Complication of Transplanted Lung
Conditions
Keywords
Lung Transplant, Lung Transplant Recipient
Brief summary
This study is a pilot two- center study to determine if aztreonam lysine for inhalation AZLI can be safely and self-administered in lung transplant recipients with newly diagnosed bronchiolitis obliterans syndrome, grade 1 (BOS) and obtain pilot data regarding its effect on lung function in order to appropriately design and power a larger multicenter randomized study. The hypothesis is that AZLI is a safe and effective treatment for declining lung function in lung transplant recipients with early stage BOS.
Detailed description
Lung transplantation is increasingly employed as a therapy for patients with advanced lung disease including cystic fibrosis, idiopathic pulmonary fibrosis or emphysema. Despite significant short-term improvements in life quality and measures of lung function after lung transplantation, long-term outcomes are disappointing primarily due to the development of a condition of airway fibrosis known as bronchiolitis obliterans (BO). It is hypothesized that aztreonam lysine for inhalation (AZLI) is a safe and effective treatment for declining lung function in lung transplant recipients with early stage BOS. In order to test the hypothesis, the investigators seek to establish the safety of AZLI in a two-center cohort of 30 lung transplant recipients with BOS treated intermittently for 5 consecutive study months and determine if this treatment leads to improvement or stabilization of lung function. The intervention will involve open label treatment with AZLI, in addition to usual transplant care, administered for 3 intermittent courses, 28 days each, over a 5 month study period.. Bronchoscopy, pulmonary function testing, and laboratory testing will be performed on a regular basis during study enrollment consistent with each center's usual standard clinical care. Patients will have a baseline screening visit, one month and five month study visit.. The study will take two years to complete from the start of funding. After a start-up period of 2 months, a total of 30 patients will be enrolled over 12 months across the two centers (15 patients each at DUMC and UCLA). Each enrolled patient will complete 5 months of intermittent therapy, and complete baseline, month 1 and month 5 visits. Over the next 6 months the study database will be finalized, statistical analysis will for primary and secondary outcomes will be performed leading to the generation of either a study abstract or manuscript.
Interventions
DRUGAztreonam Lysine for Inhalation (AZLI)
The intervention will involve open label treatment with AZLI inhaled 75mg TID self-administered intermittently for 28 days on study drug and 28 days off study drug over a study period of 5 consecutive months (on/off/on/off/on AZLI)
PROCEDUREStatus Post Lung Transplant
Bronchoscopy, pulmonary function testing, and laboratory testing will be performed on a regular basis during study enrollment consistent with each center's usual standard clinical care.
Sponsors
Gilead Sciences
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (18 or older at the time of transplant) male or female * Cadaveric first lung transplant recipient, single or bilateral; or multi-organ lung transplant recipient. * Current FEV1 66-80% of posttransplant baseline FEV1, and meets all criteria for BOS 1 as defined by the International Society of Heart and Lung Transplantation. * Onset of BOS 1 within twelve months of screening
Exclusion criteria
* Known allergy to aztreonam * Retransplant * Pediatric patients * Live lobar transplant recipients * Inability to provide informed consent. * Patients with advanced BOS (grades 2,3) or established BOS \>6 months * Pregnant Women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | Baseline, month 1 | Within-subject change to absolute FEF 25-75 month 1 vs. 0. FEF 25-75 was measured 14-35 days after the start of months 1 |
| Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 and Month 5. | Baseline, month 5 | The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 5 vs 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 and 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose). |
| Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | Baseline, month 1 | The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 1 vs. 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in the Total Score. The SGRQ was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose). |
| Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. | Baseline, month 5 | The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 5 vs 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in theTotal Score. The SGRQ was completed 14-35 days after the start of month 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose). |
| Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. | Baseline, month 5 | Within-subject change to absolute FEF 25-75 month 5 vs 0. FEF 25-75 was measured 14-35 days after the start of months 5 |
| Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry | Baseline, month 1 | Within-subject change to absolute FEV1 month 1 vs. 0. FEV1 was measured 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose). |
| Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | Baseline, month 1 | The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 1 vs. 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in HRQOL Off AZLI Therapy. | At study months 2 or 4 | This will be compared to study month 0 (baseline), when obtained at standard of care visit (SOC) |
| Among Patients Colonized With Pseudomonas Aeruginosa, Change in Infection Burden as Measured by the Culture Final Report (0,1+, 2+, 3+, 4+) of in Pseudomonas Aeruginosa Sputum or Bronchoalveolar Fluid. | Baseline, month 1 | Microbiology data was collected when performed for SOC purposes on BAL or sputum samples. Baseline and 1 month value represents the culture final report value (0,1+, 2+, 3+, 4+) of Pseudomonas aeruginosa. A value of zero represents no Pseudomonas aeruginosa sputum or bronchoalveolar fluid. A value of 4 represents high amounts of Pseudomonas aeruginosa sputum or bronchoalveolar fluid. |
| Bronchoalveolar Lavage Fluid (BALF) Neutrophilia After Treatment, When Performed as Part of Clinical Care (SOC). | Baseline - defined as a within 90 days of enrollment and After Treatment (5 months) | The study team is measuring the change in neutrophils AFTER treatment. They will compare a SOC BAL taken after AZLI with the BAL taken within 90 days of AZLI initiation (pre or baseline measure). The post AZLI BAL measurement time range is 15 days after first course of AZLI up to last day of the 3rd and final course of AZLI (over a period of 5 consecutive months). |
| Change in FEV1 Off AZLI Therapy | At Study Months 2 and 4 | This will be compared to study month 0 (baseline, when obtained as standard of care (SOC). |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from two lung transplant centers, Duke and UCLA, and 30 subjects enrolled in the study from April 2013 to July 2014.
Participants by arm
| Arm | Count |
|---|---|
| Aztreonam Lysine for Inhalation (AZLI) Patients to received Aztreonam Lysine(AZLI)
Aztreonam Lysine for Inhalation (AZLI): The intervention will involve open label treatment with AZLI inhaled 75mg TID self-administered intermittently for 28 days on study drug and 28 days off study drug over a study period of 5 consecutive months (on/off/on/off/on AZLI)
Status Post Lung Transplant: Bronchoscopy, pulmonary function testing, and laboratory testing will be performed on a regular basis during study enrollment consistent with each center's usual standard clinical care. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Aztreonam Lysine for Inhalation (AZLI) |
|---|---|
| Age, Continuous | 64 years |
| FEF 25-75 | 1.18 liters |
| FEV1 | 1.87 liters |
| FVC | 2.68 liters |
| Race/Ethnicity, Customized Black | 2 participants |
| Race/Ethnicity, Customized Caucasian | 28 participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 30 |
| serious Total, serious adverse events | 1 / 30 |
Outcome results
Primary
Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1
The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 1 vs. 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
Time frame: Baseline, month 1
Population: subjects with completed SF-36 surveys at month 1 and month 0 (n=28)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | PCS: month 1 vs. Baseline (n=28) | -1.52 units on a scale |
| Aztreonam Lysine for Inhalation (AZLI) | Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | MCS: month 1 vs. Baseline (n-28) | 0.78 units on a scale |
Comparison: P-Value for the SF-36 PCSp-value: 0.34t-test, 2 sided
Comparison: P-Value for the SF-36 MCSp-value: 0.18t-test, 2 sided
Primary
Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 and Month 5.
The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 5 vs 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 and 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
Time frame: Baseline, month 5
Population: subjects with completed SF-36 surveys at month 5 and 0 (n=26) time-points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 and Month 5. | PCS: month 5 vs. Baseline (n=26) | 1.62 units on a scale |
| Aztreonam Lysine for Inhalation (AZLI) | Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 and Month 5. | MCS: month 5 vs. Baseline (n-26) | -1.24 units on a scale |
Comparison: P-Value for SF-36 PCSp-value: 0.09t-test, 2 sided
Comparison: P-Value for SF-36 MCSp-value: 0.31t-test, 2 sided
Primary
Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1
Within-subject change to absolute FEF 25-75 month 1 vs. 0. FEF 25-75 was measured 14-35 days after the start of months 1
Time frame: Baseline, month 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | -0.025 Liter |
p-value: 0.9638t-test, 2 sided
Primary
Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5.
Within-subject change to absolute FEF 25-75 month 5 vs 0. FEF 25-75 was measured 14-35 days after the start of months 5
Time frame: Baseline, month 5
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. | -0.015 Liter |
p-value: 0.7454t-test, 2 sided
Primary
Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry
Within-subject change to absolute FEV1 month 1 vs. 0. FEV1 was measured 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
Time frame: Baseline, month 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry | -0.04 Liter |
p-value: 0.203t-test, 2 sided
Primary
Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry
Within-subject change to absolute FEV1 month 5 vs 0.
Time frame: Baseline, month 5
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry | -0.02 Liter |
p-value: 0.2527t-test, 2 sided
Primary
Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1
The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 1 vs. 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in the Total Score. The SGRQ was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
Time frame: Baseline, month 1
Population: subjects with completed SF-36 surveys at month 1 and month 0 (n=28) time-points.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 | 0.82 units on a scale |
Comparison: P-Value for SGRQ measurep-value: 0.56t-test, 2 sided
Primary
Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5.
The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 5 vs 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in theTotal Score. The SGRQ was completed 14-35 days after the start of month 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
Time frame: Baseline, month 5
Population: subjects with completed SF-36 surveys at month 5 and 0 (n=26) time-points.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. | 0.15 units on a scale |
Comparison: P-Value for SGRQ Measurep-value: 0.68t-test, 2 sided
Secondary
Among Patients Colonized With Pseudomonas Aeruginosa, Change in Infection Burden as Measured by the Culture Final Report (0,1+, 2+, 3+, 4+) of in Pseudomonas Aeruginosa Sputum or Bronchoalveolar Fluid.
Microbiology data was collected when performed for SOC purposes on BAL or sputum samples. Baseline and 1 month value represents the culture final report value (0,1+, 2+, 3+, 4+) of Pseudomonas aeruginosa. A value of zero represents no Pseudomonas aeruginosa sputum or bronchoalveolar fluid. A value of 4 represents high amounts of Pseudomonas aeruginosa sputum or bronchoalveolar fluid.
Time frame: Baseline, month 1
Population: The statistical analysis was unable to be performed due to insufficient number of paired observations. Only 9 of 30 enrolled had baseline microbiology data, 3 were cultured positive for Pseudomonas Aeruginosa. Only 1 of the 3 had a subsequent SOC BAL sample collected. Therefore, only raw data is entered for the one subject.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Among Patients Colonized With Pseudomonas Aeruginosa, Change in Infection Burden as Measured by the Culture Final Report (0,1+, 2+, 3+, 4+) of in Pseudomonas Aeruginosa Sputum or Bronchoalveolar Fluid. | Culture value at Baseline | 4 culture value of Pseudomonas aeruginosa |
| Aztreonam Lysine for Inhalation (AZLI) | Among Patients Colonized With Pseudomonas Aeruginosa, Change in Infection Burden as Measured by the Culture Final Report (0,1+, 2+, 3+, 4+) of in Pseudomonas Aeruginosa Sputum or Bronchoalveolar Fluid. | Culture value at one month | 0 culture value of Pseudomonas aeruginosa |
Secondary
Bronchoalveolar Lavage Fluid (BALF) Neutrophilia After Treatment, When Performed as Part of Clinical Care (SOC).
The study team is measuring the change in neutrophils AFTER treatment. They will compare a SOC BAL taken after AZLI with the BAL taken within 90 days of AZLI initiation (pre or baseline measure). The post AZLI BAL measurement time range is 15 days after first course of AZLI up to last day of the 3rd and final course of AZLI (over a period of 5 consecutive months).
Time frame: Baseline - defined as a within 90 days of enrollment and After Treatment (5 months)
Population: Participants with paired SOC bronchoalveolar lavage fluid cell differential counts performed within 90 days of AZLI month 1 (baseline timepoint) and \>=15 days after AZLI dose 1 through the completion of dose 3 (study month 5) were included in the analysis (n=5).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aztreonam Lysine for Inhalation (AZLI) | Bronchoalveolar Lavage Fluid (BALF) Neutrophilia After Treatment, When Performed as Part of Clinical Care (SOC). | 7.80 mean percentage of neutrophils | Standard Deviation 25.43 |
Secondary
Change in FEV1 Off AZLI Therapy
This will be compared to study month 0 (baseline, when obtained as standard of care (SOC).
Time frame: At Study Months 2 and 4
Population: Partial data for this outcome measure was collected on 4 participants and due to not having complete data set analyzation was not completed.
Secondary
Change in HRQOL Off AZLI Therapy.
This will be compared to study month 0 (baseline), when obtained at standard of care visit (SOC)
Time frame: At study months 2 or 4
Population: Partial data for this outcome measure was collected on 4 participants and due to not having a complete data set the analyzation was not completed.