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

This study has been completed.

Sponsor:

Information provided by:

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00712166

First received: July 7, 2008

Last updated: November 19, 2010

Last verified: November 2010

History of Changes

Results First Received: September 10, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Cystic Fibrosis Lung Infection Pseudomonas Aeruginosa
Interventions:	Drug: AZLI 75 mg three times daily (TID) Drug: Placebo three times daily (TID)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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 Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Participant Flow: Overall Study

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
STARTED	81	76
COMPLETED	81	75
NOT COMPLETED	0	1
Noncompliance	0	1

Baseline Characteristics

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Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.
Total	Total of all reporting groups

Baseline Measures

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)	Total
Number of Participants [units: participants]	81	76	157
Age [units: participants]
<=18 years	47	42	89
Between 18 and 65 years	34	34	68
>=65 years	0	0	0
Age [units: years] Mean ± Standard Deviation	18.9 ± 9.11	19.5 ± 9.07	19.2 ± 9.07
Gender [units: participants]
Female	37	30	67
Male	44	46	90
Region of Enrollment [units: participants]
United States	73	72	145
Canada	2	0	2
Australia	6	4	10

Outcome Measures

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1. Primary:

Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 [ Time Frame: Day 0 to Day 28 ]

Measure Type	Primary
Measure Title	Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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).

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 [units: Units on a scale] Least Squares Mean ± Standard Error	1.41 ± 1.64	3.22 ± 1.71

Statistical Analysis 1 for Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.433
Mean Difference (Final Values) ^[4]	1.80
95% Confidence Interval	( -2.83 to 6.44 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA included: treatment, baseline CFQ-R RSS, age group (<18, >=18 years). Denominator degrees of freedom computed with Satterthwaite approximation.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	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.
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

Change From Baseline in CFQ-R RSS Score at Day 14 [ Time Frame: Day 0 to Day 14 ]

Measure Type	Secondary
Measure Title	Change From Baseline in CFQ-R RSS Score at Day 14
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Change From Baseline in CFQ-R RSS Score at Day 14 [units: Units on a scale] Least Squares Mean ± Standard Error	0.28 ± 1.56	3.65 ± 1.63

Statistical Analysis 1 for Change From Baseline in CFQ-R RSS Score at Day 14

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.133
Mean Difference (Final Values) ^[4]	3.37
95% Confidence Interval	( -1.04 to 7.78 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA included terms: treatment, baseline CFQ-R RSS, age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.
[4]	Other relevant estimation information:
	No text entered.

3. Secondary:

Change From Baseline in CFQ-R RSS Score at Day 42 [ Time Frame: Day 0 to Day 42 ]

Measure Type	Secondary
Measure Title	Change From Baseline in CFQ-R RSS Score at Day 42
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Change From Baseline in CFQ-R RSS Score at Day 42 [units: Units on a scale] Least Squares Mean ± Standard Error	2.91 ± 1.65	3.02 ± 1.72

Statistical Analysis 1 for Change From Baseline in CFQ-R RSS Score at Day 42

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.965
Mean Difference (Final Values) ^[4]	0.10
95% Confidence Interval	( -4.56 to 4.76 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA model included terms for treatment, baseline CFQ-R RSS and age group (<18 years, >=18 years). Treatment differences calculated as AZLI-placebo.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.
[4]	Other relevant estimation information:
	No text entered.

4. Secondary:

Change From Baseline in CFQ-R Physical Functioning Domain Score [ Time Frame: Day 0 to Day 28 ]

Measure Type	Secondary
Measure Title	Change From Baseline in CFQ-R Physical Functioning Domain Score
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Change From Baseline in CFQ-R Physical Functioning Domain Score [units: Units on a scale] Least Squares Mean ± Standard Error	-0.69 ± 1.53	1.79 ± 1.57

Statistical Analysis 1 for Change From Baseline in CFQ-R Physical Functioning Domain Score

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.256
Mean Difference (Final Values) ^[4]	2.47
95% Confidence Interval	( -1.81 to 6.76 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA included: treatment, baseline CFQ-R Physical Function Domain score and age (<18, >=18 years). Treatment differences calculated as AZLI-placebo.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.
[4]	Other relevant estimation information:
	No text entered.

5. Secondary:

Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study [ Time Frame: Day 0 to Day 42 ]

Measure Type	Secondary
Measure Title	Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study [units: Participants]	21	19

Statistical Analysis 1 for Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study

Groups ^[1]	All groups
Method ^[2]	Fisher Exact
P Value ^[3]	>0.999

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	A participant with multiple usage was counted only once.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.

6. Secondary:

Number of Participants Hospitalized During Study [ Time Frame: Day 0 to Day 42 ]

Measure Type	Secondary
Measure Title	Number of Participants Hospitalized During Study
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Number of Participants Hospitalized During Study [units: Study participants]	3	8

Statistical Analysis 1 for Number of Participants Hospitalized During Study

Groups ^[1]	All groups
Method ^[2]	Fisher Exact
P Value ^[3]	0.122

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in proportion of participants hospitalized.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	A participant with multiple hospitalizations was counted only once.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.

7. Secondary:

Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28 [ Time Frame: Day 0 to Day 28 ]

Measure Type	Secondary
Measure Title	Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	31	37
Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28 [units: Log10 PA CFUs/gram of sputum] Least Squares Mean ± Standard Error	-0.14 ± 0.36	-1.35 ± 0.36

Statistical Analysis 1 for Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.016
Mean Difference (Final Values) ^[4]	-1.21
95% Confidence Interval	( -2.20 to -0.23 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA model included treatment, baseline log10 CFU, and age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.
[4]	Other relevant estimation information:
	No text entered.

8. Secondary:

Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted [ Time Frame: Day 0 to Day 28 ]

Measure Type	Secondary
Measure Title	Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted [units: Percent change from baseline] Least Squares Mean ± Standard Error	-2.45 ± 0.82	0.29 ± 0.85

Statistical Analysis 1 for Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.021
Mean Difference (Final Values) ^[4]	2.73
95% Confidence Interval	( 0.42 to 5.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	ANCOVA model includes treatment, baseline FEV1 % predicted, and age group (<18, >=18 years). Treatment differences were calculated as AZLI-placebo.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustments were made for multiple comparisons.
[4]	Other relevant estimation information:
	No text entered.

9. Other Pre-specified:

Number of Participants Testing Positive for Other Respiratory Pathogens [ Time Frame: Day 0 to Day 28 ]

Measure Type	Other Pre-specified
Measure Title	Number of Participants Testing Positive for Other Respiratory Pathogens
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo Three Times Daily (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 TID by inhalation using the investigational nebulizer.
AZLI 75 mg Three Times Daily (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 TID using the investigational nebulizer.

Measured Values

	Placebo Three Times Daily (TID)	AZLI 75 mg Three Times Daily (TID)
Number of Participants Analyzed [units: participants]	81	76
Number of Participants Testing Positive for Other Respiratory Pathogens [units: Participants]
B. cepacia - Day 0	1	0
B. cepacia - Day 28	1	1
S. maltophilia - Day 0	7	8
S. maltophilia - Day 28	9	8
A. xylosoxidans - Day 0	0	1
A. xylosoxidans - Day 28	2	1
MRSA - Day 0	14	14
MRSA - Day 28	13	13
MSSA - Day 0	31	28
MSSA - Day 28	31	25
Aspergillus spp. - Day 0	6	10
Aspergillus spp. - Day 28	6	11

No statistical analysis provided for Number of Participants Testing Positive for Other Respiratory Pathogens

10. Other Pre-specified:

The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) [ Time Frame: Day 0 to Day 28 ]

Measure Type	Other Pre-specified
Measure Title	The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively)
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo).

Reporting Groups

Description

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 TID by inhalation using the investigational nebulizer.

Day 0: number of isolates = 104; Day 28: number of isolates = 108

AZLI 75 mg 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 TID using the investigational nebulizer.

Day 0: number of isolates = 104; Day 28: number of isolates = 76

Measured Values

	Placebo TID	AZLI 75 mg TID
Number of Participants Analyzed [units: participants]	81	76
The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively) [units: µg/mL]
Baseline MIC50	1	1
Day 28 MIC50	1	4
Baseline MIC90	16	8
Day 28 MIC90	16	32

No statistical analysis provided for The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively)

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:

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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Mark Bresnik, MD, Director, Clinical Research
Organization: Gilead Sciences, Inc.
phone: (650) 522-5934
e-mail: mark.bresnik@gilead.com

No publications provided by Gilead Sciences

Publications automatically indexed to this study:

Wainwright CE, Quittner AL, Geller DE, Nakamura C, Wooldridge JL, Gibson RL, Lewis S, Montgomery AB. Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa. J Cyst Fibros. 2011 Jul;10(4):234-42. Epub 2011 Mar 26.

Responsible Party:	Mark Bresnik, MD, Director, Clinical Research, Gilead Sciences, Inc.
ClinicalTrials.gov Identifier:	NCT00712166 History of Changes
Other Study ID Numbers:	GS-US-205-0117
Study First Received:	July 7, 2008
Results First Received:	September 10, 2010
Last Updated:	November 19, 2010
Health Authority:	United States: Food and Drug Administration

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