Trial Outcomes & Findings for Safety of AZLI in Children With Cystic Fibrosis (CF) and Chronic Pseudomonas Aeruginosa in the Lower Airways (NCT NCT01404234)

Last Updated: 2014-05-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

61 participants

Primary outcome timeframe

Baseline to Day 168

Results posted on

2014-05-29

Participant Flow

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.

74 participants were screened; 61 participants were enrolled and treated, and comprise the Safety Analysis Set and the Full Analysis Set.

Participant milestones

Participant milestones
Measure	AZLI Participants received three 28-day courses of Aztreonam for Inhalation Solution (AZLI), each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.
Overall Study STARTED	61
Overall Study COMPLETED	59
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	AZLI Participants received three 28-day courses of Aztreonam for Inhalation Solution (AZLI), each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.
Overall Study Withdrawal by Subject	2

Baseline Characteristics

Safety of AZLI in Children With Cystic Fibrosis (CF) and Chronic Pseudomonas Aeruginosa in the Lower Airways

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AZLI n=61 Participants 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.
Age, Continuous	9.0 years STANDARD_DEVIATION 2.94 • n=5 Participants
Age, Customized < 2 years	2 participants n=5 Participants
Age, Customized ≥ 2 years to < 6 years	7 participants n=5 Participants
Age, Customized ≥ 6 years to ≤ 12 years	52 participants n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants
Sex: Female, Male Male	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African Heritage	2 participants n=5 Participants
Race/Ethnicity, Customized White	55 participants n=5 Participants
Race/Ethnicity, Customized Other	3 participants n=5 Participants
Race/Ethnicity, Customized Not Permitted	1 participants n=5 Participants
Region of Enrollment France	5 participants n=5 Participants
Region of Enrollment United States	29 participants n=5 Participants
Region of Enrollment Spain	5 participants n=5 Participants
Region of Enrollment Poland	11 participants n=5 Participants
Region of Enrollment Germany	5 participants n=5 Participants
Region of Enrollment Italy	6 participants n=5 Participants
Body Mass Index (BMI)	16.3 kg/m^2 STANDARD_DEVIATION 1.66 • n=5 Participants
Forced expiratory volume in 1 second (FEV1) % predicted	80.31 percentage of FEV1 % predicted STANDARD_DEVIATION 19.494 • n=5 Participants
FEV1	1.67 liters STANDARD_DEVIATION 0.627 • n=5 Participants
Forced vital capacity (FVC)	2.11 liters STANDARD_DEVIATION 0.687 • n=5 Participants
FEV25-75	1.82 liters/sec STANDARD_DEVIATION 1.169 • n=5 Participants
CFQ-R RSS Score	71.73 units on a scale STANDARD_DEVIATION 17.327 • n=5 Participants
Presence of Pseudomonas aeruginosa (PA) Present	58 participants n=5 Participants
Presence of Pseudomonas aeruginosa (PA) Absent	3 participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	AZLI n=59 Participants 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.
Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons	0.0 percentage of participants Interval 0.0 to 6.1

SECONDARY outcome

Timeframe: Baseline to Day 28, 84, and 140

Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.

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.

Outcome measures

Outcome measures
Measure	AZLI n=52 Participants 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.
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
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
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 10.340

SECONDARY outcome

Timeframe: Baseline to Day 28, 84, and 140

Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.

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.

Outcome measures

Outcome measures
Measure	AZLI n=52 Participants 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.
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
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
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 outcome

Timeframe: Baseline to Day 28, 84, and 140

Population: Participants in the Full Analysis Set ≥ 6 years of age were analyzed.

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.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Change in Pseudomonas Aeruginosa (PA) Sputum Density Change at Day 28 (on-treatment, n = 24)	-2.6 log10 CFU/g Standard Deviation 2.50
Change in Pseudomonas Aeruginosa (PA) Sputum Density Change at Day 84 (on-treatment, n = 25)	-2.0 log10 CFU/g Standard Deviation 2.14
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 outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

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.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics Never used non-study antipseudomonal antibiotics	42.6 percentage of participants
Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics Used non-study antipseudomonal antibiotics	57.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event Never hospitalized	82.0 percentage of participants
Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event Hospitalized at least once	18.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

The average number of days hospitalized due to a respiratory event, among the 11 participants who were hospitalized for respiratory event, was reported.

Outcome measures

Outcome measures
Measure	AZLI n=11 Participants 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.
Number of Days Participants Were Hospitalized Due to a Respiratory Event	12.6 days Standard Deviation 8.90

SECONDARY outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

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.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Percentage of Participants With Pulmonary Exacerbations No pulmonary exacerbation	62.3 percentage of participants
Percentage of Participants With Pulmonary Exacerbations At least one pulmonary exacerbation	37.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

The median days to first pulmonary exacerbation was summarized using Kaplan-Meier (KM) summary statistics.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Time to Pulmonary Exacerbation	176.0 days Interval 176.0 to Some participants did not use non-study antipseudomonal antibiotics until the end of the study, so time to non-study antipseudomonal antibiotic use was unknown. Therefore, the upper limit of the 95% CI for median time could not be estimated.

SECONDARY outcome

Timeframe: Pretreatment at Baseline to 30 minutes following treatment

Population: Full Analysis Set

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.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Percentage of Participants With Study-drug Induced Bronchospasm	3.3 percentage of participants 6.06

SECONDARY outcome

Timeframe: Baseline to Day 168

Population: Full Analysis Set

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.

Outcome measures

Outcome measures
Measure	AZLI n=61 Participants 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.
Adverse Event Rates Adjusted for Study Duration Rhinorrhoea	0.041 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Wheezing	0.033 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Sputum increased	0.033 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Productive Cough	0.030 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Lung disorder	0.025 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Haemoptysis	0.019 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Rhonchi	0.019 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Oropharyngeal pain	0.017 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Respiratory tract congestion	0.014 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Diarrhoea	0.019 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Vomiting	0.019 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Decreased appetite	0.017 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Cough	0.163 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Nasal congestion	0.050 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Rales	0.017 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Abdominal pain	0.030 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Abdominal pain upper	0.017 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Pyrexia	0.061 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Fatigue	0.025 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Rhinitis	0.030 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Pulmonary function test decreased	0.014 AEs (per patient month)
Adverse Event Rates Adjusted for Study Duration Forced expiratory volume decreased	0.011 AEs (per patient month)

Adverse Events

AZLI

Serious events: 13 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	AZLI n=61 participants at risk 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.
Gastrointestinal disorders Appendiceal mucocoele	1.6% 1/61 • Baseline to Day 168
Gastrointestinal disorders Nausea	1.6% 1/61 • Baseline to Day 168
Infections and infestations Gastrointestinal infection	1.6% 1/61 • Baseline to Day 168
Infections and infestations Bronchopneumonia	3.3% 2/61 • Baseline to Day 168
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	3.3% 2/61 • Baseline to Day 168
Metabolism and nutrition disorders Hypoglycaemia	1.6% 1/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Lung disorder	8.2% 5/61 • Baseline to Day 168

Other adverse events

Other adverse events
Measure	AZLI n=61 participants at risk 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.
Gastrointestinal disorders Diarrhoea	11.5% 7/61 • Baseline to Day 168
Gastrointestinal disorders Abdominal pain	9.8% 6/61 • Baseline to Day 168
Gastrointestinal disorders Abdominal pain upper	8.2% 5/61 • Baseline to Day 168
Gastrointestinal disorders Vomiting	9.8% 6/61 • Baseline to Day 168
General disorders Fatigue	13.1% 8/61 • Baseline to Day 168
General disorders Pyrexia	26.2% 16/61 • Baseline to Day 168
Infections and infestations Rhinitis	16.4% 10/61 • Baseline to Day 168
Investigations Pulmonary function test decreased	8.2% 5/61 • Baseline to Day 168
Investigations Forced expiratory volume decreased	6.6% 4/61 • Baseline to Day 168
Metabolism and nutrition disorders Decreased appetite	8.2% 5/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Wheezing	14.8% 9/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Cough	59.0% 36/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Sputum increased	14.8% 9/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Productive cough	13.1% 8/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Haemoptysis	9.8% 6/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Rhonchi	9.8% 6/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Rales	8.2% 5/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Nasal congestion	19.7% 12/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	8.2% 5/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	16.4% 10/61 • Baseline to Day 168
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	9.8% 6/61 • Baseline to Day 168

Additional Information

Clinical Trial Disclosures

Gilead Sciences, Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER