肺移植後の慢性肺同種移植片機能不全閉塞性細気管支炎症候群（CLAD-BOS）患者の遡及的チャートレビュー研究

CLAD-BOS Cohort

Adult patients with clinically diagnosed chronic lung allograft dysfunction-bronchiolitis obliterans syndrome (CLAD-BOS) following lung transplantation, included in a retrospective observational chart review study. No study-specific interventions were administered.

Change Per Year in FEV1 Trajectory Starting From the Onset Date Through the End of the Post-diagnosis Period.

CLAD-BOS onset was defined as the first occurrence of a forced expiratory volume in 1 second (FEV1) value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement ≤80% at least 3 months later, as documented in the medical records. The personal best FEV1 was defined as the mean of the two highest post-transplant FEV1 measurements obtained at least 3 weeks apart, derived from post-transplant spirometry data or identified in clinical records according to physician judgment. The FEV1 value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects. Results are reported as model-based estimated mean changes from baseline in FEV1 per year. The reported mean values represent estimates derived from the statistical model.

Change in FEV1 Trajectory Over Time Starting From the Onset Date Through the End of the Post-diagnosis Period.

CLAD-BOS onset was defined as the first occurrence of a forced expiratory volume in 1 second (FEV1) value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement ≤80% at least 3 months later, as documented in the medical records. The personal best FEV1 was defined as the mean of the two highest post-transplant FEV1 measurements obtained at least 3 weeks apart, derived from post-transplant spirometry data or identified in clinical records according to physician judgment. The FEV1 value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects. Results are reported as model-based estimated mean changes from baseline in FEV1 at prespecified time points after onset (1, 2, and 3 years). The reported mean values represent estimates derived from the statistical model.

Age at Transplant

This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.

Sex at Transplant

This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.

Race

This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.

Number of Participants With Pre-transplant Medical History and Lung Transplant History

This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.

Time From Lung Transplantation to CLAD-BOS Onset

This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.

Number of Participants With Clinical Characteristics Following Lung Transplantation (Acute Rejection Events, Presence of Lung Opacities, and Signs, Symptoms, or Other Clinical Records)

Descriptive clinical characteristics collected following lung transplantation in patients diagnosed with CLAD-BOS. Variables included the occurrence of acute rejection events, presence of lung opacities as documented by computed tomography (CT) scans, and signs, symptoms, or other clinical records related to mobility, self-care, usual activities, pain or discomfort, anxiety, and depression. These data were collected for descriptive purposes only.

Percentage of Participants by Donor-specific Antibodies Results

Descriptive clinical characteristics collected following lung transplantation in patients diagnosed with CLAD-BOS. Presence of donor-specific antibodies. These data were collected for descriptive purposes only.

Total Lung Capacity (Plethysmography)

Descriptive clinical characteristics collected following lung transplantation in patients diagnosed with CLAD-BOS. These data were collected for descriptive purposes only.

All available plethysmography assessments after lung transplantation were considered; therefore, data from multiple time points were collected and presented as mean and standard deviation.

Change Per Year in FVC Trajectory

Change in Forced vital capacity (FVC) were evaluated from CLAD-BOS onset through the end of the post-diagnosis period. CLAD-BOS onset was defined as the first occurrence of a forced expiratory volume in 1 second (FEV1) value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement at least 3 months later. The FVC value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects to account for within-subject correlation over time. Results are reported as model-based estimated mean changes from baseline in FVC per year. The reported mean values represent estimates derived from the statistical model.

Change in FVC Trajectory Over Time

Change in Forced vital capacity (FVC) were evaluated from CLAD-BOS onset through the end of the post-diagnosis period. CLAD-BOS onset was defined as the first occurrence of a forced expiratory volume in 1 second (FEV1) value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement at least 3 months later. The FVC value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects to account for within-subject correlation over time. Model-based estimates of mean change from baseline in FVC (absolute values) are reported at prespecified time points after onset (1, 2, and 3 years). The reported mean values represent estimates derived from the statistical model and are accompanied by standard errors.

Change Per Year in FEV1/FVC Trajectory

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured by spirometry, and the FEV1/FVC ratio was derived accordingly. CLAD-BOS onset was defined as the first occurrence of an FEV1 value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement at least 3 months later, as documented in the medical records.

The FEV1/FVC value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects to account for within-subject correlation over time.

Results are reported as model-based estimated mean changes from baseline in FEV1/FVC per year. The reported mean values represent estimates derived from the statistical model.

Change in FEV1/FVC Trajectory Over Time

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured by spirometry, and the FEV1/FVC ratio was derived accordingly. CLAD-BOS onset was defined as the first occurrence of an FEV1 value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement at least 3 months later, as documented in the medical records.

The FEV1/FVC value at CLAD-BOS onset served as the baseline for the analysis. Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects to account for within-subject correlation over time.

Results are reported as model-based estimated mean changes from baseline in FEV1/FVC at prespecified time points after onset (1, 2, and 3 years). The reported mean values represent estimates derived from the statistical model, rather than arithmetic means of observed measurements.

Change in FEF25-75% Trajectory Over Time

Change from baseline in Forced mid-expiratory flow (FEF25-75%), expressed as liters per second (L/s), was evaluated to characterize changes in mid-expiratory airflow following CLAD-BOS onset. CLAD-BOS onset was defined as the first occurrence of an FEV1 value ≤80% of the patient's post-transplant best FEV1, confirmed by a subsequent measurement.

Repeated post-onset spirometry measurements collected during routine clinical practice were analyzed using a linear mixed-effects model with random subject-specific effects to account for within-subject correlation over time. Due to non-normal distribution, FEF25-75% values were log-transformed for model fitting. Model-based estimates of mean change from baseline on the original scale are reported at prespecified follow-up time points (at 1, 2 and 3 years).

The reported values represent estimates derived from the statistical model rather than arithmetic means of observed measurements.

Overall Survival (OS) From CLAD-BOS Onset

Overall survival (OS) was defined as the time from CLAD-BOS onset to death from any cause. OS was calculated as the time from the CLAD-BOS onset date to the earliest of the date of death or the last date the patient was known to be alive, expressed in months using a conversion factor of 30.4375 days per month. Patients who were alive or had unknown vital status at the time of data abstraction were censored at the last date they were known to be alive. Median OS and corresponding 95% confidence intervals were estimated using the Kaplan-Meier method, with confidence intervals calculated using the log-log transformation.

Time to First CLAD-BOS Progression

Time to first CLAD-BOS progression was defined as the time from CLAD-BOS onset to the first documented disease progression.

Progression was defined as the earliest occurrence of any of the following events:

• an absolute decrease in FEV1 of ≥10% or ≥200 mL from a previously available spirometry assessment with a concomitant absolute decrease in FEV1/FVC of >5% confirmed at least 2 weeks apart;
• change in CLAD grade severity;
• re-transplantation;
• death from respiratory failure;
• or clinical judgment reporting CLAD-BOS progression in medical records. Patients without documented CLAD-BOS progression at the time of data abstraction were censored at the date of the last available assessment.

Median time to progression and 95% confidence intervals were estimated using the Kaplan-Meier method.

Cumulative Number of CLAD-BOS Progression Events Per Patient

Cumulative CLAD-BOS progression events were assessed from CLAD-BOS onset through the end of the post-diagnosis follow-up period. CLAD-BOS progression was defined as the earliest occurrence of an absolute decrease in FEV1 of ≥10% or ≥200 mL combined with an absolute decrease in FEV1/FVC of >5% confirmed by a subsequent assessment, change in CLAD grade severity, re-transplantation, death from respiratory failure, or clinical judgment reporting CLAD-BOS progression in patient records. Event counts and rates were analyzed using a negative binomial regression model with an offset for follow-up time.

Hospitalization Rate Due to Respiratory Failure

The rate of hospitalizations due to respiratory failure was assessed from the CLAD-BOS onset date through the end of the post-diagnosis period. Hospitalization events attributed to respiratory failure were identified from patient medical records. Event rates were estimated using a negative binomial regression model with an offset for patient observation time to account for variable observation duration. Results are reported as rates per year with 95% confidence intervals.

Number of Participants With Newly Diagnosed Cases of Concomitant Respiratory Diseases

The number of participants with concomitant respiratory diseases was assessed in the Full Analysis Set. Concomitant respiratory diseases were identified from patient records and coded using MedDRA (version 27.0) terminology. Results are summarized as the number and percentage of patients with at least one concomitant respiratory disease.

Only concomitant respiratory disease categories reported in ≥ 5% of patients are presented.

Concomitant Treatments and Procedures for CLAD-BOS Starting From the Post-transplant Date Through the End of the Post-diagnosis Period

The use of concomitant treatments and procedures for CLAD-BOS following lung transplantation was assessed in the Full Analysis Set based on medical record review.

Concomitant treatments and procedures were defined as those administered or performed after CLAD-BOS onset.

Results are reported as the number and percentage of patients receiving at least one concomitant treatment or procedure. Concomitant treatments were coded using WHO Drug Dictionary terminology (version March 2024), and procedures were summarized descriptively.

Only treatments and procedures reported in ≥ 5% of patients are presented.

Number of Participants With Newly Diagnosed Cases of Concomitant Non-respiratory Diseases

The number of participants with concomitant non-respiratory diseases was assessed in the Full Analysis Set based on medical record review. Concomitant non-respiratory diseases were coded using MedDRA (version 27.0) preferred terms and summarized descriptively. Results are reported as the number and percentage of patients with at least one concomitant non-respiratory disease. Only non-respiratory disease categories reported in ≥ 5% of patients are presented.