Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
This is an 6 month multi-centre, prospective, randomized, placebo controlled, double blind clinical trial followed by conversion of each arm to active nintedanib for an additional 6 months comparing the effect of nintedanib 150mg bis in die (BID twice daily) on the progression of IPF measured by using High Resolution Computerized Tomography(HRCT), lung function, functional component (6MWT), biomarkers, and PRO component (PROs) with continued treatment and assessments for up to 18 months.
Interventions
DRUGMatching Placebo
twice daily dosing
DRUGNintedanib
gelating capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written Informed Consent consistent with International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and local laws signed prior to entry into the study 2. Patient aged \>= 40 years at Visit 1. 3. IPF diagnosed, according to the 2011 American Thoracic Society (ATS) / European Respiratory Society (ERS) / Japanese Respiratory Society(JRS)/ Latin American Thoracic Association (ALAT)/ Latin American Thoracic Association/ Idiopathic Pulmonary Fibrosis (IPF) guidelines for diagnosis and management, within 5 years and reaffirmed applying 2011 Guidelines (P11-07084) if diagnosed \>2 years and up to 5 year from Visit 1,. Diagnosis must be confirmed by chest High Resolution Computerized Tomography (HRCT) taken within 24 months of Visit 1. All HRCT results reported to be possible or inconsistent usual interstitial pneumonia (UIP) must have confirmatory pathology. 4. Carbon monoxide Diffusing capacity or Transfer factor of the lung for carbon monoxide (DLCO) (corrected for Hb): 30%-79% predicted of normal 5. Forced Vital Capacity (FVC) \>= 50% predicted of normal at Visit 1 and Visit 2
Exclusion criteria
1. AST, ALT \> 1.5 fold ULN 2. Bilirubin \> 1.5 fold ULN 3. Bleeding risk: 1. Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, dabigatran, heparin, hirudin), or high dose antiplatelet therapy. Exceptions: prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 IU s.c. per day) and prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/d, or clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet therapy) 2. History of hemorrhagic Central Nervous System (CNS) event within 12 months 3. Any of the following within 3 months: * Haemoptysis or haematuria. * Active gastro-intestinal bleeding or ulcers. * Major injury or surgery. 4. Coagulation parameters: International normalised ratio (INR) \> 2, prothrombin time (PT) and partial thromboplastin time (PTT) \> 150% of institutional ULN. 4. Planned major surgery within the next 3 months, including lung transplantation, major abdominal or major intestinal surgery. 5. Thrombotic risk 1. Known inherited predisposition to thrombosis. 2. History of thrombotic event (including stroke and transient ischemic attacks) within 12 months 6. Current or planned usage of any investigational drug during the course of this trial 7. Previous treatment with nintedanib within a clinical trial in the previous 3 months and discontinuation of nintedanib study treatment due to an adverse event 8. Known hypersensitivity to the trial drug or its component 9. A disease or condition which in the opinion of investigator may put the patient at risk because of participation in this trial or limit the patient's ability to participate in this trial. Patients will be excluded if they require greater than 12L/min oxygen, are not ambulatory or require use of a walker or cane during the 6 Minute Titration Walk Test. Patients who cannot complete the 6 Minute Titration Walk Test are excluded from participation. 10. Alcohol or drug abuse which in the opinion of the investigator would interfere with trial participation. 11. Pregnant women or women who are breast feeding or of child bearing potential not using two effective methods of birth control (one barrier and one highly effective non-barrier) for at least 1 month prior to trial and/or not committing to using it until 3 months after end of treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in High Resolution Computerized Tomography (HRCT) Quantitative Lung Fibrosis (QLF) Score at 6 Months | Baseline and 6 Months | Relative change from baseline in HRCT QLF score at 6 months was calculated as the difference of the QLF score at month 6 minus the QLF score at baseline divided by the baseline QLF score. The QLF score itself ranges from 0 to 100%, where greater values represent a greater amount of lung fibrosis and are considered a worse health status. Hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Forced Vital Capacity (FVC) From Baseline at 6 Months | Baseline and 6 Months | Absolute change in Forced Vital Capacity (FVC) from baseline at 6 months is presented. |
| Relative Change in FVC From Baseline at 6 Months | Baseline and 6 Months | Relative change in FVC from baseline at 6 months is presented. |
| Categorical Change in FVC From Baseline at 6 Months | Baseline and 6 Months | Percentage of participants reporting categorical change in FVC from baseline at 6 months are presented. |
| St. George's Respiratory Questionnaire (SGRQ) Total Score Change From Baseline at 6 Months | Baseline and 6 Months | SGRQ total score change from baseline at 6 months is presented. 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 month 6). |
| 6MWT Total Distance Walked Change From Baseline at 6 Months | Baseline and 6 Months | Change in total distance covered in 6-minute walk test (6MWT) from baseline at 6 month is presented. The 6-Minutes Walk Test (6-MWT) was conducted according to the American Thoracic Society (ATS) Criteria. |
| Effect of Six Month Delayed Treatment Onset: Relative Change From Baseline in HRCT QLF Score at 12 Months | Baseline and 12 Months | Relative change from baseline in HRCT QLF score at 12 months was calculated as the ratio of the QLF score at 12 months to baseline. Greater values of the QLF score represented a worse health status and hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline. Note that due to the change in study design, patients randomized to the placebo group were treated with nintedanib after completion of the first 6-month treatment period. Therefore, this new endpoint was defined to address the effect of a 6-month delayed onset of nintedanib treatment. |
| All-cause Mortality at 6 Months | 6 Months | Percentage of subjects died from all causes between 0 to 6 months are presented. |
| Respiratory Hospitalizations at 6 Months | 6 Months | Percentage of subjects hospitalized due to respiratory problems between 0 to 6 months are presented. |
| Respiratory Mortality at 6 Months | 6 Months | Percentage of subjects who died due to respiratory cause between 0 to 6 months are presented. |
| Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbations at 6 Months | 6 Months | Percentage of subjects experienced first acute IPF exacerbations (based on Investigator reported adverse events) between 0 to 6 months are presented. |
| University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Change From Baseline at 6 Months | Baseline and 6 Months | University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) change from baseline at 6 months is presented. 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 month 6). |
Countries
Canada, Turkey (Türkiye), United States
Participant flow
Recruitment details
Patients were randomized to receive nintedanib or placebo in 1:1 ratio. After Global Amendment 1, study design was changed to exploratory, and duration of double blind, placebo-controlled part of study was reduced from 12 months to 6 months, followed by conversion of all patients to open-label nintedanib treatment for a duration of up to 18 months.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Patients received oral administration of 150 milligram (mg) soft gelatin capsules of nintedanib (Ofev ®) twice daily for up to 18 months. | 56 |
| Placebo Patients receive oral administration of matching placebo of 150 mg nintedanib twice daily for a period of at least 6 months after randomization | 57 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Other than specified above | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Nintedanib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 68.8 Years STANDARD_DEVIATION 7.6 | 66.2 Years STANDARD_DEVIATION 9.4 | 67.5 Years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 11 Participants | 20 Participants | 31 Participants |
| Sex: Female, Male Male | 45 Participants | 37 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 56 | 51 / 57 |
| serious Total, serious adverse events | 11 / 56 | 14 / 57 |
Outcome results
Primary
Relative Change From Baseline in High Resolution Computerized Tomography (HRCT) Quantitative Lung Fibrosis (QLF) Score at 6 Months
Relative change from baseline in HRCT QLF score at 6 months was calculated as the difference of the QLF score at month 6 minus the QLF score at baseline divided by the baseline QLF score. The QLF score itself ranges from 0 to 100%, where greater values represent a greater amount of lung fibrosis and are considered a worse health status. Hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline.
Time frame: Baseline and 6 Months
Population: Observed Cases (6 months) (OC6): The OC6 consisted of all patients in the TS (all patients who were randomized to a treatment group and received at least 1 dose of study drug) with observed data for the primary endpoint (relative change from baseline in HRCT QLF score at 6 months).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | Relative Change From Baseline in High Resolution Computerized Tomography (HRCT) Quantitative Lung Fibrosis (QLF) Score at 6 Months | 11.407 percent change | Standard Error 4.4819 |
| Placebo | Relative Change From Baseline in High Resolution Computerized Tomography (HRCT) Quantitative Lung Fibrosis (QLF) Score at 6 Months | 14.583 percent change | Standard Error 4.3297 |
Comparison: Analysis of covariance (ANCOVA) model with treatment as fixed effect and baseline HRCT QLF score as covariate95% CI: [-9.227, 15.579]ANCOVA
Secondary
6MWT Total Distance Walked Change From Baseline at 6 Months
Change in total distance covered in 6-minute walk test (6MWT) from baseline at 6 month is presented. The 6-Minutes Walk Test (6-MWT) was conducted according to the American Thoracic Society (ATS) Criteria.
Time frame: Baseline and 6 Months
Population: TS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | 6MWT Total Distance Walked Change From Baseline at 6 Months | 4.93 meters | Standard Error 11.415 |
| Placebo | 6MWT Total Distance Walked Change From Baseline at 6 Months | -13.00 meters | Standard Error 11.476 |
Comparison: MMRM model included treatment, visit, baseline value, treatment-by-visit and baseline-by-visit as fixed effects and patient as random effect. Unstructured covariance was assumed for within patient variation95% CI: [-14.21, 50.09]Mixed Models Analysis
Secondary
Absolute Change in Forced Vital Capacity (FVC) From Baseline at 6 Months
Absolute change in Forced Vital Capacity (FVC) from baseline at 6 months is presented.
Time frame: Baseline and 6 Months
Population: Treated Set (TS) (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | Absolute Change in Forced Vital Capacity (FVC) From Baseline at 6 Months | -14.18 milliliter (mL) | Standard Error 31.05 |
| Placebo | Absolute Change in Forced Vital Capacity (FVC) From Baseline at 6 Months | -83.18 milliliter (mL) | Standard Error 28.067 |
Comparison: Mixed Model for Repeated Measures (MMRM) model with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by-visit and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix.95% CI: [-8.74, 146.75]Mixed Models Analysis
Secondary
Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbations at 6 Months
Percentage of subjects experienced first acute IPF exacerbations (based on Investigator reported adverse events) between 0 to 6 months are presented.
Time frame: 6 Months
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbations at 6 Months | 1.8 Percentage of participants |
| Placebo | Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbations at 6 Months | 1.8 Percentage of participants |
Secondary
All-cause Mortality at 6 Months
Percentage of subjects died from all causes between 0 to 6 months are presented.
Time frame: 6 Months
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | All-cause Mortality at 6 Months | 0.0 Percentage of participants |
| Placebo | All-cause Mortality at 6 Months | 5.3 Percentage of participants |
Secondary
Categorical Change in FVC From Baseline at 6 Months
Percentage of participants reporting categorical change in FVC from baseline at 6 months are presented.
Time frame: Baseline and 6 Months
Population: TS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib | Categorical Change in FVC From Baseline at 6 Months | Decrease >10% or 200 mL | 6.5 Percentage of participants |
| Nintedanib | Categorical Change in FVC From Baseline at 6 Months | Change within ≤10% AND ≤200 mL | 76.1 Percentage of participants |
| Nintedanib | Categorical Change in FVC From Baseline at 6 Months | Increase >10% or 200 mL | 17.4 Percentage of participants |
| Placebo | Categorical Change in FVC From Baseline at 6 Months | Decrease >10% or 200 mL | 23.9 Percentage of participants |
| Placebo | Categorical Change in FVC From Baseline at 6 Months | Change within ≤10% AND ≤200 mL | 71.7 Percentage of participants |
| Placebo | Categorical Change in FVC From Baseline at 6 Months | Increase >10% or 200 mL | 4.3 Percentage of participants |
Secondary
Effect of Six Month Delayed Treatment Onset: Relative Change From Baseline in HRCT QLF Score at 12 Months
Relative change from baseline in HRCT QLF score at 12 months was calculated as the ratio of the QLF score at 12 months to baseline. Greater values of the QLF score represented a worse health status and hence smaller relative changes from baseline (i.e., ratios) were considered favorable. HCRT assessment obtained during screening visit was considered as baseline. Note that due to the change in study design, patients randomized to the placebo group were treated with nintedanib after completion of the first 6-month treatment period. Therefore, this new endpoint was defined to address the effect of a 6-month delayed onset of nintedanib treatment.
Time frame: Baseline and 12 Months
Population: Observed Cases (12 months) (OC12): The OC12 consisted of all patients in OC6 with observed QLF data at 12 months.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | Effect of Six Month Delayed Treatment Onset: Relative Change From Baseline in HRCT QLF Score at 12 Months | 13.103 percent change | Standard Error 4.5454 |
| Placebo | Effect of Six Month Delayed Treatment Onset: Relative Change From Baseline in HRCT QLF Score at 12 Months | 15.622 percent change | Standard Error 4.4714 |
Comparison: Analysis of covariance (ANCOVA) model with treatment as fixed effect and baseline HRCT QLF score as covariate95% CI: [-10.258, 15.296]ANCOVA
Secondary
Relative Change in FVC From Baseline at 6 Months
Relative change in FVC from baseline at 6 months is presented.
Time frame: Baseline and 6 Months
Population: TS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | Relative Change in FVC From Baseline at 6 Months | -0.67 percentage of change | Standard Error 1.05 |
| Placebo | Relative Change in FVC From Baseline at 6 Months | -3.02 percentage of change | Standard Error 0.95 |
Comparison: MMRM model with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by-visit and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix.95% CI: [-0.29, 5]Mixed Models Analysis
Secondary
Respiratory Hospitalizations at 6 Months
Percentage of subjects hospitalized due to respiratory problems between 0 to 6 months are presented.
Time frame: 6 Months
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | Respiratory Hospitalizations at 6 Months | 0.0 Percentage of participants |
| Placebo | Respiratory Hospitalizations at 6 Months | 7.0 Percentage of participants |
Secondary
Respiratory Mortality at 6 Months
Percentage of subjects who died due to respiratory cause between 0 to 6 months are presented.
Time frame: 6 Months
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | Respiratory Mortality at 6 Months | 0.0 Percentage of participants |
| Placebo | Respiratory Mortality at 6 Months | 3.5 Percentage of participants |
Secondary
St. George's Respiratory Questionnaire (SGRQ) Total Score Change From Baseline at 6 Months
SGRQ total score change from baseline at 6 months is presented. 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 month 6).
Time frame: Baseline and 6 Months
Population: TS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | St. George's Respiratory Questionnaire (SGRQ) Total Score Change From Baseline at 6 Months | -2.24 Units on a scale | Standard Error 1.682 |
| Placebo | St. George's Respiratory Questionnaire (SGRQ) Total Score Change From Baseline at 6 Months | -2.19 Units on a scale | Standard Error 1.699 |
Comparison: MMRM model included treatment, visit, baseline value, treatment-by-visit and baseline-by-visit as fixed effects and patient as random effect. Unstructured covariance was assumed for within patient variation95% CI: [-4.89, 4.79]Mixed Models Analysis
Secondary
University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Change From Baseline at 6 Months
University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) change from baseline at 6 months is presented. 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 month 6).
Time frame: Baseline and 6 Months
Population: TS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib | University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Change From Baseline at 6 Months | 3.42 Units on a scale | Standard Error 2.156 |
| Placebo | University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Change From Baseline at 6 Months | -1.46 Units on a scale | Standard Error 2.192 |
Comparison: MMRM model included treatment, visit, baseline value, treatment-by-visit and baseline-by-visit as fixed effects and patient as random effect. Unstructured covariance was assumed for within patient variation95% CI: [-1.47, 11.25]Mixed Models Analysis