocardial infarction within 6 months; Unstable angina within 1 month; Bleeding risk (genetic predisposition; fibrinolysis or full-dose therapeutic anticoagulation or high dose antiplatelet therapy; history of hemorrhagic CNS event within 12 months; haemoptysis or haematuria or active gastro-intestinal bleeding or ulcers or major injury or surgery within 3 months); Thrombotic risk (inherited predisposition; history of thrombotic event (including stroke and transient ischemic attacks) within 12 months; International normalised ratio (INR) > 2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by > 50% of institutional ULN); N-ACetyl Cystein, prednisone > 15mg/day or equivalent received within 2 weeks of visit 1; Pirfenidone, azathioprine, cyclophosphamide, cyclosporine A received within 8 weeks of visit 1;

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 |
| --- | --- |
| Placebo Comparator: placebo<br>patient receives capsules identical to those containing active drug | Drug: placebo<br>* placebo matching BIBF 1120 BID<br>|
| Experimental: BIBF 1120<br>patient receives capsules containing BIBF 1120 twice a day | Drug: BIBF 1120<br>* BIBF 1120 BID (twice daily)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks. | Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks | This is a key secondary endpoint. 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 week 52). | Baseline and 52 weeks | 
| Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and represented as a key secondary endpoint. An acute exacerbation (reported as an AE by the investigator) was defined as follows: Otherwise unexplained clinical features including all of the following: Unexplained worsening or development of dyspnoea within 30 days New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit Exclusion of infection as per routine clinical practice and microbiological studies Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury. Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks, based on all investigator-reported AEs . | 52 weeks | 
| Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks | Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52). | Baseline and 52 weeks | 
| Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks | Percentage change from baseline in FVC over 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52). | Baseline and 52 weeks | 
| Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks | Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52). | Baseline and 52 weeks | 
| Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks | Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52). | Baseline and 52 weeks | 
| Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold | Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 5% threshold (decrease by >5%, increase by >5%, and change within ≤5%). | Baseline and 52 weeks | 
| Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold | Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 10% threshold (decrease by 10%, increase by >10%, and change within ≤10%) | Baseline and 52 weeks | 
| FVC Responders Using 10% Threshold at 52 Weeks | FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC evaluation at 52 weeks. | 52 weeks | 
| Proportion of FVC Responders Using 5% Threshold at 52 Weeks | Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks. | 52 weeks | 
| Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs) | Proportion of SGRQ responders at 52 weeks. Responders defined as <= -4 points change in change from baseline in SGRQ total score at 52 weeks. | baseline and 52 weeks | 
| Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life. 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 week 52). | baseline and 52 weeks | 
| Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better impact-related quality of life. 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 week 52). | baseline and 52 weeks | 
| Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life. 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 week 52). | baseline and 52 weeks | 
| Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score. The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale. | baseline and 52 weeks | 
| Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs) | 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 week 52). | baseline and 52 weeks | 
| Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs) | The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (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 week 52). | baseline and 52 weeks | 
| Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs) | The cough domains of the Cough and Sputum Assessment Questionnaire (CASA- Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (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 week 52). | baseline and 52 weeks | 
| Proportion of Patient's Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs) | Patient's Global Impression of Change (PGI-C) responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'. | 52 weeks | 
| Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs) | The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale. | baseline, 12 weeks, 24 weeks and 52 weeks | 
| Risk of an Acute IPF Exacerbation Over 52 Weeks | The incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk in years*100) | 52 weeks | 
| Time to Death Over 52 Weeks | Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died over 52 weeks (373 days time-period). | 52 weeks | 
| Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated) | Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (373 days time-period). | 52 weeks | 
| Time to On-treatment Death | Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial medication intake + 28 days were censored at last trial medication intake + 28 days and reported. Failure is the the proportion of patients who died on-treatment. | 52 weeks | 
| Time to Death or Lung Transplant Over 52 Weeks | Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died or had lung transplant over 52 weeks (373 days time-period). | 52 weeks | 
| Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks. | Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria: FVC <45% predicted or Carbon monoxide diffusion capacity (DL(CO)) <30% pred or Oxygen saturation on pulse oximetry (SpO2) <88% at rest, at sea level (to be adapted for other heights). These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (373 days time-period). | 52 weeks | 
| Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks | Means presented are the adjusted means. Adjusted mean is based on all analyzed patients in the model (not only patients with a change from baseline to week 52) | baseline and 52 weeks | 
| Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks | Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52). | baseline and 52 weeks |