Lung Diseases, Interstitial
Conditions
Brief summary
This study is open to adults with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs). People who have a form of PF-ILD other than Idiopathic Pulmonary Fibrosis (IPF) can join the study. If they already take nintedanib, they can continue treatment throughout the study. The purpose of this study is to find out whether a medicine called BI 1015550 helps people with PF-ILD. Participants are put into 3 groups randomly, which means by chance. Participants in 2 groups take different doses of BI 1015550 as tablets twice a day. Participants in the placebo group take placebo tablets twice a day. Placebo tablets look like BI 1015550 tablets but do not contain any medicine. Participants are in the study for up to two and a half years. During the first year, they visit the study site 10 times. Afterwards, they visit the study site every 3 months. The doctors regularly test participants' lung function. The results of the lung function tests are compared between the groups. The doctors also regularly check participants' health and take note of any unwanted effects.
Interventions
DRUGBI 1015550
Participants received film-coated nerandomilast tablets orally, twice daily, at doses of either 9 mg or 18 mg, in the morning and in the evening.
DRUGPlacebo
Participants received placebo matching 9 mg or 18 mg nerandomilast film-coated tablets orally, twice daily, in the morning and in the evening.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients ≥18 years old at the time of signed informed consent. 2. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. 3. Diagnosis of progressive fibrosing ILD other than IPF (physician confirmed). 4. Patients may be either: * on a stable therapy\* with nintedanib for at least 12 weeks prior to Visit 1 and during screening and are planning to stay on this background treatment after randomization. (\*stable therapy is defined as a tolerated regimen of nintedanib (with no dose changes) for at least 12 weeks) * not on treatment with nintedanib for at least 8 weeks prior to Visit 1 and during the screening period (e.g. either Antifibrotic (AF)-treatment naïve or previously discontinued) and do not plan to start or re-start antifibrotic treatment. 5. Forced Vital Capacity (FVC) ≥45% of predicted normal at Visit 1. 6. DLCO ≥25% of predicted normal corrected for hemoglobin (Hb) at Visit 1. 7. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control. WOCBP taking oral contraceptives (OCs) also have to use one barrier method 8. Patients treated with permitted immunosuppressive agents (other than corticosteroids) for an underlying systemic disease (e.g. Methotrexate (MTX), Azathioprine (AZA)) need to be on a stable treatment for at least 12 weeks prior to Visit 1 and during the screening period.
Exclusion criteria
1. Prebronchodilator Forced Expiratory Volume in 1 second (FEV1)/Forced vital capacity (FVC) \<0.7 at Visit 1 2. In the opinion of the Investigator, other clinically significant pulmonary abnormalities. 3. Acute Interstitial Lung Disease (ILD) exacerbation within 3 months prior to Visit 1 and/or during the screening period (investigator-determined). 4. Relevant chronic or acute infections including human immunodeficiency virus (HIV) and viral hepatitis. 5. Patients having developed ILD due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/coronavirus disease 2019 (COVID-19) within 12 months of screening (based on investigators judgement). 6. Major surgery (major according to the investigator's assessment) performed within 6 weeks prior to Visit 2 or planned during the trial period, e.g. hip replacement. Registration on lung transplantation list would not be considered as planned major surgery. 7. Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1, except appropriately treated basal cell carcinoma of the skin, in situ squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix. 8. Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) \>2.5 x upper limit of normal (ULN) or total Bilirubin \>1.5 x ULN at Visit 1. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Forced Vital Capacity (FVC) in Milliliters [mL] at Week 52 | The MMRM model is a longitudinal analysis, and it incorporated FVC measurements change from baseline at Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. Data presented is the FVC adjusted change from baseline at Week 52. | The absolute change from baseline in forced vital capacity (FVC) in milliliters \[mL\] at Week 52 is reported. The absolute change from baseline in FVC was analyzed by a restricted maximum likelihood (REML)-based mixed model with repeated measurements (MMRM) comparing the change from baseline in FVC at Week 52 between treatment groups. The analysis included the fixed, categorical effects of treatment, baseline intake of antifibrotic (AF) treatment, and baseline High-resolution Computed Tomography (HRCT) pattern at each visit, as well as the fixed continuous effects of baseline FVC value at each visit. Visits were treated as a repeated measure with an unstructured covariance structure used to model within-patient measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | Time to first acute ILD exacerbation or death over the duration of the trial is reported as the number of patients who experienced either event. Acute exacerbation of ILD describes an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality with all of the following: Acute worsening or development of dyspnea typically with less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILD, and deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute IPF exacerbation followed by death. |
| Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | Time to hospitalisation for respiratory cause or death over the duration of the trial is reported as the number of participants who experienced either event. Hospitalizations due to respiratory causes were recorded on a specific non-elective hospitalization CRF page. This page captured the hospitalization date, confirmation of a respiratory cause, and the primary admission diagnosis. Time to death was based either on the date of death on the adverse event (AE) report for patients with AEs leading to death or was based on the information from the vital status assessment. |
| Time to Death Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | Time to death over the duration of the trial is reported as the number of participants who died. Time to death was based either on the date of death on the AE report for patients with AEs leading to death or based on the information from the vital status assessment. |
| Absolute Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted at Week 52 | The MMRM model is a longitudinal analysis, and it incorporated FVC % predicted change from baseline at Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. Data presented is change from baseline in FVC % predicted at Week 52. | Absolute change from baseline in forced vital capacity (FVC) percent (%) predicted at Week 52 is reported. Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates. |
| Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | The time to absolute decline of more than 10% from baseline in forced vital capacity (FVC) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. If multiple components occurred on the day of first event, then the patient was only counted in the first component based on the following hierarchy: absolute decline in FVC % predicted of \> 10% followed by death. |
| Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | Time to first occurrence of any of the components of the composite endpoint - acute interstitial lung disease (ILD) exacerbation, first hospitalisation for respiratory cause, or death (whichever occurred first) - is reported as the number of participants who experienced any of these events during the trial. Acute exacerbation of ILD describes an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality with all of the following: Acute worsening or development of dyspnea typically with less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILD, and deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute ILD exacerbation, hospitalization, death. |
| Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months. | Time to absolute decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) percentage predicted by more than 15% from baseline or death, measured over the duration of the trial is reported as the number of participants who experienced either event. The Predicted DLCO value was corrected for hemoglobin (Hb). If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: Absolute decline in DLCO % predicted of \> 15%, followed by Death. |
| Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 | The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52. | The absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnoea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, baseline HRCT pattern, and fixed continuous effect of baseline L-PF dyspnea score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates. |
| Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 | The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52. | The absolute change from baseline in the L-PF Cough domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, baseline HRCT pattern, and fixed continuous effect of baseline L-PF dyspnea score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates. |
| Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 | The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52. | The absolute change from baseline in the L-PF Fatigue domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, and baseline HRCT pattern at each visit, and fixed continuous effect of baseline L-PF Fatigue score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates. |
| Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) % Predicted (Corrected for Hb) at Week 52 | The MMRM model is a longitudinal analysis and it incorporated DLCO measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52. | The absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted (corrected for hemoglobin, Hb) at Week 52 is reported.. Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline DLCO \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Croatia, Czechia, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Puerto Rico, Saudi Arabia, Serbia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This was a multi-centre, multi-national, prospective, randomised, placebo-controlled, double-blind clinical trial, including a treatment period of at least 52 weeks, and a 1-week follow-up period in patients with progressive pulmonary fibrosis. The trial comprised two parts: Treatment Period A lasted up to 52 weeks post-randomisation, followed by Treatment Period B in which patients continued randomised blinded treatment for a variable duration.
Pre-assignment details
All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the participants) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment sequence if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients with progressive fibrosing interstitial lung disease (PF-ILD) or progressive pulmonary fibrosis (PPF), other than idiopathic pulmonary fibrosis (IPF), were administered placebo matching nerandomilast, taken orally as film-coated tablets twice daily, in the morning and in the evening for an initial 52 weeks, followed by a variable duration till end of trial. | 392 |
| Nerandomilast 9 mg Patients with progressive fibrosing interstitial lung disease (PF-ILD) or progressive pulmonary fibrosis (PPF), other than idiopathic pulmonary fibrosis (IPF), were administered 9 milligrams (mg) nerandomilast, taken orally as film-coated tablets twice daily (18 mg total), in the morning and in the evening for an initial 52 weeks, followed by a variable duration till end of trial. | 393 |
| Nerandomilast 18 mg Patients with progressive fibrosing interstitial lung disease (PF-ILD) or progressive pulmonary fibrosis (PPF), other than idiopathic pulmonary fibrosis (IPF), were administered 18 mg nerandomilast, taken orally as film-coated tablets twice daily (36 mg total), in the morning and in the evening for an initial 52 weeks, followed by a variable duration till end of trial. | 391 |
| Total | 1,176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 49 | 49 | 48 |
| Overall Study | Lack of Efficacy | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Not treated | 1 | 0 | 1 |
| Overall Study | Other than listed | 40 | 26 | 27 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 30 | 34 | 42 |
Baseline characteristics
| Characteristic | Placebo | Nerandomilast 9 mg | Nerandomilast 18 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 66.6 Years STANDARD_DEVIATION 10.3 | 66.5 Years STANDARD_DEVIATION 9.8 | 66.0 Years STANDARD_DEVIATION 9.8 | 66.4 Years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 53 Participants | 60 Participants | 57 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 339 Participants | 333 Participants | 334 Participants | 1006 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Forced vital capacity (FVC) at baseline | 2353.6 Milliliters (mL) STANDARD_DEVIATION 766.2 | 2325.5 Milliliters (mL) STANDARD_DEVIATION 767.6 | 2381.4 Milliliters (mL) STANDARD_DEVIATION 722.8 | 2353.4 Milliliters (mL) STANDARD_DEVIATION 752.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 6 Participants | 2 Participants | 13 Participants |
| Race (NIH/OMB) Asian | 149 Participants | 155 Participants | 143 Participants | 447 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 3 Participants | 6 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 226 Participants | 224 Participants | 235 Participants | 685 Participants |
| Sex: Female, Male Female | 161 Participants | 190 Participants | 171 Participants | 522 Participants |
| Sex: Female, Male Male | 231 Participants | 203 Participants | 220 Participants | 654 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 64 / 392 | 36 / 393 | 34 / 391 |
| other Total, other adverse events | 320 / 392 | 324 / 393 | 333 / 391 |
| serious Total, serious adverse events | 198 / 392 | 174 / 393 | 182 / 391 |
Outcome results
Primary
Absolute Change From Baseline in Forced Vital Capacity (FVC) in Milliliters [mL] at Week 52
The absolute change from baseline in forced vital capacity (FVC) in milliliters \[mL\] at Week 52 is reported. The absolute change from baseline in FVC was analyzed by a restricted maximum likelihood (REML)-based mixed model with repeated measurements (MMRM) comparing the change from baseline in FVC at Week 52 between treatment groups. The analysis included the fixed, categorical effects of treatment, baseline intake of antifibrotic (AF) treatment, and baseline High-resolution Computed Tomography (HRCT) pattern at each visit, as well as the fixed continuous effects of baseline FVC value at each visit. Visits were treated as a repeated measure with an unstructured covariance structure used to model within-patient measurements.
Time frame: The MMRM model is a longitudinal analysis, and it incorporated FVC measurements change from baseline at Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. Data presented is the FVC adjusted change from baseline at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group. Only patients with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Forced Vital Capacity (FVC) in Milliliters [mL] at Week 52 | -165.77 Milliliters (mL) |
| Nerandomilast 9 mg | Absolute Change From Baseline in Forced Vital Capacity (FVC) in Milliliters [mL] at Week 52 | -84.64 Milliliters (mL) |
| Nerandomilast 18 mg | Absolute Change From Baseline in Forced Vital Capacity (FVC) in Milliliters [mL] at Week 52 | -98.59 Milliliters (mL) |
Comparison: Based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[mL\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: <0.000195% CI: [45.95, 116.32]Mixed Models Analysis
Comparison: Based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[mL\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.000295% CI: [31.91, 102.46]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) % Predicted (Corrected for Hb) at Week 52
The absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted (corrected for hemoglobin, Hb) at Week 52 is reported.. Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline DLCO \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.
Time frame: The MMRM model is a longitudinal analysis and it incorporated DLCO measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.~Only participants with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) % Predicted (Corrected for Hb) at Week 52 | -2.48 DLCO percent (%) predicted |
| Nerandomilast 9 mg | Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) % Predicted (Corrected for Hb) at Week 52 | -3.38 DLCO percent (%) predicted |
| Nerandomilast 18 mg | Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) % Predicted (Corrected for Hb) at Week 52 | -2.97 DLCO percent (%) predicted |
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline DLCO \[% pred\] at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form page (CRF), was included as a covariate.p-value: 0.379395% CI: [-2.9, 1.11]Mixed Models Analysis
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline DLCO \[% pred\] at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form page (CRF), was included as a covariate.p-value: 0.635495% CI: [-2.5, 1.53]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted at Week 52
Absolute change from baseline in forced vital capacity (FVC) percent (%) predicted at Week 52 is reported. Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.
Time frame: The MMRM model is a longitudinal analysis, and it incorporated FVC % predicted change from baseline at Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. Data presented is change from baseline in FVC % predicted at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.~Only participants with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted at Week 52 | -4.88 FVC percent predicted |
| Nerandomilast 9 mg | Absolute Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted at Week 52 | -2.69 FVC percent predicted |
| Nerandomilast 18 mg | Absolute Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted at Week 52 | -2.94 FVC percent predicted |
Comparison: Based on MMRM, with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: <0.000195% CI: [1.15, 3.23]Mixed Models Analysis
Comparison: Based on MMRM, with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline FVC \[% pred\] at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.000395% CI: [0.9, 2.98]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52
The absolute change from baseline in the L-PF Cough domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, baseline HRCT pattern, and fixed continuous effect of baseline L-PF dyspnea score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates.
Time frame: The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.~Only participants with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 | 3.05 Score on a scale |
| Nerandomilast 9 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 | 1.17 Score on a scale |
| Nerandomilast 18 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 | 3.19 Score on a scale |
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Cough score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.250695% CI: [-5.08, 1.33]Mixed Models Analysis
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Cough score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.931195% CI: [-3.07, 3.35]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52
The absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnoea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, baseline HRCT pattern, and fixed continuous effect of baseline L-PF dyspnea score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates.
Time frame: The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.~Only participants with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 | 5.75 Score on a scale |
| Nerandomilast 9 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 | 4.87 Score on a scale |
| Nerandomilast 18 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 | 4.48 Score on a scale |
Comparison: Analysis was based on a Based on Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Dyspnea score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.474895% CI: [-3.3, 1.54]Mixed Models Analysis
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Dyspnea score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.304295% CI: [-3.69, 1.15]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52
The absolute change from baseline in the L-PF Fatigue domain score at Week 52 is reported. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, and baseline HRCT pattern at each visit, and fixed continuous effect of baseline L-PF Fatigue score at each visit, with an unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were covariates.
Time frame: The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the adjusted Least Square Means for change from baseline at Week 52.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.~Only participants with baseline measurement and at least one post-baseline measurement were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 | 2.95 Score on a scale |
| Nerandomilast 9 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 | 3.01 Score on a scale |
| Nerandomilast 18 mg | Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 | 3.89 Score on a scale |
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Fatigue score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.966895% CI: [-2.46, 2.57]Mixed Models Analysis
Comparison: Analysis was based on a Mixed Model for Repeated Measures (MMRM), with fixed, categorical effects of treatment at each visit, baseline antifibrotic therapy at each visit, baseline HRCT pattern at each visit, the fixed continuous effects of baseline L-PF Fatigue score at each visit and unstructured covariance for repeated measures. Baseline antifibrotic therapy and HRCT pattern as entered in the CRF pages were used as covariates.p-value: 0.464495% CI: [-1.58, 3.46]Mixed Models Analysis
Secondary
Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial
Time to first occurrence of any of the components of the composite endpoint - acute interstitial lung disease (ILD) exacerbation, first hospitalisation for respiratory cause, or death (whichever occurred first) - is reported as the number of participants who experienced any of these events during the trial. Acute exacerbation of ILD describes an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality with all of the following: Acute worsening or development of dyspnea typically with less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILD, and deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute ILD exacerbation, hospitalization, death.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analysed as their randomised treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Hospitalisation for respiratory cause as first event | 82 Participants |
| Placebo | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Acute ILD exacerbation as first event | 44 Participants |
| Placebo | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Death as first event | 17 Participants |
| Nerandomilast 9 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Hospitalisation for respiratory cause as first event | 70 Participants |
| Nerandomilast 9 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Acute ILD exacerbation as first event | 34 Participants |
| Nerandomilast 9 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Death as first event | 12 Participants |
| Nerandomilast 18 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Acute ILD exacerbation as first event | 30 Participants |
| Nerandomilast 18 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Death as first event | 9 Participants |
| Nerandomilast 18 mg | Key Secondary Endpoint: Time to First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute ILD Exacerbation, First Hospitalisation for Respiratory Cause, or Death (Whichever Occurred First) Over the Duration of the Trial | Hospitalisation for respiratory cause as first event | 74 Participants |
Comparison: The hazard ratio (HR) was estimated using a Cox proportional hazards model with treatment, baseline intake of AF (nintedanib) treatment, baseline HRCT pattern, age (continuous), baseline FVC % predicted, and baseline DLCO % predicted (corrected for hemoglobin) as covariates. Breslow's method was applied for tied event times. A two-sided p-value from the Wald test assessed the treatment effect. P-values were not adjusted for multiplicity.p-value: 0.050795% CI: [0.61, 1]Regression, Cox
Comparison: The hazard ratio (HR) was estimated using a Cox proportional hazards model with treatment, baseline intake of AF (nintedanib) treatment, baseline HRCT pattern, age (continuous), baseline FVC % predicted, and baseline DLCO % predicted (corrected for hemoglobin) as covariates. Breslow's method was applied for tied event times. A two-sided p-value from the Wald test assessed the treatment effect. P-values were not adjusted for multiplicity.p-value: 0.039595% CI: [0.6, 0.99]Regression, Cox
Secondary
Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial
Time to absolute decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) percentage predicted by more than 15% from baseline or death, measured over the duration of the trial is reported as the number of participants who experienced either event. The Predicted DLCO value was corrected for hemoglobin (Hb). If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: Absolute decline in DLCO % predicted of \> 15%, followed by Death.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Absolute decline in DLCO % predicted of > 15% | 49 Participants |
| Placebo | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Death | 58 Participants |
| Nerandomilast 9 mg | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Absolute decline in DLCO % predicted of > 15% | 53 Participants |
| Nerandomilast 9 mg | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Death | 35 Participants |
| Nerandomilast 18 mg | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Absolute decline in DLCO % predicted of > 15% | 52 Participants |
| Nerandomilast 18 mg | Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial | Death | 32 Participants |
Comparison: Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), baseline HRCT pattern, age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.p-value: 0.296795% CI: [0.65, 1.14]Regression, Cox
Comparison: Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), baseline HRCT pattern, age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.p-value: 0.481595% CI: [0.68, 1.2]Regression, Cox
Secondary
Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial
The time to absolute decline of more than 10% from baseline in forced vital capacity (FVC) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. If multiple components occurred on the day of first event, then the patient was only counted in the first component based on the following hierarchy: absolute decline in FVC % predicted of \> 10% followed by death.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set includes all randomised patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analysed as their randomised treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Absolute decline in FVC % predicted of > 10% | 130 Participants |
| Placebo | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Death | 39 Participants |
| Nerandomilast 9 mg | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Absolute decline in FVC % predicted of > 10% | 95 Participants |
| Nerandomilast 9 mg | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Death | 30 Participants |
| Nerandomilast 18 mg | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Absolute decline in FVC % predicted of > 10% | 100 Participants |
| Nerandomilast 18 mg | Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial | Death | 24 Participants |
Comparison: Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), baseline HRCT pattern, age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.p-value: 0.001895% CI: [0.54, 0.87]Regression, Cox
Comparison: Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), baseline HRCT pattern, age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.p-value: 0.003895% CI: [0.56, 0.89]Regression, Cox
Secondary
Time to Death Over the Duration of the Trial
Time to death over the duration of the trial is reported as the number of participants who died. Time to death was based either on the date of death on the AE report for patients with AEs leading to death or based on the information from the vital status assessment.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Time to Death Over the Duration of the Trial | 64 Participants |
| Nerandomilast 9 mg | Time to Death Over the Duration of the Trial | 36 Participants |
| Nerandomilast 18 mg | Time to Death Over the Duration of the Trial | 34 Participants |
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.001795% CI: [0.34, 0.78]Regression, Cox
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.001895% CI: [0.34, 0.78]Regression, Cox
Secondary
Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial
Time to first acute ILD exacerbation or death over the duration of the trial is reported as the number of patients who experienced either event. Acute exacerbation of ILD describes an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality with all of the following: Acute worsening or development of dyspnea typically with less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILD, and deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute IPF exacerbation followed by death.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Acute ILD exacerbation | 57 Participants |
| Placebo | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Death | 40 Participants |
| Nerandomilast 9 mg | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Acute ILD exacerbation | 46 Participants |
| Nerandomilast 9 mg | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Death | 24 Participants |
| Nerandomilast 18 mg | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Acute ILD exacerbation | 35 Participants |
| Nerandomilast 18 mg | Time to First Acute ILD Exacerbation or Death Over the Duration of the Trial | Death | 24 Participants |
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.025895% CI: [0.51, 0.96]Regression, Cox
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.001795% CI: [0.43, 0.82]Regression, Cox
Secondary
Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial
Time to hospitalisation for respiratory cause or death over the duration of the trial is reported as the number of participants who experienced either event. Hospitalizations due to respiratory causes were recorded on a specific non-elective hospitalization CRF page. This page captured the hospitalization date, confirmation of a respiratory cause, and the primary admission diagnosis. Time to death was based either on the date of death on the adverse event (AE) report for patients with AEs leading to death or was based on the information from the vital status assessment.
Time frame: From first administration of trial drug (Nerandomilast or Placebo) till end of study, up to 26.2 months.
Population: Full Analysis Set (FAS): This patient set included all randomized patients who received at least one dose of study drug. The FAS was used for baseline demographics and characteristics, protocol deviations, and all efficacy analyses, in which patients were analyzed as their randomized treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Hospitalization for respiratory cause | 113 Participants |
| Placebo | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Death | 18 Participants |
| Nerandomilast 9 mg | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Hospitalization for respiratory cause | 90 Participants |
| Nerandomilast 9 mg | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Death | 13 Participants |
| Nerandomilast 18 mg | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Hospitalization for respiratory cause | 94 Participants |
| Nerandomilast 18 mg | Time to Hospitalisation for Respiratory Cause or Death Over the Duration of the Trial | Death | 9 Participants |
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.023795% CI: [0.57, 0.96]Regression, Cox
Comparison: Analysis performed using a Cox proportional hazards model that included baseline antifibrotic therapy (AF group vs non-AF group), baseline HRCT pattern, age, baseline FVC % predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (corrected for Hb) and treatment as covariates.p-value: 0.042795% CI: [0.59, 0.99]Regression, Cox