Burkholderia Infections, Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Aztreonam Lysine, lung infection, Burkholderia, CFQ-R, inhaled antibiotic
Brief summary
The purpose of this research study was to determine if an experimental drug called Aztreonam for Inhalation Solution (AZLI) was safe and effective to treat Burkholderia lung infections in patients with cystic fibrosis (CF). Spirometry was used to assess pulmonary function, and the revised Cystic Fibrosis Questionnaire (CFQ-R) was used to assess quality of life. The CFQ-R is a validated, patient-reported outcome tool used to measure health-related quality of life for children and adults with CF. The study consisted of a 24-week randomized phase, and a 24-week open-label phase. Primary and secondary efficacy analyses were conducted for the 24-week randomized phase only. Safety data were collected for both the randomized and open-label phases.
Interventions
DRUGAZLI
Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.
DRUGPlacebo
Placebo to match AZLI (lactose and sodium chloride) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 6 years of age 2. Subjects with CF as diagnosed by one of the following: * Documented sweat chloride ≥ 60 milliequivalent (mEq)/L by quantitative pilocarpine iontophoresis test * Documented sweat sodium ≥ 60 mmol/L * Two well-characterized genetic mutations in the CF transmembrane conductance regulator (CFTR) gene * Abnormal nasal potential difference (NPD) with accompanying symptoms characteristic of CF 3. Chronic infection with Burkholderia spp. defined by: * One sputum (or bronchoalveolar lavage) culture positive for Burkholderia spp. within 6 months prior to baseline assessment, * At least 50% of sputum (or bronchoalveolar lavage) cultures collected at least one month apart over the previous 12 months prior to baseline assessment positive for Burkholderia spp. (minimum of 2 positive cultures), and * At least one positive sputum (or bronchoalveolar lavage) culture (obtained at any point in time) confirmed to be Burkholderia spp. by the Cystic Fibrosis Foundation (CFF) Burkholderia cepacia Research Laboratory and Repository at the University of Michigan (or equivalent Canadian reference laboratory). 4. Concomitant aerosolized antibiotic treatment: subjects receiving intermittent (alternating month on/month off) aerosolized antibiotic treatment were eligible, but must have been at least 1 week into their off-treatment cycle at the time of baseline assessment. Subjects receiving continuous aerosolized antibiotic treatment were eligible without restriction on their aerosolized antibiotic treatment. 5. Chest radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) (most recent, obtained within 90 days of screening) without significant acute findings (eg, infiltrates \[lobar or diffuse interstitial\], pleural effusion, pneumothorax), and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) were allowed. 6. Subjects (and parent/guardian as required) must have been able to provide written informed consent/assent prior to any study-related procedures, 7. Ability to perform reproducible pulmonary function tests 8. Sexually active females of childbearing potential must have agreed to use a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of study drug. A highly effective method of birth control was defined as a method that would result in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), or a vasectomized partner.
Exclusion criteria
1. Administration of any investigational drug or use of any investigational device within 28 days of randomization/baseline and within six half-lives of the investigational drug (whichever is longer) 2. Administration of AZLI treatment within the 28 days prior to randomization/baseline 3. Known local or systemic hypersensitivity to monobactam antibiotics 4. History of lung transplantation 5. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as: * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times the upper limit of the normal range (ULN) * Serum creatinine \> 2 times ULN 6. Known portal hypertension or complications of CF hepatopathy 7. Positive urine pregnancy test (confirmed by serum pregnancy test) at screening; all women of childbearing potential were tested 8. Any female of childbearing potential who was lactating or not practicing a highly effective method of birth control as defined in the protocol 9. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with subject treatment, assessment or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUCave of Relative Change in FEV1 % Predicted From Baseline to Week 24 | Baseline to Week 24 | The relative change (AUCave) in FEV1 % predicted from baseline to Week 24 was analyzed. FEV1 % predicted is defined as FEV1 % of the patient divided by the average FEV1 % in the population for any person of similar age, sex and body composition. AUCave is the calculated area under the curve corrected for baseline and adjusted by the number of days on study through Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events | Baseline to Week 24 | The total number of systemic and/or inhaled antibiotic courses for respiratory events from baseline to Week 24 was analyzed. A single antibiotic course may represent the use of multiple antibiotics. |
| AUCave of Change in CFQ-R RSS Scores From Baseline to Week 24 | Baseline to Week 24 | The change (AUCave) in CFQ-R RSS scores from baseline to Week 24 was analyzed. The range of scores (units) within the RSS domain is 0 to 100 with higher scores indicating fewer symptoms. |
| AUCave of Relative Change From Baseline to Week 24 in FEV1 | Baseline to Week 24 | The relative change (AUCave) from baseline to Week 24 in mean (SE) FEV1 was analyzed. FEV1 is defined as the maximal volume of air that can be exhaled in 1 second. |
| AUCave of Relative Change From Baseline to Week 24 in FEF25-75 | Baseline to Week 24 | The relative change (AUCave) from baseline to Week 24 in mean (SE) FEF25-75 was analyzed. FEF25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC. |
| AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R | Baseline to Week 24 | The change (AUCave) from baseline to Week 24 in the physical functioning score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R physical functioning domain is 0 to 100 with higher scores indicating better QOL. |
| AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R | Baseline to Week 24 | The change (AUCave) from baseline to Week 24 in the weight score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R weight domain is 0 to 100 with higher scores indicating better QOL. |
| AUCave of Relative Change From Baseline to Week 24 in FVC | Baseline to Week 24 | The relative change (AUCave) from baseline to Week 24 in mean (SE) FVC was analyzed. FVC is defined as the volume of air that can forcibly be blown out after taking a full breath. |
| Change in BMI From Baseline to Week 24 | Baseline to Week 24 | The change in BMI from baseline to Week 24 was analyzed. |
| Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24 | Baseline to Week 24 | The change in Burkholderia spp. CFU in sputum from baseline to Week 24 was analyzed. |
| Percentage of Days Participants Used Antibiotics | Baseline to Week 24 | The percentage of days participants used antibiotics from baseline to Week 24 was analyzed. Antibiotics ongoing at baseline or started on or after first dose date were included in the analysis. A single antibiotic course could represent the use of multiple antibiotics. Days of antibiotic use included unique days. |
| Percent of Days Hospitalized | Baseline to Week 24 | The percentage of days hospitalized from baseline to Week 24 was analyzed. |
| Percentage of Missed School or Work Days | Baseline to Week 24 | The percentage of days participants missed school or work from baseline to Week 24 was analyzed. |
| AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R | Baseline to Week 24 | The change (AUCave) from baseline to Week 24 in the treatment burden score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R treatment burden domain is 0 to 100 with higher scores indicating better QOL. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at 34 sites in the United States and 1 site in Canada. The first participant was screened on 22 February 2010. The last participant observation was on 28 December 2010.
Pre-assignment details
102 participants were screened and 101 were randomized. Of those participants randomized, 100 received at least one dose of study drug, and comprise the Safety Analysis Set and the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| AZLI Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, for up 48 weeks using the investigational nebulizer. | 48 |
| Placebo Placebo to match AZLI (lactose and sodium chloride) was administered three times a day, with at least 4 hours between doses, for up 48 weeks using the investigational nebulizer. | 52 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 24-Week Open-Label Phase | Adverse Event | 2 | 0 |
| 24-Week Open-Label Phase | Pulmonologist/participant decision | 0 | 1 |
| 24-Week Open-Label Phase | Subject noncompliance | 1 | 0 |
| 24-Week Open-Label Phase | Unable to clean device (hospitalization) | 0 | 1 |
| 24-Week Open-Label Phase | Withdrawal by Subject | 1 | 0 |
| 24-Week Open-Label Phase | Worsening health (physician decision) | 1 | 1 |
| 24-Week Randomized Phase | Adverse Event | 5 | 0 |
| 24-Week Randomized Phase | Lost to Follow-up | 0 | 1 |
| 24-Week Randomized Phase | Noncompliance with Study Drug Regimen | 1 | 5 |
| 24-Week Randomized Phase | Randomized but not treated | 1 | 0 |
| 24-Week Randomized Phase | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | AZLI | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 28.0 years STANDARD_DEVIATION 10.3 | 24.7 years STANDARD_DEVIATION 10 | 26.3 years STANDARD_DEVIATION 10.2 |
| Age, Customized > 12 to < 18 years | 3 participants | 8 participants | 11 participants |
| Age, Customized ≥ 18 years | 42 participants | 41 participants | 83 participants |
| Age, Customized ≥ 6 to ≤ 12 years | 3 participants | 3 participants | 6 participants |
| Body Mass Index (BMI) | 21.9 kg/m^2 STANDARD_DEVIATION 4.5 | 20.7 kg/m^2 STANDARD_DEVIATION 3.2 | 21.3 kg/m^2 STANDARD_DEVIATION 3.9 |
| Burkholderia spp colony-forming units (CFU) in sputum | 6.39 log_10 CFU per gram STANDARD_DEVIATION 2.47 | 6.41 log_10 CFU per gram STANDARD_DEVIATION 2.52 | 6.40 log_10 CFU per gram STANDARD_DEVIATION 2.48 |
| Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score | 58.3 units on a scale STANDARD_DEVIATION 21.4 | 59.0 units on a scale STANDARD_DEVIATION 17.6 | 58.6 units on a scale STANDARD_DEVIATION 19.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 51 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1 | 2.13 liters STANDARD_DEVIATION 0.93 | 1.93 liters STANDARD_DEVIATION 0.96 | 2.02 liters STANDARD_DEVIATION 0.95 |
| Forced expiratory flow 25% to 75% (FEF25-75) | 1.33 liters per second STANDARD_DEVIATION 0.95 | 1.31 liters per second STANDARD_DEVIATION 1.22 | 1.32 liters per second STANDARD_DEVIATION 1.09 |
| Forced expiratory volume in 1 second (FEV1) percent predicted | 60.67 percentage of FEV1 % predicted STANDARD_DEVIATION 21.71 | 52.59 percentage of FEV1 % predicted STANDARD_DEVIATION 23.71 | 56.47 percentage of FEV1 % predicted STANDARD_DEVIATION 23.02 |
| Forced vital capacity (FVC) | 3.23 liters STANDARD_DEVIATION 1.18 | 2.99 liters STANDARD_DEVIATION 1.14 | 3.11 liters STANDARD_DEVIATION 1.16 |
| Race/Ethnicity, Customized Black or African Heritage | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 46 participants | 50 participants | 96 participants |
| Region of Enrollment Canada | 3 participants | 3 participants | 6 participants |
| Region of Enrollment United States | 45 participants | 49 participants | 94 participants |
| Sex: Female, Male Female | 22 Participants | 17 Participants | 39 Participants |
| Sex: Female, Male Male | 26 Participants | 35 Participants | 61 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 | 46 / 48 | 46 / 52 | 39 / 39 | 44 / 45 |
| serious Total, serious adverse events | 17 / 48 | 21 / 52 | 19 / 39 | 24 / 45 |
Outcome results
Primary
AUCave of Relative Change in FEV1 % Predicted From Baseline to Week 24
The relative change (AUCave) in FEV1 % predicted from baseline to Week 24 was analyzed. FEV1 % predicted is defined as FEV1 % of the patient divided by the average FEV1 % in the population for any person of similar age, sex and body composition. AUCave is the calculated area under the curve corrected for baseline and adjusted by the number of days on study through Week 24.
Time frame: Baseline to Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of Relative Change in FEV1 % Predicted From Baseline to Week 24 | 0.16 percent change in FEV1% predicted | Standard Error 1.5 |
| Placebo | AUCave of Relative Change in FEV1 % Predicted From Baseline to Week 24 | -0.75 percent change in FEV1% predicted | Standard Error 1.43 |
Comparison: The primary analysis was a test for superiority. Null hypothesis was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.~A sample size of 50 participants per group provided at least 80% power to detect an 8.5% difference in mean AUCave of relative change from baseline in FEV1 % predicted through Week 24 using a two-sided 0.05-level test, assuming a common standard deviation of 15.p-value: 0.66395% CI: [-3.24, 5.06]ANCOVA
Secondary
AUCave of Change in CFQ-R RSS Scores From Baseline to Week 24
The change (AUCave) in CFQ-R RSS scores from baseline to Week 24 was analyzed. The range of scores (units) within the RSS domain is 0 to 100 with higher scores indicating fewer symptoms.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of Change in CFQ-R RSS Scores From Baseline to Week 24 | 2.97 units on a scale | Standard Error 1.7 |
| Placebo | AUCave of Change in CFQ-R RSS Scores From Baseline to Week 24 | 2.79 units on a scale | Standard Error 1.58 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.93995% CI: [-4.43, 1.78]ANCOVA
Secondary
AUCave of Relative Change From Baseline to Week 24 in FEF25-75
The relative change (AUCave) from baseline to Week 24 in mean (SE) FEF25-75 was analyzed. FEF25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of Relative Change From Baseline to Week 24 in FEF25-75 | 1.40 percent change in FEF25-75 (liters/sec) | Standard Error 2.37 |
| Placebo | AUCave of Relative Change From Baseline to Week 24 in FEF25-75 | -0.55 percent change in FEF25-75 (liters/sec) | Standard Error 2.25 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.55395% CI: [-4.54, 8.44]ANCOVA
Secondary
AUCave of Relative Change From Baseline to Week 24 in FEV1
The relative change (AUCave) from baseline to Week 24 in mean (SE) FEV1 was analyzed. FEV1 is defined as the maximal volume of air that can be exhaled in 1 second.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of Relative Change From Baseline to Week 24 in FEV1 | 0.36 percent change in FEV1 (liters) | Standard Error 1.49 |
| Placebo | AUCave of Relative Change From Baseline to Week 24 in FEV1 | -0.41 percent change in FEV1 (liters) | Standard Error 1.42 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.71195% CI: [-3.33, 4.86]ANCOVA
Secondary
AUCave of Relative Change From Baseline to Week 24 in FVC
The relative change (AUCave) from baseline to Week 24 in mean (SE) FVC was analyzed. FVC is defined as the volume of air that can forcibly be blown out after taking a full breath.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of Relative Change From Baseline to Week 24 in FVC | 0.77 percent change in FVC (liters) | Standard Error 1.42 |
| Placebo | AUCave of Relative Change From Baseline to Week 24 in FVC | 0.17 percent change in FVC (liters) | Standard Error 1.35 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.76295% CI: [-3.3, 4.49]ANCOVA
Secondary
AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R
The change (AUCave) from baseline to Week 24 in the physical functioning score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R physical functioning domain is 0 to 100 with higher scores indicating better QOL.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R | 1.06 units on a scale | Standard Error 1.57 |
| Placebo | AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R | -1.93 units on a scale | Standard Error 1.48 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.1795% CI: [-1.2, 7.28]ANCOVA
Secondary
AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R
The change (AUCave) from baseline to Week 24 in the treatment burden score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R treatment burden domain is 0 to 100 with higher scores indicating better QOL.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R | -2.73 units on a scale | Standard Error 1.73 |
| Placebo | AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R | -6.35 units on a scale | Standard Error 1.62 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.13295% CI: [-1.11, 8.34]ANCOVA
Secondary
AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R
The change (AUCave) from baseline to Week 24 in the weight score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R weight domain is 0 to 100 with higher scores indicating better QOL.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R | 0.54 units on a scale | Standard Error 2.9 |
| Placebo | AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R | 3.11 units on a scale | Standard Error 2.8 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.52895% CI: [-10.62, 5.49]ANCOVA
Secondary
Change in BMI From Baseline to Week 24
The change in BMI from baseline to Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Change in BMI From Baseline to Week 24 | 0.34 kg/m^2 | Standard Error 0.16 |
| Placebo | Change in BMI From Baseline to Week 24 | 0.21 kg/m^2 | Standard Error 0.15 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.53195% CI: [-0.29, 0.56]Mixed Models Analysis
Secondary
Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24
The change in Burkholderia spp. CFU in sputum from baseline to Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available change data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24 | 1.41 log_10 CFU per gram of sputum | Standard Error 0.58 |
| Placebo | Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24 | 0.48 log_10 CFU per gram of sputum | Standard Error 0.5 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.23295% CI: [-0.62, 2.48]ANCOVA
Secondary
Percentage of Days Participants Used Antibiotics
The percentage of days participants used antibiotics from baseline to Week 24 was analyzed. Antibiotics ongoing at baseline or started on or after first dose date were included in the analysis. A single antibiotic course could represent the use of multiple antibiotics. Days of antibiotic use included unique days.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Percentage of Days Participants Used Antibiotics | 44.4 percentage of days | Standard Deviation 35.2 |
| Placebo | Percentage of Days Participants Used Antibiotics | 56.3 percentage of days | Standard Deviation 34.8 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.103Wilcoxon (Mann-Whitney)
Secondary
Percentage of Missed School or Work Days
The percentage of days participants missed school or work from baseline to Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Percentage of Missed School or Work Days | 1.9 percentage of days | Standard Deviation 3.3 |
| Placebo | Percentage of Missed School or Work Days | 4.7 percentage of days | Standard Deviation 7.2 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.284Wilcoxon (Mann-Whitney)
Secondary
Percent of Days Hospitalized
The percentage of days hospitalized from baseline to Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Percent of Days Hospitalized | 4.9 percentage of days | Standard Deviation 10.3 |
| Placebo | Percent of Days Hospitalized | 4.8 percentage of days | Standard Deviation 8.7 |
Comparison: Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.646Wilcoxon (Mann-Whitney)
Secondary
Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events
The total number of systemic and/or inhaled antibiotic courses for respiratory events from baseline to Week 24 was analyzed. A single antibiotic course may represent the use of multiple antibiotics.
Time frame: Baseline to Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI | Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events | 54 antibiotic treatment courses |
| Placebo | Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events | 73 antibiotic treatment courses |
Comparison: The primary analysis was a test for superiority. Null hypothesis was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.p-value: 0.4158Negative binomial regression