Cystic Fibrosis, Lung Infection, Pseudomonas Aeruginosa
Conditions
Keywords
cystic fibrosis, pseudomonas aeruginosa, lung infection, CFQ-R, inhaled antibiotic, aztreonam lysine
Brief summary
The purpose of this study was to evaluate the safety and efficacy of a 28-day course of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF), mild lung disease (forced expiratory volume in 1 second \[FEV1\] \>75% predicted, and Pseudomonas aeruginosa (PA) infection.
Detailed description
CF patients often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called Pseudomonas aeruginosa (PA). Treatment with antibiotics can stop or slow down the growth of the bacteria. The antibiotics may be given by mouth, intravenously (IV), or by inhalation as a mist. The purpose of this study was to evaluate the safety and efficacy of AZLI, an investigational formulation of the antibiotic aztreonam and administered three times a day using the PARI eFlow® electronic nebulizer, in CF patients with PA and mild lung disease. In this study, participant eligibility was assessed at a screening visit that occurred up to 14 days prior to the baseline visit (Day 0). Those participants who met eligibility criteria at Day 0 were randomized and began a 28-day course of blinded study treatment (AZLI or placebo TID). Participants returned for clinic visits at Day 14, an end of treatment visit at Day 28, and a follow up visit 14 days after the last dose of the trial drug (Day 42).
Interventions
DRUGAZLI 75 mg three times daily (TID)
DRUGPlacebo three times daily (TID)
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
* Participants ≥ 6 years of age * Documentation of CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria: * Sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test * Two well characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene * Abnormal nasal potential difference * PA present in expectorated sputum or throat swab culture at Visit 1 OR documented PA in 2 expectorated sputum or throat swab cultures within the 12 months prior to Visit 1 (one of the previous PA positive cultures must have been no more than 3 months prior to Visit 1) * FEV1 \> 75% predicted at Visit 1 * Participants must have exhibited two or more of the following chronic and/or intermittent CF symptoms, for a minimum of 28 days prior to randomization and with no worsening of symptoms within 7 days prior to randomization: * Chest congestion * Daily cough * Productive cough * Wheezing * Trouble breathing * Nocturnal wakening due to coughing * Participants (and parent/guardian as required) had to be able to provide written informed consent/assent prior to any study related procedures * Females of childbearing potential had to have a negative urine pregnancy test at Visit 1 * Ability to perform reproducible pulmonary function tests * In the opinion of the Investigator, the participant did not require immediate antipseudomonal antibiotic intervention to treat an impending exacerbation, and the participant's condition was stable enough to enroll in the study
Exclusion criteria
* Administration of any investigational drug or device within 28 days prior to Visit 1 or within 6 half-lives of the investigational drug (whichever was longer) * Administration of any IV, oral, or inhaled antipseudomonal antibiotic within 28 days prior to Visit 1 * Known local or systemic hypersensitivity to monobactam antibiotics * Inability to tolerate short-acting bronchodilator (BD) use at least TID * Changes in or initiation of chronic azithromycin treatment within 28 days prior to Visit 1 * Changes in or initiation of chronic hypertonic saline treatment within 28 days prior to Visit 1 * Changes in or initiation of dornase alfa within 28 days prior to Visit 1 * Changes in antimicrobial, BD, or corticosteroid medications within 7 days prior to Visit 1 * Changes in physiotherapy technique or schedule within 7 days prior to Visit 1 * History of lung transplantation * History of participation (enrollment) in any prior clinical studies with AZLI * A chest radiograph at Visit 1 (or within the previous 180 days of Visit 1), with abnormalities indicating a significant acute finding (e.g., lobar infiltrate and atelectasis, pneumothorax, or pleural effusion); a chest radiograph obtained and interpreted between Visits 1 and 2 was also acceptable for determining eligibility * Positive urine pregnancy test at Visit 1; all women of childbearing potential were to be tested * Females of childbearing potential who were lactating or were not (in the opinion of the investigator) practicing an acceptable method of birth control; female participants who utilized hormonal contraceptives as their birth control method must have used the same method for at least 3 months before study dosing * Participant was being assessed at Visit 1 by the investigator for an acute change in respiratory symptoms * Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would have interfered with participant treatment, assessment, or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | Day 0 to Day 28 | The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CFQ-R RSS Score at Day 14 | Day 0 to Day 14 | The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
| Change From Baseline in CFQ-R RSS Score at Day 42 | Day 0 to Day 42 | The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
| Change From Baseline in CFQ-R Physical Functioning Domain Score | Day 0 to Day 28 | The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0 (baseline), 14, 28, and 42 (the last study visit). The endpoint was change from baseline in the physical functioning domain (e.g., ability to walk and engage in physical activities) of the CFQ-R at Day 28 (range of scores: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R physical functioning domain score and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
| Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study | Day 0 to Day 42 | The number of participants requiring additional antipseudomonal antibiotics (oral, intravenous \[IV\], or by inhalation), the time to use of these antibiotics, and the reasons for use was recorded. A binary variable was defined to indicate whether the participants needed any antipseudomonal antibiotics that were non-study drug via the oral, IV, or inhalation route between Day 0 (Baseline Visit) and Day 42 (Visit 5). Fisher's Exact Test was implemented on the intent-to-treat (ITT) and per protocol analysis sets to detect treatment effects on need for additional antipseudomonal antibiotics. |
| Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28 | Day 0 to Day 28 | Sputum samples were collected at all study visits for quantitative and qualitative culture for PA. Sputum PA density was quantified by logarithm transformation of the CFU value with base 10. Change from baseline in sputum PA density was calculated as the difference between the log10 CFU values at Day 28 (Visit 4) and the baseline value. Missing data was not imputed. Baseline log10 CFU and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
| Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted | Day 0 to Day 28 | Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested by the ANCOVA model using the ITT analysis set. Baseline FEV1 percent predicted and age group (\<18 vs. \>=18 years) were included as covariates in the analysis. |
| Number of Participants Hospitalized During Study | Day 0 to Day 42 | Hospitalization was defined as any hospital admission lasting for more than 1 calendar day that had been recorded as a serious adverse event (SAE) on the electronic case report form (eCRF). Binary variables were defined to indicate whether participants experienced any hospitalization. Number of hospitalizations was summarized by treatment group. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Testing Positive for Other Respiratory Pathogens | Day 0 to Day 28 | Sputum/throat swab samples were collected at all visits for quantitative and qualitative culture of Burkholderia species, Stenotrophomonas maltophilia, Achromobacter xylosidans, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), and Aspergillus species. One CFU on the culture from either a sputum or throat swab sample was considered presence of the particular organism. |
| The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Day 0 to Day 28 | Aztreonam susceptibility of PA isolates from expectorated sputum samples (collected at all visits) was assessed. The minimum inhibitory concentration (MIC) is the lowest concentration of antimicrobial agent that inhibits visible growth of a microorganism. The MIC50 and MIC90 for PA is the MIC required to inhibit the growth of 50% or 90% of PA isolates, respectively. Given that there might be multiple PA isolates for each participant, the MIC50 and MIC90 for PA was calculated using the MIC values for all PA isolates. The MIC50 and MIC90 were calculated by treatment group. |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
Participants were randomized at 39 sites in total: 34 in the United States, 1 in Canada, and 4 in Australia. Date of first screening was 16 June 2008, and date of last participant observation was 19 June 2009.
Pre-assignment details
Planned trial size was approximately 140 participants randomized in 1:1 ratio to aztreonam for inhalation solution (AZLI) three times daily (TID) or placebo TID. 160 participants were randomized, 157 received blinded study drug (76 AZLI; 81 placebo). One participant who was randomized and treated with study drug discontinued the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Three Times Daily (TID) Placebo (5 mg/mL lactose when reconstituted in diluent \[0.17% saline\]; sterile, pH 4.2 to 7.5, and osmolality 200 to 400 mOsmol/kg). Placebo was self-administered TID by inhalation using the investigational nebulizer. | 81 |
| AZLI 75 mg Three Times Daily (TID) AZLI (75 mg/mL aztreonam lysine when reconstituted in diluent \[0.17% saline\]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation TID using the investigational nebulizer. | 76 |
| Total | 157 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Noncompliance | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Three Times Daily (TID) | AZLI 75 mg Three Times Daily (TID) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 47 Participants | 42 Participants | 89 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 34 Participants | 68 Participants |
| Age Continuous | 18.9 years STANDARD_DEVIATION 9.11 | 19.5 years STANDARD_DEVIATION 9.07 | 19.2 years STANDARD_DEVIATION 9.07 |
| Region of Enrollment Australia | 6 participants | 4 participants | 10 participants |
| Region of Enrollment Canada | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 73 participants | 72 participants | 145 participants |
| Sex: Female, Male Female | 37 Participants | 30 Participants | 67 Participants |
| Sex: Female, Male Male | 44 Participants | 46 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 62 / 81 | 58 / 76 |
| serious Total, serious adverse events | 3 / 81 | 9 / 76 |
Outcome results
Primary
Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 28
Population: Analysis on intent-to-treat (ITT) population (received at least part of 1 dose of AZLI/placebo). Missing baseline data not imputed. Missing post-baseline data imputed with worst-case value for participants who withdrew due to an adverse event (AE)/study drug intolerance. Imputation for other missing data was last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | 1.41 Units on a scale | Standard Error 1.64 |
| AZLI 75 mg Three Times Daily (TID) | Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | 3.22 Units on a scale | Standard Error 1.71 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change from baseline in CFQ-R RSS score at Day 28.~At the 5% significance level (i.e., α = 0.05) using a two-sided significance test, a sample size of 70 participants per treatment group provided at least 90% power to detect a 10 point difference between groups in the mean change from baseline at Day 28 in the CFQ-R RSS score, assuming a common standard deviation (SD) of 17.5.p-value: 0.43395% CI: [-2.83, 6.44]ANCOVA
Secondary
Change From Baseline in CFQ-R Physical Functioning Domain Score
The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0 (baseline), 14, 28, and 42 (the last study visit). The endpoint was change from baseline in the physical functioning domain (e.g., ability to walk and engage in physical activities) of the CFQ-R at Day 28 (range of scores: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R physical functioning domain score and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants receiving at least part of one dose of AZLI or placebo). Missing baseline data were not imputed. Missing post-baseline data were imputed using worst-case value for participants who withdrew due to an AE or study drug intolerance. For all other missing data, LOCF imputation method was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Change From Baseline in CFQ-R Physical Functioning Domain Score | -0.69 Units on a scale | Standard Error 1.53 |
| AZLI 75 mg Three Times Daily (TID) | Change From Baseline in CFQ-R Physical Functioning Domain Score | 1.79 Units on a scale | Standard Error 1.57 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change from baseline in the CFQ-R physical functioning domain score at Day 28.p-value: 0.25695% CI: [-1.81, 6.76]ANCOVA
Secondary
Change From Baseline in CFQ-R RSS Score at Day 14
The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 14
Population: Analysis based on ITT population (all participants receiving at least part of one dose of AZLI or placebo). Missing baseline data were not imputed. Missing post-baseline data were imputed using worst-case value for participants who withdrew due to an AE or study drug intolerance. For all other missing data, LOCF imputation method was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Change From Baseline in CFQ-R RSS Score at Day 14 | 0.28 Units on a scale | Standard Error 1.56 |
| AZLI 75 mg Three Times Daily (TID) | Change From Baseline in CFQ-R RSS Score at Day 14 | 3.65 Units on a scale | Standard Error 1.63 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change from baseline in the CFQ-R RSS score at Day 14.p-value: 0.13395% CI: [-1.04, 7.78]ANCOVA
Secondary
Change From Baseline in CFQ-R RSS Score at Day 42
The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 42
Population: Analysis based on ITT population (all participants receiving at least part of one dose of AZLI or placebo). Missing baseline data were not imputed. Missing post-baseline data were imputed using worst-case value for participants who withdrew due to an AE or study drug intolerance. For all other missing data, LOCF imputation method was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Change From Baseline in CFQ-R RSS Score at Day 42 | 2.91 Units on a scale | Standard Error 1.65 |
| AZLI 75 mg Three Times Daily (TID) | Change From Baseline in CFQ-R RSS Score at Day 42 | 3.02 Units on a scale | Standard Error 1.72 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change from baseline in the CFQ-R RSS score at Day 42.p-value: 0.96595% CI: [-4.56, 4.76]ANCOVA
Secondary
Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28
Sputum samples were collected at all study visits for quantitative and qualitative culture for PA. Sputum PA density was quantified by logarithm transformation of the CFU value with base 10. Change from baseline in sputum PA density was calculated as the difference between the log10 CFU values at Day 28 (Visit 4) and the baseline value. Missing data was not imputed. Baseline log10 CFU and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). No imputation methods were used for the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28 | -0.14 Log10 PA CFUs/gram of sputum | Standard Error 0.36 |
| AZLI 75 mg Three Times Daily (TID) | Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28 | -1.35 Log10 PA CFUs/gram of sputum | Standard Error 0.36 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change from baseline in the log10 CFU at Day 28.p-value: 0.01695% CI: [-2.2, -0.23]ANCOVA
Secondary
Number of Participants Hospitalized During Study
Hospitalization was defined as any hospital admission lasting for more than 1 calendar day that had been recorded as a serious adverse event (SAE) on the electronic case report form (eCRF). Binary variables were defined to indicate whether participants experienced any hospitalization. Number of hospitalizations was summarized by treatment group.
Time frame: Day 0 to Day 42
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). No imputation methods were used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Three Times Daily (TID) | Number of Participants Hospitalized During Study | 3 Study participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Hospitalized During Study | 8 Study participants |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in proportion of participants hospitalized.p-value: 0.122Fisher Exact
Secondary
Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study
The number of participants requiring additional antipseudomonal antibiotics (oral, intravenous \[IV\], or by inhalation), the time to use of these antibiotics, and the reasons for use was recorded. A binary variable was defined to indicate whether the participants needed any antipseudomonal antibiotics that were non-study drug via the oral, IV, or inhalation route between Day 0 (Baseline Visit) and Day 42 (Visit 5). Fisher's Exact Test was implemented on the intent-to-treat (ITT) and per protocol analysis sets to detect treatment effects on need for additional antipseudomonal antibiotics.
Time frame: Day 0 to Day 42
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). No imputation methods were used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Three Times Daily (TID) | Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study | 21 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study | 19 Participants |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study.p-value: >0.999Fisher Exact
Secondary
Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested by the ANCOVA model using the ITT analysis set. Baseline FEV1 percent predicted and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). Missing baseline data were not imputed. Missing post-baseline data were imputed using worst-case value for participants who withdrew due to an AE or study drug intolerance. For all other missing data, LOCF method was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted | -2.45 Percent change from baseline | Standard Error 0.82 |
| AZLI 75 mg Three Times Daily (TID) | Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted | 0.29 Percent change from baseline | Standard Error 0.85 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in % change from baseline in FEV1 % predicted at Day 28.p-value: 0.02195% CI: [0.42, 5.04]ANCOVA
Other Pre-specified
Number of Participants Testing Positive for Other Respiratory Pathogens
Sputum/throat swab samples were collected at all visits for quantitative and qualitative culture of Burkholderia species, Stenotrophomonas maltophilia, Achromobacter xylosidans, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), and Aspergillus species. One CFU on the culture from either a sputum or throat swab sample was considered presence of the particular organism.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | B. cepacia - Day 28 | 1 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MRSA - Day 0 | 14 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | S. maltophilia - Day 28 | 9 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MRSA - Day 28 | 13 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | B. cepacia - Day 0 | 1 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MSSA - Day 0 | 31 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | A. xylosoxidans - Day 0 | 0 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MSSA - Day 28 | 31 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | S. maltophilia - Day 0 | 7 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | A. xylosoxidans - Day 28 | 2 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | Aspergillus spp. - Day 28 | 6 Participants |
| Placebo Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | Aspergillus spp. - Day 0 | 6 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | Aspergillus spp. - Day 28 | 11 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | B. cepacia - Day 0 | 0 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | B. cepacia - Day 28 | 1 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | S. maltophilia - Day 0 | 8 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | S. maltophilia - Day 28 | 8 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | A. xylosoxidans - Day 0 | 1 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | A. xylosoxidans - Day 28 | 1 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MRSA - Day 0 | 14 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MRSA - Day 28 | 13 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MSSA - Day 0 | 28 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | MSSA - Day 28 | 25 Participants |
| AZLI 75 mg Three Times Daily (TID) | Number of Participants Testing Positive for Other Respiratory Pathogens | Aspergillus spp. - Day 0 | 10 Participants |
Other Pre-specified
The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively)
Aztreonam susceptibility of PA isolates from expectorated sputum samples (collected at all visits) was assessed. The minimum inhibitory concentration (MIC) is the lowest concentration of antimicrobial agent that inhibits visible growth of a microorganism. The MIC50 and MIC90 for PA is the MIC required to inhibit the growth of 50% or 90% of PA isolates, respectively. Given that there might be multiple PA isolates for each participant, the MIC50 and MIC90 for PA was calculated using the MIC values for all PA isolates. The MIC50 and MIC90 were calculated by treatment group.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Baseline MIC50 | 1 µg/mL |
| Placebo Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Day 28 MIC50 | 1 µg/mL |
| Placebo Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Baseline MIC90 | 16 µg/mL |
| Placebo Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Day 28 MIC90 | 16 µg/mL |
| AZLI 75 mg Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Day 28 MIC90 | 32 µg/mL |
| AZLI 75 mg Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Baseline MIC50 | 1 µg/mL |
| AZLI 75 mg Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Baseline MIC90 | 8 µg/mL |
| AZLI 75 mg Three Times Daily (TID) | The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) | Day 28 MIC50 | 4 µg/mL |