Bronchiectasis
Conditions
Brief summary
The AIR-BX2 study enrolled people with non-cystic fibrosis (non-CF) bronchiectasis and gram-negative airway infection. Participants received two 28-day courses of either Aztreonam for Inhalation Solution (AZLI) or placebo taken 3 times a day. Each course was followed by a 28-day off-drug period. Following the two blinded courses, all participants received a 28-day course of open-label AZLI then were followed for an additional 56 days.
Interventions
DRUGAZLI
AZLI 75 mg reconstituted with diluent and administered via nebulizer three times daily
DRUGPlacebo
Placebo to match AZLI administered via nebulizer three times daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male/Female 18 years or older with non-CF bronchiectasis * Chronic sputum production on most days * Positive sputum culture for gram-negative organisms * Must have met lung function requirements
Exclusion criteria
* History of CF * Hospitalized within 14 days prior to joining the study * Previous exposure to AZLI * Pregnant, breastfeeding, or unwilling to follow contraceptive measures for the study * Must have met liver and kidney function requirements * Continuous oxygen use of greater than 2 liters per minute (supplemental oxygen with activity and at night was allowed) * Treatment for nontuberculous mycobacteria infection or active mycobacterium tuberculosis infection within 1 year of enrollment * Other serious medical conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in QOL-B Respiratory Symptoms Score at Day 28 | Baseline to Day 28 | The mean (SD) change in the Respiratory Symptoms score on the Quality of Life Questionnaire-Bronchiectasis (QOL-B) was measured from baseline to the end of Course 1 (Day 28). The QOL-B respiratory symptoms score was transformed onto a scale of 0-100, with higher scores representing a better quality of life. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in QOL-B Respiratory Symptoms Score at Day 84 | Baseline to Day 84 | The mean (SD) change in the Respiratory Symptoms score on the QOL-B was measured from baseline to the end of Course 2 (Day 84). The QOL-B respiratory symptoms score was transformed onto a scale of 0-100, with higher scores representing a better quality of life. |
| Time to Protocol-Defined Exacerbation (PDE) | Baseline to Day 112 | Protocol-defined exacerbation was defined as an acute worsening of respiratory disease that triggered the initiation of a non-study antibiotic meeting at least 3 major criteria, or 2 major and at least 2 minor criteria. * Major Criteria: increased sputum production; increased discoloration of sputum; increased dyspnea; increased cough * Minor Criteria: fever (\> 38º C) measured during clinic visit; increased malaise or fatigue; forced expiratory volume in 1 second (FEV1) (L) or forced vital capacity (FVC) decreased \> 10% from baseline; new or increased hemoptysis |
Countries
Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled in a total of 90 study sites in the North America, Europe, and Australia. The first participant was screened on 25 April 2011. The last participant observation was on 01 July 2013.
Pre-assignment details
404 participants were screened, 274 were randomized and comprise the Intent-to-Treat (ITT) Analysis Set. 272 randomized participants received at least one dose of study drug and comprise the Safety Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| AZLI-AZLI Participants were randomized to receive blinded AZLI 75 mg three times daily via investigational nebulizer for 2 cycles of 28 days on treatment with each cycle followed by 28 days off treatment, followed by open-label AZLI 75 mg three times daily for 28 days plus 56 days of treatment-free follow-up. | 136 |
| Placebo-AZLI Participants were randomized to receive blinded placebo to match AZLI three times daily via investigational nebulizer for 2 cycles of 28 days on treatment with each cycle followed by 28 days off treatment, followed by open-label AZLI 75 mg three times daily for 28 days plus 56 days of treatment-free follow-up. | 138 |
| Total | 274 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Phase | Adverse Event | 10 | 4 |
| Double-Blind Phase | Lost to Follow-up | 0 | 1 |
| Double-Blind Phase | Physician Decision | 0 | 1 |
| Double-Blind Phase | Randomized but not treated | 1 | 1 |
| Double-Blind Phase | Sponsor request | 1 | 2 |
| Double-Blind Phase | Withdrawal by Subject | 5 | 6 |
| Open-Label Phase | Adverse Event | 4 | 6 |
| Open-Label Phase | Physician Decision | 5 | 4 |
| Open-Label Phase | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | AZLI-AZLI | Placebo-AZLI | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 83 Participants | 72 Participants | 155 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 66 Participants | 119 Participants |
| Age, Continuous | 63.3 years STANDARD_DEVIATION 14.22 | 62.7 years STANDARD_DEVIATION 13.33 | 63.0 years STANDARD_DEVIATION 13.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 112 Participants | 234 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 19 Participants | 28 Participants |
| QOL-B Respiratory Symptom Score | 56.2 units on a scale STANDARD_DEVIATION 17.98 | 57.4 units on a scale STANDARD_DEVIATION 18.07 | 56.8 units on a scale STANDARD_DEVIATION 18 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African Heritage | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Not permitted | 11 participants | 4 participants | 15 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 119 participants | 128 participants | 247 participants |
| Region of Enrollment Australia | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Belgium | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Canada | 0 participants | 2 participants | 2 participants |
| Region of Enrollment France | 11 participants | 3 participants | 14 participants |
| Region of Enrollment Germany | 16 participants | 21 participants | 37 participants |
| Region of Enrollment Italy | 5 participants | 12 participants | 17 participants |
| Region of Enrollment Netherlands | 5 participants | 12 participants | 17 participants |
| Region of Enrollment Spain | 22 participants | 17 participants | 39 participants |
| Region of Enrollment United Kingdom | 11 participants | 11 participants | 22 participants |
| Region of Enrollment United States | 58 participants | 52 participants | 110 participants |
| Sex: Female, Male Female | 89 Participants | 101 Participants | 190 Participants |
| Sex: Female, Male Male | 47 Participants | 37 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 112 / 135 | 101 / 137 | 54 / 112 | 58 / 110 |
| serious Total, serious adverse events | 18 / 135 | 16 / 137 | 8 / 112 | 9 / 110 |
Outcome results
Primary
Change in QOL-B Respiratory Symptoms Score at Day 28
The mean (SD) change in the Respiratory Symptoms score on the Quality of Life Questionnaire-Bronchiectasis (QOL-B) was measured from baseline to the end of Course 1 (Day 28). The QOL-B respiratory symptoms score was transformed onto a scale of 0-100, with higher scores representing a better quality of life.
Time frame: Baseline to Day 28
Population: Participants in the ITT Analysis Set with scores at both baseline and Day 28 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI-AZLI | Change in QOL-B Respiratory Symptoms Score at Day 28 | 8.2 units on a scale | Standard Deviation 17.13 |
| Placebo-AZLI | Change in QOL-B Respiratory Symptoms Score at Day 28 | 3.2 units on a scale | Standard Deviation 14.67 |
p-value: 0.01195% CI: [1.1, 8.2]MMRM
Secondary
Change in QOL-B Respiratory Symptoms Score at Day 84
The mean (SD) change in the Respiratory Symptoms score on the QOL-B was measured from baseline to the end of Course 2 (Day 84). The QOL-B respiratory symptoms score was transformed onto a scale of 0-100, with higher scores representing a better quality of life.
Time frame: Baseline to Day 84
Population: Participants in the ITT Analysis Set with scores at both baseline and Day 84 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI-AZLI | Change in QOL-B Respiratory Symptoms Score at Day 84 | 5.6 units on a scale | Standard Deviation 16.44 |
| Placebo-AZLI | Change in QOL-B Respiratory Symptoms Score at Day 84 | 3.9 units on a scale | Standard Deviation 17.73 |
p-value: 0.5695% CI: [-2.7, 5]MMRM
Secondary
Time to Protocol-Defined Exacerbation (PDE)
Protocol-defined exacerbation was defined as an acute worsening of respiratory disease that triggered the initiation of a non-study antibiotic meeting at least 3 major criteria, or 2 major and at least 2 minor criteria. * Major Criteria: increased sputum production; increased discoloration of sputum; increased dyspnea; increased cough * Minor Criteria: fever (\> 38º C) measured during clinic visit; increased malaise or fatigue; forced expiratory volume in 1 second (FEV1) (L) or forced vital capacity (FVC) decreased \> 10% from baseline; new or increased hemoptysis
Time frame: Baseline to Day 112
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI-AZLI | Time to Protocol-Defined Exacerbation (PDE) | NA days |
| Placebo-AZLI | Time to Protocol-Defined Exacerbation (PDE) | NA days |