AIR-CF4: Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis, Mild Lung Disease, and P. Aeruginosa

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00712166
• Collaborator: (none)
• Enrollment: 160
• Locations: 40
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis; Lung Infection; Pseudomonas Aeruginosa	Drug: AZLI 75 mg three times daily (TID); Drug: Placebo three times daily (TID)	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Multicenter, Multinational, Randomized, Placebo-Controlled Trial Evaluating Aztreonam Lysine For Inhalation in Patients With Cystic Fibrosis, Mild Lung Disease, and P. Aeruginosa (AIR-CF4)
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo three times daily (TID)	Drug: Placebo three times daily (TID)
Experimental: AZLI 75 mg three times daily (TID)	Drug: AZLI 75 mg three times daily (TID)

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

Other Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States
2	University Medical Center	Tucson	Arizona	United States
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States
4	University of Arkansas for Medical Sciences, Division of Pulmonary and Critical Care Medicine	Little Rock	Arkansas	United States
5	Kaiser Permanente	Oakland	California	United States
6	Children's Hospital of Orange County	Orange	California	United States
7	The Children's Hospital	Aurora	Colorado	United States
8	Connecticut Children's Medical Center	Hartford	Connecticut	United States
9	Nemours Children's Clinic	Jacksonville	Florida	United States
10	Nemours Children's Clinic	Orlando	Florida	United States
11	Children's Memorial Hospital	Chicago	Illinois	United States
12	Indiana University, Outpatient Clinical Research Facility	Indianapolis	Indiana	United States
13	James Whitcomb Riley Hospital for Children	Indianapolis	Indiana	United States
14	Children's Hospital, Boston	Boston	Massachusetts	United States
15	Tufts Medical Center, Pediatric Pulmonary Clinic	Boston	Massachusetts	United States
16	University of Michigan Health System	Ann Arbor	Michigan	United States
17	The Children's Hospital of Michigan, Detroit Medical Center	Detroit	Michigan	United States
18	The Minnesota CF Center, University of Minnesota Medical Center	Minneapolis	Minnesota	United States
19	Children's Lung Specialists	Las Vegas	Nevada	United States
20	Albany Medical College	Albany	New York	United States
21	The Lung & Cystic Fibrosis Center, University of Buffalo Pediatric Associates, Inc., Women & Children's Hospital of Buffalo	Buffalo	New York	United States
22	Long Island Jewish Medical Center	New Hyde Park	New York	United States
23	SUNY Upstate Medical University	Syracuse	New York	United States
24	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States
25	Nationwide Children's Hospital	Columbus	Ohio	United States
26	Toledo Children's Hospital/Toledo Hospital, Cystic Fibrosis Research Center	Toledo	Ohio	United States
27	Santiago Reyes, MD	Oklahoma City	Oklahoma	United States
28	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States
29	Drexel University College of Medicine, Pulmonary Associates	Philadelphia	Pennsylvania	United States
30	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States
31	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States
32	Baylor College of Medicine	Houston	Texas	United States
33	Primary Children's Medical Center	Salt Lake City	Utah	United States
34	Children's Hospital and Regional Medical Center	Seattle	Washington	United States
35	Department of Respiratory Medicine, The Children's Hospital at Westmead	Westmead	New South Wales	Australia
36	Department of Respiratory Medicine, Westmead Hospital	Westmead	New South Wales	Australia
37	The Prince Charles Hospital, Adult Cystic Fibrosis Centre	Chermside	Queensland	Australia
38	Respiratory Medicine, Royal Children's Hospital	Herston	Queensland	Australia
39	Child and Adolescent Health Services, Princess Margaret Hospital	Perth	Western Australia	Australia
40	Centre de Recherche du CHUM	Montreal	Quebec	Canada

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Principal Investigator: Claire Wainwright, MD, Royal Children's Hospital, Brisbane, QLD, Australia
• Principal Investigator: Ron Gibson, MD, Children's Hospital & Regional Medical Center, Seattle WA, USA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00712166
• Other Study ID Numbers: GS-US-205-0117
• First Posted: Jul 9, 2008
• Last Update Posted: Dec 20, 2010
• Last Verified: Nov 1, 2010

• Keywords provided by , ,: cystic fibrosis; pseudomonas aeruginosa; lung infection; CFQ-R; inhaled antibiotic; aztreonam lysine
• Additional relevant MeSH terms: Pseudomonas Infections; Cystic Fibrosis; Lung Diseases; Fibrosis

Study Results

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 Detail	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.

Arm/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	81	76
COMPLETED	81	75
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	81	76	157
Age (Count of Participants)
<=18 years	47 58%	42 55.3%	89 56.7%
Between 18 and 65 years	34 42%	34 44.7%	68 43.3%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.9 (9.11)	19.5 (9.07)	19.2 (9.07)
Sex: Female, Male (Count of Participants)
Female	37 45.7%	30 39.5%	67 42.7%
Male	44 54.3%	46 60.5%	90 57.3%
Region of Enrollment (participants) [Number]
United States	73 90.1%	72 94.7%	145 92.4%
Canada	2 2.5%	0 0%	2 1.3%
Australia	6 7.4%	4 5.3%	10 6.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Least Squares Mean (Standard Error) [Units on a scale]	1.41 (1.64)	3.22 (1.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.433
	Comments	The primary endpoint analysis was based on a two-sided test with an 0.05 a priori threshold for statistical significance. A gate-keeper approach was established a priori to control the type 1 error rate, however, the primary endpoint was not met.
	Method	ANCOVA
	Comments	ANCOVA included: treatment, baseline CFQ-R RSS, age group (<18, >=18 years). Denominator degrees of freedom computed with Satterthwaite approximation.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.80
	Confidence Interval	(2-Sided) 95%; -2.83 to 6.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in CFQ-R RSS Score at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Least Squares Mean (Standard Error) [Units on a scale]	0.28 (1.56)	3.65 (1.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.133
	Comments	No adjustments were made for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA included terms: treatment, baseline CFQ-R RSS, age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.37
	Confidence Interval	(2-Sided) 95%; -1.04 to 7.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in CFQ-R RSS Score at Day 42
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Least Squares Mean (Standard Error) [Units on a scale]	2.91 (1.65)	3.02 (1.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.965
	Comments	No adjustments were made for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA model included terms for treatment, baseline CFQ-R RSS and age group (<18 years, >=18 years). Treatment differences calculated as AZLI-placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -4.56 to 4.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in CFQ-R Physical Functioning Domain Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Least Squares Mean (Standard Error) [Units on a scale]	-0.69 (1.53)	1.79 (1.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.256
	Comments	No adjustments were made for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA included: treatment, baseline CFQ-R Physical Function Domain score and age (<18, >=18 years). Treatment differences calculated as AZLI-placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.47
	Confidence Interval	() 95%; -1.81 to 6.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Number [Participants]	21 25.9%	19 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	No adjustments were made for multiple comparisons.
	Method	Fisher Exact
	Comments	A participant with multiple usage was counted only once.

6. Secondary Outcome

Title	Number of Participants Hospitalized During Study
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Number [Study participants]	3 3.7%	8 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in proportion of participants hospitalized.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments	No adjustments were made for multiple comparisons.
	Method	Fisher Exact
	Comments	A participant with multiple hospitalizations was counted only once.

7. Other Pre-specified Outcome

Title	Number of Participants Testing Positive for Other Respiratory Pathogens
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
B. cepacia - Day 0	1 1.2%	0 0%
B. cepacia - Day 28	1 1.2%	1 1.3%
S. maltophilia - Day 0	7 8.6%	8 10.5%
S. maltophilia - Day 28	9 11.1%	8 10.5%
A. xylosoxidans - Day 0	0 0%	1 1.3%
A. xylosoxidans - Day 28	2 2.5%	1 1.3%
MRSA - Day 0	14 17.3%	14 18.4%
MRSA - Day 28	13 16%	13 17.1%
MSSA - Day 0	31 38.3%	28 36.8%
MSSA - Day 28	31 38.3%	25 32.9%
Aspergillus spp. - Day 0	6 7.4%	10 13.2%
Aspergillus spp. - Day 28	6 7.4%	11 14.5%

8. Other Pre-specified Outcome

Title	The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively)
Description	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

Outcome Measure Data

Analysis Population Description

Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo).

Arm/Group Title	Placebo TID	AZLI 75 mg TID
Arm/Group Description	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. Day 0: number of isolates = 104; Day 28: number of isolates = 108	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. Day 0: number of isolates = 104; Day 28: number of isolates = 76
Measure Participants	81	76
Baseline MIC50	1	1
Day 28 MIC50	1	4
Baseline MIC90	16	8
Day 28 MIC90	16	32

9. Secondary Outcome

Title	Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	31	37
Least Squares Mean (Standard Error) [Log10 PA CFUs/gram of sputum]	-0.14 (0.36)	-1.35 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	No adjustments were made for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA model included treatment, baseline log10 CFU, and age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 95%; -2.20 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.	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.
Measure Participants	81	76
Least Squares Mean (Standard Error) [Percent change from baseline]	-2.45 (0.82)	0.29 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Three Times Daily (TID), AZLI 75 mg Three Times Daily (TID)
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	No adjustments were made for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA model includes treatment, baseline FEV1 % predicted, and age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.73
	Confidence Interval	(2-Sided) 95%; 0.42 to 5.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent AEs were collected continuously from the first dose (Day 0) until 14 days after last AZLI/placebo dose (typically Day 42). Participants who discontinued were evaluated for at least 14 days after last dose of study drug.
Adverse Event Reporting Description	An AE was any physical/clinical worsening in symptoms/disease (including clinically significant change in lab values) experienced by participant at any time during study, whether or not event was considered related to study participation or study procedures. Participants were only counted once within a System Organ Class (SOC) and preferred term.
Arm/Group Title	Placebo Three Times Daily (TID)		AZLI 75 mg Three Times Daily (TID)
Arm/Group Description	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.		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.
All Cause Mortality
	Placebo Three Times Daily (TID)		AZLI 75 mg Three Times Daily (TID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Three Times Daily (TID)		AZLI 75 mg Three Times Daily (TID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/81 (3.7%)		9/76 (11.8%)
Gastrointestinal disorders
Abdominal pain	1/81 (1.2%)	1	0/76 (0%)	0
Abdominal pain upper	1/81 (1.2%)	1	0/76 (0%)	0
Gastrooesophageal reflux disease	0/81 (0%)	0	1/76 (1.3%)	1
Melaena	1/81 (1.2%)	1	0/76 (0%)	0
General disorders
Pain	1/81 (1.2%)	1	0/76 (0%)	0
Pyrexia	2/81 (2.5%)	2	1/76 (1.3%)	1
Investigations
Breath sounds abnormal	0/81 (0%)	0	1/76 (1.3%)	1
Pulmonary function test decreased	1/81 (1.2%)	1	1/76 (1.3%)	1
Metabolism and nutrition disorders
Malnutrition	0/81 (0%)	0	1/76 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/81 (1.2%)	1	3/76 (3.9%)	3
Dyspnoea	0/81 (0%)	0	1/76 (1.3%)	1
Haemoptysis	1/81 (1.2%)	1	0/76 (0%)	0
Pseudomonas bronchitis	0/81 (0%)	0	1/76 (1.3%)	1
Sinusitis	0/81 (0%)	0	1/76 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Placebo Three Times Daily (TID)		AZLI 75 mg Three Times Daily (TID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/81 (76.5%)		58/76 (76.3%)
Gastrointestinal disorders
Abdominal pain	9/81 (11.1%)		1/76 (1.3%)
Abdominal pain upper	3/81 (3.7%)		5/76 (6.6%)
Diarrhoea	9/81 (11.1%)		3/76 (3.9%)
Nausea	6/81 (7.4%)		2/76 (2.6%)
General disorders
Fatigue	10/81 (12.3%)		6/76 (7.9%)
Pyrexia	7/81 (8.6%)		5/76 (6.6%)
Investigations
Pulmonary function test decreased	8/81 (9.9%)		6/76 (7.9%)
Metabolism and nutrition disorders
Decreased appetite	0/81 (0%)		6/76 (7.9%)
Musculoskeletal and connective tissue disorders
Chest pain	2/81 (2.5%)		4/76 (5.3%)
Nervous system disorders
Dizziness	1/81 (1.2%)		5/76 (6.6%)
Headache	10/81 (12.3%)		14/76 (18.4%)
Respiratory, thoracic and mediastinal disorders
Chest discomfort	2/81 (2.5%)		6/76 (7.9%)
Cough	30/81 (37%)		32/76 (42.1%)
Dyspnoea	4/81 (4.9%)		7/76 (9.2%)
Nasal congestion	15/81 (18.5%)		13/76 (17.1%)
Oropharyngeal pain	11/81 (13.6%)		12/76 (15.8%)
Pleuritic pain	0/81 (0%)		4/76 (5.3%)
Postnasal drip	7/81 (8.6%)		3/76 (3.9%)
Productive cough	13/81 (16%)		18/76 (23.7%)
Rales	5/81 (6.2%)		7/76 (9.2%)
Respiratory tract congestion	6/81 (7.4%)		11/76 (14.5%)
Rhinitis	4/81 (4.9%)		5/76 (6.6%)
Rhinorrhoea	12/81 (14.8%)		8/76 (10.5%)
Sinus headache	3/81 (3.7%)		5/76 (6.6%)
Sputum discolored	5/81 (6.2%)		3/76 (3.9%)
Wheezing	5/81 (6.2%)		5/76 (6.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 scholarly 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.