A Retrospective Chart Review Study of Patients With CLAD-BOS Post Lung Transplantation

A Retrospective Chart Review Study of Patients With Chronic Lung Allograft Dysfunction-Bronchiolitis Obliterans Syndrome (CLAD-BOS) Post Lung Transplantation

The Primary Objective of this study was to evaluate the FEV1 trajectory of patients diagnosed with CLAD-BOS.

The Secondary Objectives of this study were:

• To describe demographics of patients diagnosed with CLAD-BOS
• To describe clinical characteristics following lung transplantation for patients diagnosed with CLAD-BOS
• To evaluate the trajectory of other relevant spirometry parameters (ie, FVC, FEV1/FVC, FEF25-75%)
• To evaluate the OS of patients diagnosed with CLAD-BOS
• To evaluate the time to first CLAD-BOS progression
• To evaluate the cumulative incidence of CLAD-BOS progression
• To evaluate the rate of hospitalization due to respiratory failure after CLAD-BOS onset
• To evaluate the incidence of concomitant respiratory disease
• To evaluate the incidence of concomitant non-respiratory disease
• To describe the use of concomitant treatments and procedures for CLAD-BOS.

Study Overview

• Status: Completed
• Conditions: Bronchiolitis Obliterans Syndrome

Detailed Description

This was a retrospective, multinational, multicenter, observational chart review study conducted in adult patients with clinically diagnosed chronic lung allograft dysfunction-bronchiolitis obliterans syndrome (CLAD-BOS) following lung transplantation.

All data were retrospectively collected from existing patient medical records; no interventions were applied as part of the study, and no protocol-mandated patient assessments or follow-up visits were required.

The observational period for each patient encompassed multiple time points relevant to the development and progression of CLAD-BOS. Patients were identified within a CLAD-BOS diagnosis window spanning from 01 January 2013 through the most recent data available at the participating study sites.

The index date was defined as the date of clinician diagnosis of CLAD-BOS as documented in the medical record. Spirometry parameters at diagnosis were based on the spirometry assessment closest to the diagnosis date.

Personal best FEV1 was defined as the highest post-transplant FEV1 value documented prior to the diagnosis of CLAD-BOS, based on available spirometry measurements collected after lung transplantation and before diagnosis. The personal best FEV1 date corresponded to the time point at which this best post-transplant FEV1 value was identified. The personal best post-transplant FEV1 value was defined as the mean of the 2 best post-transplant FEV1 measurements taken at least 3 weeks apart, with the date being that of the first value.

CLAD-BOS onset (≤ 80% vs best-FEV1) was defined based on a sustained decline in FEV1 relative to the post-transplant best value, as documented in clinical records, with the onset date corresponding to the first occurrence of a decline meeting this criterion and confirmed by a subsequent measurement occurring at least 3 months apart. For each patient, the onset date will be programmatically derived from the data collected starting from the lung transplant date.

For other spirometric parameters, including forced vital capacity (FVC), FEV1/FVC ratio, and forced mid-expiratory flow (FEF25-75%), best post-transplant and onset values were derived from the same spirometry assessments in which the corresponding FEV1 best and onset values were measured.

The pre-diagnosis period extended from lung transplantation up to, but not including, the index date.

The post-diagnosis period extended from, and included, the index date through the last available follow-up or death.

The observation period ended at the earliest occurrence of death or the last date on which the patient was known to be alive based on available medical record documentation.

• Study Type: Observational
• Enrollment (Actual): 284

Contacts and Locations

Study Locations

• Belgium
  • Leuven
    • Leuven, Leuven, Belgium, 3000
      • Universitaire Ziekenhuizen Leuven (UZ Leuven)
• Spain
  • Andalusia
    • Córdoba, Andalusia, Spain, 14004
      • Hospital Universitario Reina Sofia
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla (HUMV)
• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Transplantation Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Scott and White Health Center for Advanced Heart and Lung Disease

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study population included adult patients (aged ≥ 18) years who were recipients of a lung transplant and diagnosed with CLAD-BOS from the first of 01 January 2013 following transplantation.

Description

Inclusion Criteria:

1. Adult patients ≥ 18 years of age on the date of CLAD-BOS diagnosis
2. Patients with a CLAD-BOS clinician diagnosis from as early as 01 January 2013
3. Patients with CLAD-BOS clinician diagnosis made at least 12 months after lung transplant
4. Patients received at least basic maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to mycophenolate mofetil or azathioprine (or other anti-proliferative agent), and a systemic corticosteroid such as prednisone as third agent for at least 1 month before the index date. As long as the basic maintenance regimen is maintained for the abovementioned period, patients will still be considered eligible for the study even if they are receiving other immunosuppressive agents in addition to the basic maintenance regimen.

Exclusion Criteria:

1. Patients with severe concomitant disease at the time of index date, which according to physician's judgment, can interfere with CLAD-BOS progression and mortality (e.g., malignancies, severe chronic diseases)
2. Patients who have been exposed to any investigational medical products in the 4 weeks prior to index date or during the post-diagnosis period
3. Patients with confirmed other CLAD phenotype (e.g., restrictive allograft syndrome) according to physician's judgment.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset up to 3 years post-onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age at Transplant	This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.	At transplant date
Sex at Transplant	This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.	At transplant date
Race	This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.	At transplant date
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.	Up to transplant date
Time From Lung Transplantation to CLAD-BOS Onset	This secondary outcome summarizes descriptive characteristics collected at the time of lung transplantation.	From transplant date to onset date
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.	From lung transplantation until last date of data available or death. Specifically, from transplantation to CLAD-BOS onset, a median of 40.5 (max 227) months; from CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From lung transplantation until last date of data available or death. Specifically, from transplantation to CLAD-BOS onset, a median of 40.5 (max 227) months; from CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From lung transplantation until last date of data available or death. Specifically, from transplantation to CLAD-BOS onset, a median of 40.5 (max 227) months; from CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset up to 3 years post-onset
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.	From CLAD-BOS onset through death, up to 120 months
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.	From CLAD-BOS onset through death (median follow up time 38.6 months)
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.	From CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From lung transplantation until last date of data available or death. Specifically, from transplantation to CLAD-BOS onset, a median of 40.5 (max 227) months; from CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months
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.	From CLAD-BOS onset to last data available or death a median of 38.6 (max 173) months

Collaborators and Investigators

• Sponsor: Zambon SpA
• Investigators: Study Director: Paola Castellani, MD, Zambon SpA

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2024
• Primary Completion (Actual): April 9, 2025
• Study Completion (Actual): April 9, 2025

Study Registration Dates

• First Submitted: July 8, 2024
• First Submitted That Met QC Criteria: July 15, 2024
• First Posted (Actual): July 16, 2024

Study Record Updates

• Last Update Posted (Actual): September 1, 2026
• Last Update Submitted That Met QC Criteria: August 26, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Bronchiolitis Obliterans Syndrome; Retrospective Chart Review; Chronic Lung Allograft Dysfunction; Post-Lung Transplantation
• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Graft vs Host Disease; Bronchiolitis Obliterans Syndrome
• Other Study ID Numbers: Z8000N01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No