Pulmonary Fibrosis
Conditions
Brief summary
The aim of this trial is to offer continuation of BIBF 1120 treatment for patients with Idiopathic Pulmonary Fibrosis (IPF) who have completed a prior clinical trial with that drug. The primary objective will be to establish the long term tolerability and safety profile of BIBF 1120 in Idiopathic Pulmonary Fibrosis (IPF). As a secondary objective the effects of long term treatment with BIBF 1120 on survival as well as safety and efficacy parameters will be investigated in an open-label, not randomized, un-controlled design.
Interventions
DRUGBIBF 1120
Intermediate dose BIBF 1120 twice daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient with a primary diagnosis of IPF (according to the 2000 American Thoracic Society/European Respiratory Society (ATS/ERS) criteria, who are willing to continue trial medication. 2. Written informed consent signed prior to entry into the study, in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local law 3. Completion of 1199.30 study and still under treatment (i.e. not discontinued in parent trial)
Exclusion criteria
1. Any disease that may put the patient at risk when participating in this trial. Reconsider carefully all
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Decline in Forced Vital Capacity (FVC) | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | From first trial drug intake in 1199.35 to disease progression; up to 61.8 months | Progression-free survival was defined as the time from the first nintedanib intake in trial 1199.35 to disease progression. For presentation of progression-free survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment progression-free survival is calculated within each treatment arm. |
| Overall Survival | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | Overall survival is defined as the time from the first intake of nintedanib in trial 1199.35 to death. For presentation of overall survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment survival is calculated within each treatment arm. |
| Annual Rate of Decline in Haemoglobin Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Decrease | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | Haemoglobin corrected DLCO decrease was a secondary endpoint for the trial. It was considered important that all investigators used the same method of testing and recording data at each visit for each patient. Haemoglobin corrected DLCO was calculated for each patient using the following formulae: Males: Hb corrected DLCO = measured DLCO x (10.22 + Hb concentration) / (1.7 x Hb concentration) Females: Hb corrected DLCO = measured DLCO x (9.38 + Hb concentration) / (1.7 x Hb concentration). Annual rate of decline in haemoglobin corrected diffusing capacity of the lung for carbon monoxide (DLCO) decrease is presented. |
| Percentage of Patients With at Least One Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | Percentage of patients with at least one acute idiopathic pulmonary fibrosis (IPF) exacerbation are presented. An exacerbation was defined as otherwise unexplained clinical features occurring within 1 month including all of the following: * Progression of dyspnoea over several days to 4 weeks * New diffuse pulmonary infiltrates on chest X-ray and/or high-resolution computerised tomography (HRCT) Parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit * A decrease in arterial oxygen partial pressure (PaO2) of ≥10 mmHg or PaO2/fraction of inspired oxygen (FiO2) of \<225 mmHg since the last visit * Exclusion of infection based on routine clinical practice and microbiological studies * Absence of other contributory causes such as congestive heart failure, pulmonary embolism, etc. |
| Incidence of Patients With at Least One Acute IPF Exacerbation Over Time | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | Incidence rate = (Patients with at least one acute IPF exacerbation / Total number of years at risk) x 100 |
| Time to First Acute IPF Exacerbation | From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months | Due to rare events, the median of time to event is not calculable, thus Kaplan-Meier estimates (providing the percentage of patients without acute IPF exacerbation for a certain amount of time after treatment) and confidence intervals (using Greenwood variance formula) are reported and presented within each treatment arm as secondary endpoint. |
| Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | From the first nintedanib intake in trial 1199.35 to the last nintedanib intake + 28 days; up to 61.8 months + 28 days | Percentage of patients with at least one Adverse events (AEs), with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, serious AEs are presented |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, France, Germany, Greece, Hungary, Ireland, Italy, Mexico, Netherlands, Portugal, Russia, Spain, United Kingdom
Participant flow
Recruitment details
Treatment groups are displayed according to dose at randomisation in 1199.30 (NCT00514683).
Pre-assignment details
Patients were not randomised to study medication in trial 1199.35 but were to receive open-label nintedanib, either at the dose received in period 2 of parent trial 1199.30 (NCT00514683) or they could increase their dose to nintedanib 150 mg twice daily (bid) after implementation of protocol amendment 1.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid) | 37 |
| Nintedanib 50 mg- 100 mg Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid. | 126 |
| Nintedanib 150 mg Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial. | 35 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 17 | 50 | 10 |
| Overall Study | Consent withdrawn, not due to AE | 2 | 4 | 2 |
| Overall Study | Lost to Follow-up | 1 | 4 | 1 |
| Overall Study | Ongoing after planned observation time | 5 | 26 | 10 |
| Overall Study | Reason other than specified | 3 | 8 | 3 |
Baseline characteristics
| Characteristic | Placebo | Nintedanib 50 mg- 100 mg | Nintedanib 150 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 7.3 | 65.4 years STANDARD_DEVIATION 8.6 | 65.2 years STANDARD_DEVIATION 7.2 | 65.2 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 14 Participants | 36 Participants | 7 Participants | 57 Participants |
| Sex: Female, Male Male | 23 Participants | 90 Participants | 28 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 37 | 111 / 126 | 32 / 35 |
| serious Total, serious adverse events | 25 / 37 | 94 / 126 | 22 / 35 |
Outcome results
Primary
Annual Rate of Decline in Forced Vital Capacity (FVC)
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.
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: The full analysis set (FAS): which included all patients in the treated set who provided baseline data (for the first trial visit) for at least 1 endpoint in trial 1199.35
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Annual Rate of Decline in Forced Vital Capacity (FVC) | -129.0 milliliters per year (mL/ yr) | Standard Error 29.47 |
| Nintedanib 50 mg- 100 mg | Annual Rate of Decline in Forced Vital Capacity (FVC) | -137.5 milliliters per year (mL/ yr) | Standard Error 14.6 |
| Nintedanib 150 mg | Annual Rate of Decline in Forced Vital Capacity (FVC) | -132.9 milliliters per year (mL/ yr) | Standard Error 28.22 |
Secondary
Annual Rate of Decline in Haemoglobin Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Decrease
Haemoglobin corrected DLCO decrease was a secondary endpoint for the trial. It was considered important that all investigators used the same method of testing and recording data at each visit for each patient. Haemoglobin corrected DLCO was calculated for each patient using the following formulae: Males: Hb corrected DLCO = measured DLCO x (10.22 + Hb concentration) / (1.7 x Hb concentration) Females: Hb corrected DLCO = measured DLCO x (9.38 + Hb concentration) / (1.7 x Hb concentration). Annual rate of decline in haemoglobin corrected diffusing capacity of the lung for carbon monoxide (DLCO) decrease is presented.
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Annual Rate of Decline in Haemoglobin Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Decrease | -0.4 mmol/min/kPa/yr | Standard Error 0.08 |
| Nintedanib 50 mg- 100 mg | Annual Rate of Decline in Haemoglobin Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Decrease | -0.3 mmol/min/kPa/yr | Standard Error 0.04 |
| Nintedanib 150 mg | Annual Rate of Decline in Haemoglobin Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Decrease | -0.2 mmol/min/kPa/yr | Standard Error 0.07 |
Secondary
Incidence of Patients With at Least One Acute IPF Exacerbation Over Time
Incidence rate = (Patients with at least one acute IPF exacerbation / Total number of years at risk) x 100
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: FAS
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Incidence of Patients With at Least One Acute IPF Exacerbation Over Time | 6.1 Exacerbations Per Year | 0.08 |
| Nintedanib 50 mg- 100 mg | Incidence of Patients With at Least One Acute IPF Exacerbation Over Time | 7.6 Exacerbations Per Year | 0.04 |
| Nintedanib 150 mg | Incidence of Patients With at Least One Acute IPF Exacerbation Over Time | 7.8 Exacerbations Per Year | 0.07 |
Secondary
Overall Survival
Overall survival is defined as the time from the first intake of nintedanib in trial 1199.35 to death. For presentation of overall survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment survival is calculated within each treatment arm.
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: FAS
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Overall Survival | 37.4 percentage of participants | 95% Confidence Interval 29.47 |
| Nintedanib 50 mg- 100 mg | Overall Survival | 46.8 percentage of participants | 95% Confidence Interval 14.6 |
| Nintedanib 150 mg | Overall Survival | 66.2 percentage of participants | 95% Confidence Interval 28.22 |
Secondary
Percentage of Patients With at Least One Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation
Percentage of patients with at least one acute idiopathic pulmonary fibrosis (IPF) exacerbation are presented. An exacerbation was defined as otherwise unexplained clinical features occurring within 1 month including all of the following: * Progression of dyspnoea over several days to 4 weeks * New diffuse pulmonary infiltrates on chest X-ray and/or high-resolution computerised tomography (HRCT) Parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit * A decrease in arterial oxygen partial pressure (PaO2) of ≥10 mmHg or PaO2/fraction of inspired oxygen (FiO2) of \<225 mmHg since the last visit * Exclusion of infection based on routine clinical practice and microbiological studies * Absence of other contributory causes such as congestive heart failure, pulmonary embolism, etc.
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: FAS
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With at Least One Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | 13.5 Percentage of participants | 0.08 |
| Nintedanib 50 mg- 100 mg | Percentage of Patients With at Least One Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | 19.8 Percentage of participants | 0.04 |
| Nintedanib 150 mg | Percentage of Patients With at Least One Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | 20.0 Percentage of participants | 0.07 |
Secondary
Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs
Percentage of patients with at least one Adverse events (AEs), with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, serious AEs are presented
Time frame: From the first nintedanib intake in trial 1199.35 to the last nintedanib intake + 28 days; up to 61.8 months + 28 days
Population: TS
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Placebo | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs | 100.0 Percentage of participants | 0.08 |
| Placebo | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Investigator defined drug-related AEs | 70.3 Percentage of participants | — |
| Placebo | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs leading to discontinuation of trial drug | 48.6 Percentage of participants | — |
| Placebo | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Serious AE | 67.6 Percentage of participants | — |
| Nintedanib 50 mg- 100 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Serious AE | 74.6 Percentage of participants | — |
| Nintedanib 50 mg- 100 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs | 99.2 Percentage of participants | 0.04 |
| Nintedanib 50 mg- 100 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs leading to discontinuation of trial drug | 41.3 Percentage of participants | — |
| Nintedanib 50 mg- 100 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Investigator defined drug-related AEs | 65.9 Percentage of participants | — |
| Nintedanib 150 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Serious AE | 62.9 Percentage of participants | — |
| Nintedanib 150 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | Investigator defined drug-related AEs | 54.3 Percentage of participants | — |
| Nintedanib 150 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs leading to discontinuation of trial drug | 34.3 Percentage of participants | — |
| Nintedanib 150 mg | Percentage of Patients With at Least One Adverse Events (AEs), With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, Serious AEs | AEs | 97.1 Percentage of participants | 0.07 |
Secondary
Progression-Free Survival
Progression-free survival was defined as the time from the first nintedanib intake in trial 1199.35 to disease progression. For presentation of progression-free survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment progression-free survival is calculated within each treatment arm.
Time frame: From first trial drug intake in 1199.35 to disease progression; up to 61.8 months
Population: FAS
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Progression-Free Survival | 9.6 percentage of participants | 95% Confidence Interval 29.47 |
| Nintedanib 50 mg- 100 mg | Progression-Free Survival | 3.5 percentage of participants | 95% Confidence Interval 14.6 |
| Nintedanib 150 mg | Progression-Free Survival | 12.2 percentage of participants | 95% Confidence Interval 28.22 |
Secondary
Time to First Acute IPF Exacerbation
Due to rare events, the median of time to event is not calculable, thus Kaplan-Meier estimates (providing the percentage of patients without acute IPF exacerbation for a certain amount of time after treatment) and confidence intervals (using Greenwood variance formula) are reported and presented within each treatment arm as secondary endpoint.
Time frame: From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
Population: FAS
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Time to First Acute IPF Exacerbation | 67.7 percentage of participants | 95% Confidence Interval 29.47 |
| Nintedanib 50 mg- 100 mg | Time to First Acute IPF Exacerbation | 68.6 percentage of participants | 95% Confidence Interval 14.6 |
| Nintedanib 150 mg | Time to First Acute IPF Exacerbation | 73.5 percentage of participants | 95% Confidence Interval 28.22 |