Cystic Fibrosis, Pseudomonas Aeruginosa
Conditions
Keywords
Cystic fibrosis, CF, PA, Pseudomonas aeruginosa, AZLI, aztreonam, Chronic Pseudomonas aeruginosa
Brief summary
This was an open-label, multicenter study in children ≤ 12 years of age with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (PA) infection in the lower airways using three 28-day courses of Aztreonam for Inhalation Solution (AZLI) 75 mg three times daily, each followed by 28 days off AZLI. The total treatment duration was to be 6 months.
Interventions
DRUGAZLI
AZLI 75 mg was administered 3 times daily via the investigational nebulizer.
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 12 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria: * Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test OR * Abnormal nasal transepithelial potential difference (NPD) test OR * A genotype with 2 identifiable mutations consistent with CF AND * One or more clinical features consistent with CF. * Documented positive lower respiratory tract culture for PA at the screening visit plus two documented positive lower respiratory tract cultures for PA within 12 months prior to study entry (must have been a minimum 3 months apart.) * Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no chest radiograph findings at screening that would have required administration of IV antipseudomonal antibiotics, oxygen supplementation, or hospitalization.
Exclusion criteria
* Use of IV or inhaled antipseudomonal antibiotics within 14 days of study entry * Presence of a condition or abnormality that would have compromised the participant's safety or the quality of study data, in the opinion of the investigator * History of sputum or throat swab culture yielding Burkholderia spp. within 2 years prior to screening visit * History of hypersensitivity/adverse reaction to aztreonam * History of hypersensitivity/adverse reaction to beta-agonists * History of lung transplantation * Administration of any investigational drug or device within 30 days prior to screening visit or within 6 half-lives of the investigational drug (whichever was longer) * Hospitalization for pulmonary-related illness within 28 days prior to screening visit * Changes in or initiation of chronic azithromycin treatment within 28 days prior to screening visit * Changes in or initiation of hypertonic saline treatment within 7 days prior to screening visit; for subjects on a stable regimen of hypertonic saline (28 days on/28 days off), beginning or ending a cycle of hypertonic saline was allowed * Changes in antimicrobial, bronchodilator (BD), corticosteroid or dornase alfa medications within 7 days prior to screening visit; * Changes in physiotherapy technique or schedule within 7 days prior to screening visit * Abnormal renal or hepatic function results at most recent test within the previous 90 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons | Baseline to Day 168 | Participants who discontinued study drug due to safety or tolerability reasons were defined as those with Adverse Event (AE)/Safety or Tolerability on the Study Drug Completion electronic case report form as the reason for early discontinuation. The 95% confidence interval (CI) was calculated using the exact binomial method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years | Baseline to Day 28, 84, and 140 | The change in FEV1 % predicted was assessed at the end of each 28-day AZLI treatment course. FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition. |
| Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years | Baseline to Day 28, 84, and 140 | The change in CFQ-R RSS score was assessed at the end of each 28-day AZLI treatment course. The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. |
| Change in Pseudomonas Aeruginosa (PA) Sputum Density | Baseline to Day 28, 84, and 140 | The change in PA sputum density (log10 colony-forming units per gram \[cfu/g\]) was assessed at the end of each 28-day AZLI treatment course. |
| Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics | Baseline to Day 168 | The percentage of participants who used additional (non-study) antipseudomonal antibiotics (IV, inhaled, oral, IV/inhaled, IV/inhaled/oral) was summarized (number and percent) for all subjects. |
| Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event | Baseline to Day 168 | — |
| Percentage of Participants With Pulmonary Exacerbations | Baseline to Day 168 | Pulmonary exacerbations were defined as respiratory hospitalizations or discrete courses of non-study IV/inhaled antipseudomonal antibiotics. Use of oral antibiotics alone for respiratory signs or symptoms was considered to be representative of milder clinical events and, therefore, was not included in the definition of pulmonary exacerbations. |
| Time to Pulmonary Exacerbation | Baseline to Day 168 | The median days to first pulmonary exacerbation was summarized using Kaplan-Meier (KM) summary statistics. |
| Percentage of Participants With Study-drug Induced Bronchospasm | Pretreatment at Baseline to 30 minutes following treatment | Study-drug induced bronchospasm (airway reactivity) was assessed at the baseline visit as the percent change in FEV1 from the pretreatment measurement to 30 minutes following treatment for subjects ≥ 6 years or as from the Investigator's assessment for subjects \< 6 years. |
| Adverse Event Rates Adjusted for Study Duration | Baseline to Day 168 | Adverse events occurring in ≥ 5% of participants adjusted for study duration were summarized. The adjustment was made by using a standardized rate calculated as the sum of study duration across patients divided by 28 for the total number of patient months. Rate calculations presented are the number of adverse events (AEs) per patient month. |
| Number of Days Participants Were Hospitalized Due to a Respiratory Event | Baseline to Day 168 | The average number of days hospitalized due to a respiratory event, among the 11 participants who were hospitalized for respiratory event, was reported. |
Countries
France, Germany, Italy, Poland, Spain, United States
Participant flow
Recruitment details
Subjects were enrolled at a total of 25 study sites in the United States and Europe. The first participant was screened on 29 December 2011. The last participant observation was on 03 April 2013.
Pre-assignment details
74 participants were screened; 61 participants were enrolled and treated, and comprise the Safety Analysis Set and the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| AZLI Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer. | 61 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | AZLI |
|---|---|
| Age, Continuous | 9.0 years STANDARD_DEVIATION 2.94 |
| Age, Customized < 2 years | 2 participants |
| Age, Customized ≥ 2 years to < 6 years | 7 participants |
| Age, Customized ≥ 6 years to ≤ 12 years | 52 participants |
| Body Mass Index (BMI) | 16.3 kg/m^2 STANDARD_DEVIATION 1.66 |
| CFQ-R RSS Score | 71.73 units on a scale STANDARD_DEVIATION 17.327 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| FEV1 | 1.67 liters STANDARD_DEVIATION 0.627 |
| FEV25-75 | 1.82 liters/sec STANDARD_DEVIATION 1.169 |
| Forced expiratory volume in 1 second (FEV1) % predicted | 80.31 percentage of FEV1 % predicted STANDARD_DEVIATION 19.494 |
| Forced vital capacity (FVC) | 2.11 liters STANDARD_DEVIATION 0.687 |
| Presence of Pseudomonas aeruginosa (PA) Absent | 3 participants |
| Presence of Pseudomonas aeruginosa (PA) Present | 58 participants |
| Race/Ethnicity, Customized Black or African Heritage | 2 participants |
| Race/Ethnicity, Customized Not Permitted | 1 participants |
| Race/Ethnicity, Customized Other | 3 participants |
| Race/Ethnicity, Customized White | 55 participants |
| Region of Enrollment France | 5 participants |
| Region of Enrollment Germany | 5 participants |
| Region of Enrollment Italy | 6 participants |
| Region of Enrollment Poland | 11 participants |
| Region of Enrollment Spain | 5 participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 50 / 61 |
| serious Total, serious adverse events | 13 / 61 |
Outcome results
Primary
Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons
Participants who discontinued study drug due to safety or tolerability reasons were defined as those with Adverse Event (AE)/Safety or Tolerability on the Study Drug Completion electronic case report form as the reason for early discontinuation. The 95% confidence interval (CI) was calculated using the exact binomial method.
Time frame: Baseline to Day 168
Population: Participants in the Full Analysis Set (enrolled and received at least 1 dose of study medication) who completed the study or discontinued study drug due to safety or tolerability reasons were analyzed. Two participants voluntarily withdrew from the study prior to completion (not due to AEs/safety or tolerability reasons).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI | Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons | 0.0 percentage of participants |
Secondary
Adverse Event Rates Adjusted for Study Duration
Adverse events occurring in ≥ 5% of participants adjusted for study duration were summarized. The adjustment was made by using a standardized rate calculated as the sum of study duration across patients divided by 28 for the total number of patient months. Rate calculations presented are the number of adverse events (AEs) per patient month.
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZLI | Adverse Event Rates Adjusted for Study Duration | Forced expiratory volume decreased | 0.011 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Decreased appetite | 0.017 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Cough | 0.163 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Nasal congestion | 0.050 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Rhinorrhoea | 0.041 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Wheezing | 0.033 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Sputum increased | 0.033 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Productive Cough | 0.030 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Lung disorder | 0.025 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Haemoptysis | 0.019 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Rhonchi | 0.019 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Oropharyngeal pain | 0.017 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Rales | 0.017 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Respiratory tract congestion | 0.014 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Abdominal pain | 0.030 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Diarrhoea | 0.019 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Vomiting | 0.019 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Abdominal pain upper | 0.017 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Pyrexia | 0.061 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Fatigue | 0.025 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Rhinitis | 0.030 AEs (per patient month) |
| AZLI | Adverse Event Rates Adjusted for Study Duration | Pulmonary function test decreased | 0.014 AEs (per patient month) |
Secondary
Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years
The change in CFQ-R RSS score was assessed at the end of each 28-day AZLI treatment course. The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms.
Time frame: Baseline to Day 28, 84, and 140
Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZLI | Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years | Change at Day 28 (on-treatment, n = 51) | 8.66 units on a scale | Standard Deviation 14.903 |
| AZLI | Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years | Change at Day 84 (on-treatment, n = 48) | 9.38 units on a scale | Standard Deviation 18.243 |
| AZLI | Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years | Change at Day 140 (on-treatment, n = 48) | 5.90 units on a scale | Standard Deviation 15.372 |
Secondary
Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years
The change in FEV1 % predicted was assessed at the end of each 28-day AZLI treatment course. FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition.
Time frame: Baseline to Day 28, 84, and 140
Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZLI | Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years | Change at Day 28 (on-treatment, n = 52) | 4.73 percentage of FEV1 % predicted | Standard Deviation 11.703 |
| AZLI | Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years | Change at Day 84 (on-treatment, n = 51) | 1.72 percentage of FEV1 % predicted | Standard Deviation 12.516 |
| AZLI | Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years | Change at Day 140 (on-treatment, n = 50) | 1.65 percentage of FEV1 % predicted | Standard Deviation 10.34 |
Secondary
Change in Pseudomonas Aeruginosa (PA) Sputum Density
The change in PA sputum density (log10 colony-forming units per gram \[cfu/g\]) was assessed at the end of each 28-day AZLI treatment course.
Time frame: Baseline to Day 28, 84, and 140
Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZLI | Change in Pseudomonas Aeruginosa (PA) Sputum Density | Change at Day 28 (on-treatment, n = 24) | -2.6 log10 CFU/g | Standard Deviation 2.5 |
| AZLI | Change in Pseudomonas Aeruginosa (PA) Sputum Density | Change at Day 84 (on-treatment, n = 25) | -2.0 log10 CFU/g | Standard Deviation 2.14 |
| AZLI | Change in Pseudomonas Aeruginosa (PA) Sputum Density | Change at Day 140 (on-treatment, n = 23) | -1.2 log10 CFU/g | Standard Deviation 2.13 |
Secondary
Number of Days Participants Were Hospitalized Due to a Respiratory Event
The average number of days hospitalized due to a respiratory event, among the 11 participants who were hospitalized for respiratory event, was reported.
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Number of Days Participants Were Hospitalized Due to a Respiratory Event | 12.6 days | Standard Deviation 8.9 |
Secondary
Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZLI | Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event | Never hospitalized | 82.0 percentage of participants |
| AZLI | Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event | Hospitalized at least once | 18.0 percentage of participants |
Secondary
Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics
The percentage of participants who used additional (non-study) antipseudomonal antibiotics (IV, inhaled, oral, IV/inhaled, IV/inhaled/oral) was summarized (number and percent) for all subjects.
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZLI | Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics | Never used non-study antipseudomonal antibiotics | 42.6 percentage of participants |
| AZLI | Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics | Used non-study antipseudomonal antibiotics | 57.4 percentage of participants |
Secondary
Percentage of Participants With Pulmonary Exacerbations
Pulmonary exacerbations were defined as respiratory hospitalizations or discrete courses of non-study IV/inhaled antipseudomonal antibiotics. Use of oral antibiotics alone for respiratory signs or symptoms was considered to be representative of milder clinical events and, therefore, was not included in the definition of pulmonary exacerbations.
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZLI | Percentage of Participants With Pulmonary Exacerbations | At least one pulmonary exacerbation | 37.7 percentage of participants |
| AZLI | Percentage of Participants With Pulmonary Exacerbations | No pulmonary exacerbation | 62.3 percentage of participants |
Secondary
Percentage of Participants With Study-drug Induced Bronchospasm
Study-drug induced bronchospasm (airway reactivity) was assessed at the baseline visit as the percent change in FEV1 from the pretreatment measurement to 30 minutes following treatment for subjects ≥ 6 years or as from the Investigator's assessment for subjects \< 6 years.
Time frame: Pretreatment at Baseline to 30 minutes following treatment
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| AZLI | Percentage of Participants With Study-drug Induced Bronchospasm | 3.3 percentage of participants | 6.06 |
Secondary
Time to Pulmonary Exacerbation
The median days to first pulmonary exacerbation was summarized using Kaplan-Meier (KM) summary statistics.
Time frame: Baseline to Day 168
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI | Time to Pulmonary Exacerbation | 176.0 days |