Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Pseudomonas aeruginosa, Pulmonary Cystic Fibrosis
Brief summary
The purpose of this study was to evaluate the safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).
Detailed description
Patients with CF often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called 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 aztreonam for inhalation solution (AZLI), an investigational formulation of the antibiotic administered using the eFlow® Electronic Nebulizer by PARI GmbH, in CF patients with PA. In this study, participants were screened for eligibility at Visit 1 (Day -42) and returned to the center for Visit 2 after a 14-day evaluation period. At Visit 2 (Day -28), participants began a 28-day course of open-label Tobramycin Inhalation Solution (TIS). At Visit 3 (Day 0), following completion of the 28-day course of TIS, participants began randomized, blinded treatment with either AZLI twice a day (BID) or three times a day (TID) or placebo BID or TID, and continued treatment for a total of 28 days, with a clinic visit at Day 14 (Visit 4) and at the end of treatment (Visit 5 \[Day 28\]). Participants returned for visits every 2 weeks for 8 weeks after the end of the blinded treatment (Visits 6 to 9 \[Days 42 to 84\]). Two hundred and forty-seven participants were treated in the TIS phase of this study. Two hundred and eleven subjects completed the TIS phase and were treated in the placebo-controlled phase with study drug (AZLI or placebo).
Interventions
DRUGAZLI 75 mg two times a day (BID)/three times a day (TID)
DRUGPlacebo two times a day (BID)/three times a day (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
* CF as diagnosed by: 1. Documented sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test; or 2. Two well-characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or 3. Abnormal nasal potential difference with accompanying symptoms characteristic of CF. * PA present in expectorated sputum or throat swab culture at Screening. * Participants must have received three or more courses of TIS within the previous 12 months. * Participants on chronic azithromycin must have had no change in regimen in the previous 3 months and must have had a need for TIS and/or additional antipseudomonal therapy since initiation of azithromycin. * Forced expiratory volume in 1 second (FEV1) between (and including) 25% and 75% predicted at Screening. * Ability to perform reproducible pulmonary function tests. * Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening.
Exclusion criteria
* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day. * History of sputum or throat culture swab yielding Burkholderia cepacia in the past 2 years. * History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night. * Administration of any investigational drug or device within 28 days of Screening (Visit 1) or within 6 half-lives of the investigational drug (whichever was longer). * Known local or systemic hypersensitivity to monobactam antibiotics. * Inability to tolerate inhalation of a short acting Beta-2 agonist. * Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days before Screening or between Screening and the next visit. * Changes in physiotherapy technique or schedule within 7 days before Screening or between Screening and the next visit. * History of lung transplantation. * A chest X-ray indicating abnormal findings at Screening or within the previous 90 days. * Abnormal renal or hepatic function or serum chemistry at Screening (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] greater than 5 times the upper limit of normal range; Creatinine greater than 2 times the upper limit of normal range). * Positive pregnancy test at Screening. * Female of childbearing potential who was lactating or in the opinion of the investigator was not practicing acceptable birth control. * 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 |
|---|---|---|
| Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics | Day 0 to Day 84 (end of study) | The primary endpoint was time to need for a course of inhaled or IV antipseudomonal antibiotics with documented physician assessment of need for antibiotics. Antipseudomonal Antibiotic need was documented based on the presence of at least one of the following four symptoms predictive of pulmonary exacerbation: decreased exercise tolerance, increased cough, increased sputum / chest congestion, decreased appetite, or other. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score | Day 0 to Day 28 | The CFQ-R was administered at Day -28, baseline, Day 14, Day 28, and Day 84 (end of study). The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms). |
| Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L) | Day 0 to Day 28 | Spirometry was performed at each visit. FEV1 was recorded according to American Thoracic Society (ATS) guidelines. FEV1(L) is the measurement of the volume of air (expressed in liters) exhaled in 1 second. The percent change in this parameter from Day 0 to Day 28 was determined for each treatment group. |
| Number of Hospitalization Days | Day 0 to Day 84 | Details of all hospitalizations, including the dates of admission and discharge, were recorded on the electronic case report form (eCRF). |
| Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | Day 0 to Day 28 | Sputum samples were collected at all participant visits of the study for analysis of microbiology endpoints. Sputum samples were processed for qualitative and quantitative culture of PA (each morphotype). Due to the skewness of the distribution of CFU data, the data were transformed using the base 10 logarithm, in an attempt to normalize the data and allow for parametric tests, before calculating changes. To account for zero values, 1 was added to each CFU measurement before being transformed. Any CFU data values where PA was not isolated from a valid culture were set to zero. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Other Pathogens | Day 0 and Day 28 | Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Number of participants with other pathogens at baseline and at the end of treatment (28 days) are reported. |
| Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 to Day 28 | The aztreonam susceptibility of PA isolates from sputum samples (collected at all visits) was assessed. MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism). MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism). MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 56 sites in the United States. Date of first enrollment was 24 February 2005, and date of last participant follow-up was 07 September 2006.
Pre-assignment details
Subjects were randomized in 1:1:2:2 ratio to placebo twice a day (BID) or three times a day (TID) and AZLI BID or TID, respectively. A total of 211 subjects were included in the ITT analyses: 38 placebo BID, 38 placebo TID, 69 AZLI BID, and 66 AZLI TID. All analyses were conducted on pooled placebo (n = 76) versus pooled AZLI (n = 135) groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Pooled BID/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 twice daily (BID) or three times daily (TID) by inhalation using the investigational nebulizer. All analyses were conducted on the pooled placebo vs pooled AZLI treatment groups. | 76 |
| AZLI (Pooled BID/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 BID or TID using the investigational nebulizer. All analyses were conducted on the pooled placebo vs pooled AZLI treatment groups. | 135 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Noncompliance | 0 | 2 |
| Overall Study | Other | 1 | 5 |
| Overall Study | Personal/administrative | 1 | 1 |
| Overall Study | Related adverse event | 13 | 15 |
| Overall Study | Study drug intolerance | 0 | 1 |
| Overall Study | Unrelated adverse event | 34 | 47 |
Baseline characteristics
| Characteristic | AZLI (Pooled BID/TID) | Placebo (Pooled BID/TID) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 34 Participants | 12 Participants | 46 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 101 Participants | 63 Participants | 164 Participants |
| Age Continuous | 25.3 years STANDARD_DEVIATION 10.2 | 27.9 years STANDARD_DEVIATION 10.4 | 26.2 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 135 participants | 76 participants | 211 participants |
| Sex: Female, Male Female | 59 Participants | 31 Participants | 90 Participants |
| Sex: Female, Male Male | 76 Participants | 45 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 76 | 121 / 135 |
| serious Total, serious adverse events | 3 / 76 | 13 / 135 |
Outcome results
Primary
Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics
The primary endpoint was time to need for a course of inhaled or IV antipseudomonal antibiotics with documented physician assessment of need for antibiotics. Antipseudomonal Antibiotic need was documented based on the presence of at least one of the following four symptoms predictive of pulmonary exacerbation: decreased exercise tolerance, increased cough, increased sputum / chest congestion, decreased appetite, or other.
Time frame: Day 0 to Day 84 (end of study)
Population: Analysis based on intents to treat (ITT) population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (Pooled BID/TID) | Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics | 71 Days |
| AZLI (Pooled BID/TID) | Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics | 92 Days |
Comparison: H0: no difference between AZLI and placebo (pooled treatment groups) in time to need for inhaled or IV antibiotics. Assuming 2-sided significance level of 0.05, \~210 subjects (70 in each AZLI group, 35 in each placebo group) provided \>90% power to reject null hypothesis based on Lakatos normal approximation method with weights being one. Therefore, 250 subjects were to be randomized at Visit 2 (Day -28) to ensure at least 210 participants entered double-blind treatment period at Day 0.p-value: 0.007Log Rank
Secondary
Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum
Sputum samples were collected at all participant visits of the study for analysis of microbiology endpoints. Sputum samples were processed for qualitative and quantitative culture of PA (each morphotype). Due to the skewness of the distribution of CFU data, the data were transformed using the base 10 logarithm, in an attempt to normalize the data and allow for parametric tests, before calculating changes. To account for zero values, 1 was added to each CFU measurement before being transformed. Any CFU data values where PA was not isolated from a valid culture were set to zero.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). No imputation methods were used for the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Pooled BID/TID) | Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | 0.225 Log10 PA CFUs/gram of sputum | Standard Error 0.209 |
| AZLI (Pooled BID/TID) | Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | -0.434 Log10 PA CFUs/gram of sputum | Standard Error 0.167 |
Comparison: Null hypothesis was there is no difference between 75 mg AZLI and placebo (pooled treatment groups) in mean change from baseline in log10 PA CFUs in sputum.p-value: 0.005995% CI: [-1.125, -0.193]ANCOVA
Secondary
Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score
The CFQ-R was administered at Day -28, baseline, Day 14, Day 28, and Day 84 (end of study). The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms).
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants randomized to tx who received at least part of one dose of study drug). Missing baseline data were not imputed. Missing post-baseline data were imputed using worst-case value for participants who withdrew due to AE or study drug intolerance. For all other missing data, LOCF method was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Pooled BID/TID) | Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score | -0.66 Units on a scale | Standard Error 1.708 |
| AZLI (Pooled BID/TID) | Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score | 4.34 Units on a scale | Standard Error 1.27 |
Comparison: Null hypothesis was there is no difference between 75 mg AZLI and placebo (pooled treatment groups) in change from baseline in CFQ-R RSS scores.p-value: 0.019695% CI: [0.81, 9.21]ANCOVA
Secondary
Number of Hospitalization Days
Details of all hospitalizations, including the dates of admission and discharge, were recorded on the electronic case report form (eCRF).
Time frame: Day 0 to Day 84
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). No imputation methods were used for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Pooled BID/TID) | Number of Hospitalization Days | 0.5 Days | Standard Deviation 2.4 |
| AZLI (Pooled BID/TID) | Number of Hospitalization Days | 0.9 Days | Standard Deviation 3.9 |
Secondary
Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L)
Spirometry was performed at each visit. FEV1 was recorded according to American Thoracic Society (ATS) guidelines. FEV1(L) is the measurement of the volume of air (expressed in liters) exhaled in 1 second. The percent change in this parameter from Day 0 to Day 28 was determined for each 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 study drug). 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 (Pooled BID/TID) | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L) | -2.363 Percent change in FEV1 (L) | Standard Error 1.534 |
| AZLI (Pooled BID/TID) | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L) | 3.917 Percent change in FEV1 (L) | Standard Error 1.151 |
Comparison: Null hypothesis was there is no difference between 75 mg AZLI and placebo (pooled treatment groups) in percent change from baseline in FEV1 (L).p-value: 0.001295% CI: [2.5, 10.06]ANCOVA
Other Pre-specified
Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL)
The aztreonam susceptibility of PA isolates from sputum samples (collected at all visits) was assessed. MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism). MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism). MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis.
Time frame: Day 0 to Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of study drug). No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Baseline MIC50 | 1 μg/mL |
| Placebo (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC50 | 1 μg/mL |
| Placebo (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Baseline MIC90 | 64 μg/mL |
| Placebo (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC90 | 64 μg/mL |
| AZLI (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC90 | 64 μg/mL |
| AZLI (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Baseline MIC50 | 2 μg/mL |
| AZLI (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Baseline MIC90 | 32 μg/mL |
| AZLI (Pooled BID/TID) | Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC50 | 4 μg/mL |
Other Pre-specified
Number of Participants With Other Pathogens
Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Number of participants with other pathogens at baseline and at the end of treatment (28 days) are reported.
Time frame: Day 0 and Day 28
Population: Analysis based on ITT population (all participants who received at least part of one dose of study drug). No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | S. aureus - Day 0 | 23 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | S. aureus - Day 28 | 23 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | B. cepacia - Day 0 | 0 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | B. cepacia - Day 28 | 0 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | S. maltophilia - Day 0 | 9 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | S. maltophilia - Day 28 | 8 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | A. xylosoxidans - Day 0 | 6 Participants |
| Placebo (Pooled BID/TID) | Number of Participants With Other Pathogens | A. xylosoxidans - Day 28 | 6 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | A. xylosoxidans - Day 28 | 7 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | S. aureus - Day 0 | 58 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | S. maltophilia - Day 0 | 18 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | S. aureus - Day 28 | 63 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | A. xylosoxidans - Day 0 | 10 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | B. cepacia - Day 0 | 0 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | S. maltophilia - Day 28 | 19 Participants |
| AZLI (Pooled BID/TID) | Number of Participants With Other Pathogens | B. cepacia - Day 28 | 0 Participants |