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 a 28-day course of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).
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 TID using the PARI eFlow® electronic nebulizer, in CF patients with PA. In this study, participant eligibility was assessed at a screening visit 7 to 14 days prior to the baseline visit (Day 0). Those participants who continued to meet eligibility criteria at Day 0 were randomized and began a 28-day course of blinded study treatment (AZLI TID 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 study drug (Day 42).
Interventions
DRUGAZLI 75 mg three times a day (TID)
DRUGPlacebo 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
* 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 greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT); * Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or * Abnormal nasal potential difference. * PA present in expectorated sputum or throat swab culture at Screening. * FEV1 between (and including) 25% and 75% predicted at Screening. * Negative pregnancy test at Screening. * Ability to perform reproducible pulmonary function tests. * Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening. * Ability to provide written informed consent.
Exclusion criteria
* Administration of antipseudomonal antibiotics by inhalation, IV, or oral routes (including azithromycin) within 14 days of Screening. * Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day. * History of sputum or throat swab culture yielding Burkholderia cepacia in the previous 2 years. * History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night. * Administration of any investigational drug or use of any investigational device within 28 days of Screening and within 6 half-lives of the investigational drug (whichever was longer). * Known local or systemic hypersensitivity to monobactam antibiotics. * Inability to tolerate short-acting bronchodilator use at least three times daily. * Changes in protocol-permitted antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days prior to Screening or between Screening and the next visit. * Changes in physiotherapy technique or schedule within 7 days prior to 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 at Screening. * 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. * Use of aerosolized hypertonic saline (except for sputum induction) during the 14 days preceding Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in CFQ-R Respiratory Symptoms Scale (RSS) Score | Day 0 to Day 28 | The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R respiratory symptoms scale (RSS; range of scores: 0-100; higher scores indicate fewer symptoms). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CFQ-R RSS Score | Day 0 to Day 14 | The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms). |
| Percent Change in FEV1 (L) | Day 0 to Day 28 | Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. The percent change from baseline in forced expiratory volume (liters) in one second (FEV1) was determined at Day 28. |
| 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. |
| Number of Participants Receiving Intravenous (IV) or Inhaled Antipseudomonal Antibiotics Other Than Trial Drug | Day 0 to Day 42 | Use of IV and inhaled antipseudomonal antibiotics was compiled from data recorded on the Concomitant Medications eCRF. |
| Number of Participants Hospitalized at Least Once Between Day 0 and Day 42 | Day 0 to Day 42 | Details of all hospitalizations, including the dates of admission and discharge, were recorded on the SAE eCRF. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Other Pathogens Present | Day 0 to Day 28 | Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans. |
| Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 | PA isolates from sputum samples (collected at all visits) were assessed for their susceptibility to aztreonam. 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
Australia, Canada, New Zealand, United States
Participant flow
Recruitment details
Phase 3, double-blind, multicenter, multinational, randomized, placebo-controlled trial evaluating AZLI in patients with CF and PA. Participants were enrolled at 53 sites total: 40 in United States, 5 in Canada, 7 in Australia, and 1 in New Zealand. Date of first enrollment was 10 Jun 2005, and date of last participant follow-up was 3 Apr 2007.
Pre-assignment details
Planned study size was 140 participants to be randomized in a 1:1 ratio to AZLI or placebo TID, with 166 actually randomized (83 AZLI, 83 placebo). However, two participants did not receive a dose of drug, and one participant randomized to receive AZLI received placebo in error. Thus, 80 participants received AZLI and 84 received placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 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 three times a day by inhalation using the investigational nebulizer. | 84 |
| 75 mg AZLI 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 three times a day using the investigational nebulizer. | 80 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 3 | 0 |
| Overall Study | Personal/administrative | 1 | 1 |
| Overall Study | Related adverse event | 5 | 3 |
| Overall Study | Trial drug intolerance (adverse event) | 2 | 0 |
| Overall Study | Unrelated adverse event | 16 | 8 |
Baseline characteristics
| Characteristic | Placebo TID | 75 mg AZLI TID | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 21 Participants | 37 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 66 Participants | 59 Participants | 125 Participants |
| Age Continuous | 31.7 years STANDARD_DEVIATION 14.8 | 27.4 years STANDARD_DEVIATION 12.8 | 29.6 years STANDARD_DEVIATION 14 |
| Disease severity based on forced expiratory volume in 1 second (FEV1) % predicted Disease severity: FEV1 <= 50% predicted | 30 participants | 30 participants | 60 participants |
| Disease severity based on forced expiratory volume in 1 second (FEV1) % predicted Disease severity: FEV1 > 50% predicted | 54 participants | 50 participants | 104 participants |
| Region of Enrollment Australia | 21 participants | 18 participants | 39 participants |
| Region of Enrollment North America | 63 participants | 62 participants | 125 participants |
| Sex: Female, Male Female | 39 Participants | 32 Participants | 71 Participants |
| Sex: Female, Male Male | 45 Participants | 48 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 84 | 63 / 80 |
| serious Total, serious adverse events | 12 / 84 | 5 / 80 |
Outcome results
Primary
Change in CFQ-R Respiratory Symptoms Scale (RSS) Score
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R respiratory symptoms scale (RSS; range of scores: 0-100; higher scores indicate fewer symptoms).
Time frame: Day 0 to Day 28
Population: ITT population: participants randomized to treatment who received at least part of 1 dose of study drug. Participants summarized by actual treatment received. Missing baseline data not imputed. Missing post-baseline data imputed using worst-case value for withdrawals due to AE or study drug intolerance. All other missing data: LOCF method used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo TID | Change in CFQ-R Respiratory Symptoms Scale (RSS) Score | -2.63 units on a scale | Standard Error 1.95 |
| 75 mg AZLI TID | Change in CFQ-R Respiratory Symptoms Scale (RSS) Score | 7.08 units on a scale | Standard Error 1.98 |
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.~A sample size of 70 participants per treatment group provided approximately 77% power to detect an 8-point difference in CFQ-R RSS score between treatment groups, assuming a standard deviation (SD) of 20 and a Type I error rate of 0.05.p-value: 0.000595% CI: [4.31, 15.11]ANCOVA
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 1 dose of study drug). Participants were summarized by the actual treatment received. No imputation methods were used for the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo TID | Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | 0.069 Log10 PA CFUs/gram of sputum | Standard Error 0.231 |
| 75 mg AZLI TID | Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | -1.384 Log10 PA CFUs/gram of sputum | Standard Error 0.247 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in change in log10 PA CFUs in sputum at Day 28.p-value: <0.000195% CI: [-2.115, -0.791]ANCOVA
Secondary
Change in CFQ-R RSS Score
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms).
Time frame: Day 0 to Day 14
Population: ITT population: participants randomized to treatment who received at least part of 1 dose of study drug. Participants summarized by actual treatment received. Missing baseline data not imputed. Missing post-baseline data imputed using worst-case value for withdrawals due to AE or study drug intolerance. All other missing data: LOCF method used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo TID | Change in CFQ-R RSS Score | 0.976 units on a scale | Standard Error 1.624 |
| 75 mg AZLI TID | Change in CFQ-R RSS Score | 7.007 units on a scale | Standard Error 1.647 |
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 14.p-value: 0.000695% CI: [3.5, 12.47]ANCOVA
Secondary
Change in CFQ-R RSS Score
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms).
Time frame: Day 0 to Day 42
Population: ITT population: participants randomized to treatment who received at least part of 1 dose of study drug. Participants summarized by actual treatment received. Missing baseline data not imputed. Missing post-baseline data imputed using worst-case value for withdrawals due to AE or study drug intolerance. All other missing data: LOCF method used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo TID | Change in CFQ-R RSS Score | -5.711 units on a scale | Standard Error 1.849 |
| 75 mg AZLI TID | Change in CFQ-R RSS Score | 0.618 units on a scale | Standard Error 1.875 |
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 42.p-value: 0.015495% CI: [1.22, 11.43]ANCOVA
Secondary
Number of Participants Hospitalized at Least Once Between Day 0 and Day 42
Details of all hospitalizations, including the dates of admission and discharge, were recorded on the SAE eCRF.
Time frame: Day 0 to Day 42
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Participants were summarized by the actual treatment received. No imputation methods were used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo TID | Number of Participants Hospitalized at Least Once Between Day 0 and Day 42 | 12 participants |
| 75 mg AZLI TID | Number of Participants Hospitalized at Least Once Between Day 0 and Day 42 | 4 participants |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in number of participants hospitalized at least once during the study.p-value: 0.064Fisher Exact
Secondary
Number of Participants Receiving Intravenous (IV) or Inhaled Antipseudomonal Antibiotics Other Than Trial Drug
Use of IV and inhaled antipseudomonal antibiotics was compiled from data recorded on the Concomitant Medications eCRF.
Time frame: Day 0 to Day 42
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Participants were summarized by the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo TID | Number of Participants Receiving Intravenous (IV) or Inhaled Antipseudomonal Antibiotics Other Than Trial Drug | 19 participants |
| 75 mg AZLI TID | Number of Participants Receiving Intravenous (IV) or Inhaled Antipseudomonal Antibiotics Other Than Trial Drug | 12 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: 0.2364Fisher Exact
Secondary
Percent Change in FEV1 (L)
Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. The percent change from baseline in forced expiratory volume (liters) in one second (FEV1) was determined at Day 28.
Time frame: Day 0 to Day 28
Population: ITT population: participants randomized to treatment who received at least part of 1 dose of study drug. Participants summarized by actual treatment received. Missing baseline data not imputed. Missing post-baseline data imputed using worst-case value for withdrawals due to AE or study drug intolerance. All other missing data: LOCF method used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo TID | Percent Change in FEV1 (L) | -2.408 Percent change in FEV1 (L) | Standard Error 1.466 |
| 75 mg AZLI TID | Percent Change in FEV1 (L) | 7.886 Percent change in FEV1 (L) | Standard Error 1.481 |
Comparison: Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in percent change in FEV1 at Day 28.p-value: <0.000195% CI: [6.288, 14.299]ANCOVA
Other Pre-specified
Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL)
PA isolates from sputum samples (collected at all visits) were assessed for their susceptibility to aztreonam. 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 28
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Participants were summarized by the actual treatment received. No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC50 | 2 μg/mL |
| Placebo TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC90 | 64 μg/mL |
| 75 mg AZLI TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC50 | 8 μg/mL |
| 75 mg AZLI TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 28 MIC90 | 128 μg/mL |
Other Pre-specified
Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL)
PA isolates from sputum samples (collected at all visits) were assessed for their susceptibility to aztreonam. 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
Population: Analysis based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Participants were summarized by the actual treatment received. No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 MIC50 | 2 μg/mL |
| Placebo TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 MIC90 | 64 μg/mL |
| 75 mg AZLI TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 MIC50 | 4 μg/mL |
| 75 mg AZLI TID | Minimum Inhibitory Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL) | Day 0 MIC90 | 128 μg/mL |
Other Pre-specified
Number of Participants With Other Pathogens Present
Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans.
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). Participants were summarized by the actual treatment received. No imputation methods were used for the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo TID | Number of Participants With Other Pathogens Present | Staphylococcus aureus - Day 0 | 30 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Burkholderia cepacia - Day 0 | 0 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Stenotrophomonas maltophilia - Day 28 | 2 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Staphylococcus aureus - Day 28 | 31 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Achromobacter xylosoxidans - Day 0 | 5 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Burkholderia cepacia - Day 28 | 0 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Achromobacter xylosoxidans - Day 28 | 7 participants |
| Placebo TID | Number of Participants With Other Pathogens Present | Stenotrophomonas maltophilia - Day 0 | 4 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Achromobacter xylosoxidans - Day 28 | 1 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Staphylococcus aureus - Day 0 | 37 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Staphylococcus aureus - Day 28 | 35 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Burkholderia cepacia - Day 0 | 1 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Burkholderia cepacia - Day 28 | 0 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Stenotrophomonas maltophilia - Day 0 | 1 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Stenotrophomonas maltophilia - Day 28 | 2 participants |
| 75 mg AZLI TID | Number of Participants With Other Pathogens Present | Achromobacter xylosoxidans - Day 0 | 1 participants |