Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
Identifying biomarkers to predict the clinical course and benefits of therapy early in the course of the disease remains one of the most urgent and relevant challenges to improve overall patient management, to prevent treatment delay or overtreatment. This study is conducted to examine the effect of nintedanib treatment on change in biomarkers indicative of extracellular matrix turnover which have been shown recently to correlate with disease progression. This study further aims to confirm the association of biomarker course during the first three months of treatment and disease progression.
Interventions
DRUGnintedanib
DRUGplacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent consistent with International Conference on Harmonisation Good Clinical Practice and local laws, signed prior to participation in the trial including any study related procedures being performed; * Male or female patients aged \>=40 years at Visit 1; * A clinical diagnosis of Idiopathic pulmonary fibrosis (IPF) within the last 3 years from visit 0, based upon the American Thoracic Society/ European Respiratory Society /Japanese Respiratory Society/ Latin American Thoracic Association 2011 guideline; * Chest high resolution computed tomography (HRCT) scan performed within 18 months of Visit 0; * Combination of HRCT pattern, and surgical lung biopsy pattern (the latter if available) as assessed by central review are consistent with the diagnosis of Idiopathic pulmonary fibrosis; * Forced vital capacity (FVC) \>=80% of predicted normal at Visit 1.
Exclusion criteria
* Alanine transaminase, Aspartate aminotransferase \> 1.5 fold upper limit of normal (ULN) at Visit 1; * Total bilirubin \> 1.5 fold ULN at Visit 1; * Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment); * Relevant airways obstruction, i.e. pre-bronchodilator Forced expiratory volume in 1 second / Forced vital capacity \< 0.70; * History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 month of Visit 1; * Bleeding Risk: * Known genetic predisposition to bleeding; * Patients who require fibrinolysis, full-dose therapeutic anticoagulation or high dose antiplatelet therapy; * History of haemorrhagic central nervous system (CNS) event within 12 months prior to Visit 1; * History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to Visit 1; * International normalised ratio (INR) \> 2 at Visit 1; * Prothrombin time (PT) and partial thromboplastin time (PTT) \> 150% of ULN at Visit 1; * Planned major surgery during the trial participation, including lung transplantation, major abdominal or major intestinal surgery; * History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1; * Creatinine clearance \< 30 mL/min calculated by Cockcroft-Gault formula at Visit 1; * Treatment with nintedanib, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, any other investigational drug, n-acetylcysteine, prednisone/prednisolone \>15 mg daily or \>30 mg every 2 days OR use of other systemic corticosteroids as well as any investigational drugs within 4 weeks of Visit 2; * Known hypersensitivity to nintedanib, peanut, soya or to any other components of the study medication; * Prior discontinuation of nintedanib treatment due to intolerability/ adverse events considered drug related; * A disease or condition which in the opinion of the investigator may interfere with testing procedures or put the patient at risk when participating in this trial; * Alcohol or drug abuse which in the opinion of the treating physician would interfere with the treatment and would affect patient's ability to participate in this trial; * Patients not able to understand and follow any study procedures such as but not limited to home spirometry, including completion of self-administered questionnaires without help; * Women who are pregnant, nursing, who plan to become pregnant while in the trial or female patients with positive pregnancy (ß-HCG) test at Visit 1 and/or Visit 2; * Women of childbearing potential4 not willing or able to use highly effective methods of birth control per International Conference on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. * Patients with acute IPF exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period; * Patients who are or have been participating in another trial with investigational drug/s within one month prior to Visit 1 and patients who have previously been enrolled in this trial; * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12. | baseline and 12 weeks | The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52 | 52 weeks | For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry. This is a key secondary endpoint of the trial. This outcome measure is percentage of patients with disease progression and CRPM is included in the various models as a factor/covariate, and that this outcome measure, the percentage of progressors are displayed under Measured values |
| The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12 | baseline and 12 weeks | The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time. |
| The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12 | baseline and 12 weeks | The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time. |
Countries
Australia, Belgium, Czechia, Finland, France, Germany, Hungary, Japan, Poland, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
The trial comprised of 2 treatment periods (52 weeks). The first treatment period was a 12-week, randomised, double-blind, placebo-controlled, parallel-group period whereas the second treatment period was a 40-week, single-arm, open-label, active treatment (nintedanib 150 milligram (mg) twice daily (bid)) period.
Pre-assignment details
Participants with idiopathic pulmonary fibrosis (IPF) were eligible for the trial if they fulfilled all of the inclusion criteria and none of the exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/ Nintedanib Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period.
1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs) | 230 |
| Nintedanib/ Nintedanib Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period.
1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs) | 116 |
| Total | 346 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment Period | Adverse Event | 6 | 4 |
| Double Blind Treatment Period | Not treated | 1 | 0 |
| Double Blind Treatment Period | Patient's refusal | 3 | 0 |
| Open Label Treatment Period | Adverse Event | 29 | 9 |
| Open Label Treatment Period | Non-compliance | 1 | 0 |
| Open Label Treatment Period | Other than reason specified | 1 | 0 |
| Open Label Treatment Period | Patient's refusal | 1 | 3 |
Baseline characteristics
| Characteristic | Nintedanib/ Nintedanib | Total | Placebo/ Nintedanib |
|---|---|---|---|
| Age, Continuous | 70.5 years STANDARD_DEVIATION 7.7 | 70.3 years STANDARD_DEVIATION 7.4 | 70.2 years STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 28 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 289 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 29 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 103 Participants | 68 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 29 Participants | 18 Participants |
| Race (NIH/OMB) White | 70 Participants | 214 Participants | 144 Participants |
| Sex: Female, Male Female | 23 Participants | 84 Participants | 61 Participants |
| Sex: Female, Male Male | 93 Participants | 262 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 230 | 0 / 116 | 9 / 333 |
| other Total, other adverse events | 103 / 230 | 80 / 116 | 277 / 333 |
| serious Total, serious adverse events | 18 / 230 | 8 / 116 | 65 / 333 |
Outcome results
Primary
The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12.
The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
Time frame: baseline and 12 weeks
Population: Treated set (TS) including participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/ Nintedanib | The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12. | -0.00190 nanogram/ millitre/ month (ng/ mL/ mth) | Standard Error 0.00165 |
| Nintedanib/ Nintedanib | The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12. | -0.00257 nanogram/ millitre/ month (ng/ mL/ mth) | Standard Error 0.00232 |
Comparison: The rate of change (slope) in blood CRPM was assumed to be linear in each subject over the 12 weeks of treatment. The intercepts and slopes were assumed to be normally distributed with arbitrary covariance matrix.~Since the distribution of the data was not normal, a log10 transformation was performed before conducting the statistical analyses.~Significance tests were based on least-square means using 2-sided 95% confidence intervals (2-sided α=0.05).p-value: 0.814695% CI: [-0.00621, 0.00488]random coefficient regression
Secondary
Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52
For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry. This is a key secondary endpoint of the trial. This outcome measure is percentage of patients with disease progression and CRPM is included in the various models as a factor/covariate, and that this outcome measure, the percentage of progressors are displayed under Measured values
Time frame: 52 weeks
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/ Nintedanib | Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52 | 30.43 Percentage of participants |
| Nintedanib/ Nintedanib | Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52 | 25.00 Percentage of participants |
Comparison: To assess the association between disease progression (as defined by absolute forced vital capacity (FVC) decline \>=10% or death) and the change in the Extracellular matrix (ECM) biomarker CRPM in the first 12 weeks, a logistic regression analysis including baseline blood CRPM and the monthly rate of change (slope) in blood CRPM in the first 12 weeks as covariates was applied for placebo-treated patients only to evaluate the potential of CRPM as a prognostic biomarker.p-value: 0.208495% CI: [-11.83, 57.58]Regression, Logistic
Comparison: To assess how nintedanib treatment affected the association between disease progression (as defined by absolute forced vital capacity (FVC) decline \>=10% or death) and the change in CRPM in the first 12 weeks, a logistic regression analysis including baseline blood CRPM, the monthly rate of change (slope) in blood CRPM up to Week 12, treatment and treatment-CRPM slope interaction as covariates was applied.p-value: 0.153795% CI: [-109.55, 16.37]Regression, Logistic
Comparison: To assess whether the overall treatment regimen affected disease progression (as defined by absolute forced vital capacity (FVC) decline \>=10% or death), a logistic regression analysis including baseline blood CRPM and randomised treatment as covariates was applied.p-value: 0.311695% CI: [0.46, 1.27]Regression, Logistic
Comparison: To assess whether the monthly rate of change (slope) in blood CRPM in the first 12 weeks could explain the effect of treatment on disease progression (as defined by absolute forced vital capacity (FVC) decline \>=10% or death), a logistic regression analysis including baseline blood CRPM, the rate of change (slope) in blood CRPM in the first 12 weeks and randomised treatment as covariates was applied.p-value: 0.317595% CI: [0.46, 1.27]Regression, Logistic
Secondary
The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12
The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
Time frame: baseline and 12 weeks
Population: Treated set (TS) including participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/ Nintedanib | The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12 | 0.00041 ng/ml/mth | Standard Error 0.00127 |
| Nintedanib/ Nintedanib | The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12 | 0.00162 ng/ml/mth | Standard Error 0.00172 |
Comparison: The rate of change (slope) in blood C1M was assumed to be linear in each subject over the 12 weeks of treatment.~Within-patient errors are modelled by an Unstructured variance-covariance matrix.p-value: 0.546995% CI: [-0.00273, 0.00515]random coefficient regression
Secondary
The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12
The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
Time frame: baseline and 12 weeks
Population: Treated set (TS) including participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/ Nintedanib | The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12 | -0.00091 ng/ml/mth | Standard Error 0.00158 |
| Nintedanib/ Nintedanib | The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12 | -0.00398 ng/ml/mth | Standard Error 0.00219 |
Comparison: The rate of change (slope) in blood C3M was assumed to be linear in each subject over the 12 weeks of treatment.~Within-patient errors are modelled by an Unstructured variance-covariance matrix.p-value: 0.242995% CI: [-0.00823, 0.00209]random coefficient regression