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Aztreonam for Inhalation Solution vs Tobramycin Inhalation Solution in Patients With Cystic Fibrosis & Pseudomonas Aeruginosa

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ClinicalTrials.gov Identifier: NCT00757237
Recruitment Status : Completed
First Posted : September 23, 2008
Results First Posted : July 4, 2011
Last Update Posted : July 4, 2011
Sponsor:
Collaborators:
Chiltern International Inc.
ClinPhone, Inc.
Covance
Information provided by:
Gilead Sciences

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cystic Fibrosis
Interventions Drug: Aztreonam for Inhalation Solution (AZLI)
Drug: Tobramycin Inhalation Solution (TIS)
Enrollment 274

Recruitment Details Seventy-three sites in the United States (US) and European Union (EU) enrolled a total of 274 participants in the study.
Pre-assignment Details Of the 274 participants enrolled in the study, 273 were randomized between 07 August 2008 and 12 November 2009. One subject experienced a serious adverse event (SAE) between Visits 1 and 2; this subject did not receive study drug. A total of 268 participants received study drug (136 AZLI; 132 TIS).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer. TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Period Title: Overall Study
Started 137 136
Treated 136 132
Completed 124 111
Not Completed 13 25
Reason Not Completed
Lost to Follow-up             0             1
Protocol Violation             0             2
Physician Decision             2             3
Withdrawal by Subject             8             12
Safety or Tolerability             3             5
Other             0             2
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID) Total
Hide Arm/Group Description AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer. TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor. Total of all reporting groups
Overall Number of Baseline Participants 136 132 268
Hide Baseline Analysis Population Description
[Not Specified]
Age Categorical  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
>= 6 years to <= 12 years 8 5 13
> 12 years to < 18 years 20 26 46
>= 18 years 108 101 209
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 136 participants 132 participants 268 participants
25.8  (9.1) 25.1  (9.0) 25.5  (9.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
Female
68
  50.0%
66
  50.0%
134
  50.0%
Male
68
  50.0%
66
  50.0%
134
  50.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   0.7%
0
   0.0%
1
   0.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   0.8%
1
   0.4%
White
130
  95.6%
131
  99.2%
261
  97.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
5
   3.7%
0
   0.0%
5
   1.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
United States 44 50 94
Europe 92 82 174
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 136 participants 132 participants 268 participants
20.22  (2.95) 20.49  (2.82) 20.35  (2.88)
Inhaled Tobramycin Use in the Previous 12 Months  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
< 84 days 21 19 40
>= 84 days 115 113 228
Disease Severity   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 136 participants 132 participants 268 participants
<= 50% predicted 60 57 117
> 50% predicted 76 75 151
[1]
Measure Description: Forced Expiratory Volume (FEV1) percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. This baseline measure indicates the number of participants with FEV1 greater than 50% and less than or equal to 50% of the predicted value based on age, gender, and height at screening.
Forced Expiratory Volume (FEV1) Percent Predicted   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent
Number Analyzed 136 participants 132 participants 268 participants
52.30  (15.56) 52.24  (14.57) 52.27  (15.06)
[1]
Measure Description: FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height.
Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 136 participants 132 participants 268 participants
62.87  (20.42) 58.02  (20.76) 60.44  (20.69)
[1]
Measure Description: The CFQ-R is a validated, patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. Respiratory symptoms (e.g., coughing, congestion, wheezing) are assessed with the CFQ-R Respiratory Symptoms Scale (RSS). The range of scores (units) is 0 to 100 with higher scores indicating fewer symptoms.
1.Primary Outcome
Title Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28
Hide Description Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an analysis of covariance (ANCOVA) model-based method.
Time Frame Baseline and end of treatment Course 1 (Day 28)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). The last observation carried forward (LOCF) method was used to impute missing data.
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Least Squares Mean (Standard Error)
Unit of Measure: percent change in FEV1 percent predicted
8.35  (1.70) 0.55  (1.77)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: AZLI was inferior to TIS by more than 4% in the mean relative change of FEV1 percent predicted at Day 28. With 120 subjects per treatment group there was at least 85% power to declare noninferiority based on relative change from baseline at Day 28 in FEV1 percent predicted using the upper bound of a 2-tailed 95% CI for the difference in means with a noninferiority margin of 4, assuming a common standard deviation of 18% and true difference in means [TIS-AZLI] of -3.2%.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The treatment difference (TIS-AZLI) and standard error from the ANCOVA model were used to compute the two-sided 95% confidence interval. If the 95% upper boundary was less than the pre-specified non-inferiority margin of 4%, then the null hypothesis was rejected.
Statistical Test of Hypothesis P-Value 0.0001
Comments Based on the Benjamini & Hochberg method, non-inferiority at Day 28 for relative change in FEV1 percent predicted was assessed at the 0.05 level, given the significance of the coprimary endpoint (p<0.05).
Method ANCOVA
Comments ANCOVA model included treatment, Day 0 FEV1 percent predicted, and previous inhaled tobramycin use for all participants.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.80
Confidence Interval (2-Sided) 95%
-11.73 to -3.86
Estimation Comments Treatment difference refers to TIS-AZLI.
2.Primary Outcome
Title Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses
Hide Description

Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height.

Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by mixed-effect model repeated measures (MMRM) analysis using the ITT population analysis set.

Time Frame Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Least Squares Mean (Standard Error)
Unit of Measure: actual change in FEV1 percent predicted
2.05  (0.69) -0.66  (0.72)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments

Null hypothesis: there was no difference between AZLI and TIS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses among all participants.

With 120 subjects per treatment group, there was at least 90% power at a 5% significance level to detect differences based upon actual change from baseline in FEV1 percent predicted (3.61%, 2.98%, 2.32%) between AZLI and TIS at Weeks 4, 12, and 20 with a common standard deviation of 9%.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments Based on the Benjamini & Hochberg method, superiority at Weeks 4, 12, and 20 of actual change in FEV1 percent predicted was tested at the 0.05 level, given the significance of the coprimary endpoint (p<0.05).
Method MMRM analysis
Comments MMRM analysis included Day 0 FEV1 percent predicted, previous inhaled tobramycin use, treatment, visit, and treatment/visit interaction.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.70
Estimation Comments Treatment difference refers to TIS-AZLI.
3.Secondary Outcome
Title Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
Hide Description Spirometry was performed according to ATS guidelines. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an ANCOVA model-based method, using the population of participants with prior inhaled tobramycin use of >= 84 days in the previous 12 months.
Time Frame Baseline and end of treatment Course 1 (Day 28)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on participants with previous inhaled tobramycin use of >= 84 days within the previous 12 months using the ITT analysis set. The last observation carried forward (LOCF) method was used to impute missing data for statistical analyses.
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 115 113
Least Squares Mean (Standard Error)
Unit of Measure: percent change in FEV1 percent predicted
10.04  (1.56) 0.54  (1.57)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: AZLI was inferior to TIS by more than 4% in terms of the participant means in relative change of FEV1 percent predicted at Day 28 among all participants having >= 84 days of inhaled tobramycin use in the previous 12 months.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The treatment difference (TIS-AZLI) and standard error from the ANCOVA model were used to compute the two-sided 95% confidence interval. If the 95% upper boundary was less than the pre-specified non-inferiority margin of 4%, then the null hypothesis was rejected.
Statistical Test of Hypothesis P-Value <0.0001
Comments Secondary endpoints were tested sequentially by the closed testing procedure initiated by the significance of the primary endpoints. Given the coprimary endpoints were met at the 0.05 level, this non-inferiority endpoint was tested at the 0.05 level.
Method ANCOVA
Comments ANCOVA model included treatment and Day 0 FEV1 percent predicted.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.50
Confidence Interval (2-Sided) 95%
-13.86 to -5.14
Estimation Comments Treatment difference refers to TIS-AZLI.
4.Secondary Outcome
Title Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
Hide Description

Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height.

Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by MMRM analysis using the population of participants with prior inhaled tobramycin use of >=84 days in the previous 12 months.

Time Frame Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on participants with prior inhaled tobramycin use >= 84 days in the previous 12 months using the ITT analysis set.
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 115 113
Least Squares Mean (Standard Error)
Unit of Measure: actual change in FEV1 percent predicted
3.26  (0.65) -0.21  (0.66)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses in the stratum of subjects having >=84 days of inhaled tobramycin use in the previous 12 months.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.
Method MMRM analysis
Comments MMRM analysis included treatment, Day 0 FEV1 percent predicted, visit, treatment, and treatment/visit interaction for all participants.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.47
Estimation Comments Treatment difference refers to TIS-AZLI
5.Secondary Outcome
Title Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events
Hide Description

IV antipseudomonal antibiotic use for a respiratory event was determined through the adjudication of events by a sponsor-independent, blinded review committee.

Use was compiled from data recorded on the concomitant medications electronic case report form (eCRF) and compared to reported adverse events (AEs) to determine use for a respiratory event. The time to IV antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored.

Time Frame Day 0 to Day 168 (end of study)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(177 to NA)
151 [1] 
(113 to NA)
[1]
NA = Not estimable; less than 50% of the participants had an event by the end of the study.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to need for IV antipseudomonal antibiotics for respiratory events.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0025
Comments Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.
Method Log Rank
Comments [Not Specified]
6.Secondary Outcome
Title Time to First Respiratory Hospitalization
Hide Description

This endpoint was determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed all hospitalizations and determined which were related to respiratory events.

Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) eCRF.

Time to first respiratory hospitalization was the number of days from baseline (Visit 2) to the date of first respiratory hospitalization or the date of study completion (last visit) /or early withdrawal if censored.

Time Frame Day 0 to Day 168 (end of study)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA = Not estimable; less than 50% of the participants had an event by the end of the study.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to first respiratory hospitalization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1114
Comments Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.
Method Log Rank
Comments [Not Specified]
7.Other Pre-specified Outcome
Title Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
Hide Description The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores [units]: 0-100; higher scores indicate fewer symptoms).
Time Frame Baseline and end of treatment Course 1 (Day 28)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). LOCF method was used to impute missing data for statistical analyses.
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
8.20  (1.68) 2.59  (1.73)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in change from baseline in CFQ-R RSS scores at Day 28.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0048
Comments No adjustments were made for multiple comparisons.
Method ANCOVA
Comments ANCOVA model included treatment, Day 0 FEV1 percent predicted, Day 0 CFQ-R RSS score, and previous inhaled tobramycin use.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.61
Estimation Comments Treatment difference refers to TIS-AZLI.
8.Other Pre-specified Outcome
Title Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses
Hide Description The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was the average actual change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores [units]: 0-100; higher scores indicate fewer symptoms) at the end of each treatment course (Weeks 4, 12, and 20).
Time Frame Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). The LOCF method was used to impute missing data for statistical purposes.
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
6.30  (1.49) 2.17  (1.54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in the average actual change in respiratory symptoms at the end of each treatment course (Weeks 4, 12, and 20).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0189
Comments No adjustments were made for multiple comparisons.
Method ANCOVA
Comments ANCOVA model included treatment, Day 0 FEV1 percent predicted, Day 0 CFQ-R RSS score, and previous inhaled tobramycin use.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.13
Estimation Comments Treatment difference refers to TIS-AZLI.
9.Other Pre-specified Outcome
Title Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20
Hide Description This 14 item questionnaire consists of 3 subscales that gauge participant perceptions of a medication’s effectiveness, side effects, and convenience. The measure also contains a global satisfaction scale to evaluate overall participant satisfaction. The global satisfaction score is the endpoint reported here. The range of scores is 0 to 100, with higher scores indicating greater satisfaction.
Time Frame At Week 20
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 130 126
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
75.85  (4.58) 61.73  (4.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in the global satisfaction results of the TSQM at Week 20 (Day 140).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0097
Comments No adjustments were made for multiple comparisons.
Method ANCOVA
Comments ANCOVA model included treatment, Day 0 FEV1 percent predicted, and previous inhaled tobramycin use.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -14.12
Estimation Comments Treatment difference refers to TIS-AZLI.
10.Other Pre-specified Outcome
Title Total Number of Respiratory Hospitalizations
Hide Description Respiratory hospitalizations were determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed hospitalizations and determined which were related to respiratory events.
Time Frame Day 0 to Day 168 (end of study)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Measure Type: Number
Unit of Measure: hospitalizations
40 58
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in the total number of respiratory hospitalizations from Day 0 to Day 168 (end of study).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.044
Comments No adjustments were made for multiple comparisons.
Method negative binomial regression method
Comments [Not Specified]
11.Other Pre-specified Outcome
Title Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment)
Hide Description Inhaled and/or IV antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee. Use of IV and/or inhaled antipseudomonal antibiotics was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to IV and/or inhaled antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored.
Time Frame Day 0 through Day 168 (end of study)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Measure Type: Number
Unit of Measure: events
84 121
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups in the total number of respiratory events requiring IV and/or inhaled antipseudomonal antibiotics (other than randomized treatment) from Day 0 to Day 168 (end of study).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments No adjustments were made for multiple comparisons.
Method negative binomial regression method
Comments [Not Specified]
12.Other Pre-specified Outcome
Title Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment)
Hide Description

Antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee.

Use of IV and/or inhaled antibiotics for a respiratory event was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to antibiotic use for a respiratory event was measured in days from baseline (Day 0) to the date of first antibiotic use for a respiratory event or the date of study completion (last visit)/or early withdrawal if censored.

Time Frame Day 0 to Day 168 (end of study)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description:
AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer.
TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
Overall Number of Participants Analyzed 136 132
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(177 to NA)
117
(102 to 169)
[1]
NA = Not estimable; less than 50% of the participants had an event by the end of the study.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI (75 mg TID), TIS (300 mg BID)
Comments Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to need for inhaled and/or IV antipseudomonal antibiotics for respiratory events.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments No adjustments were made for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Time Frame Treatment-emergent adverse events (AEs) were collected continuously from Day 0 (first dose) through Day 168 (Week 24).
Adverse Event Reporting Description An AE was any physical/clinical worsening in symptoms/disease (including clinically significant change in lab values) experienced by a participant at any time during study, whether or not the AE was considered related to study participation or procedures. Participants were only counted once within a System Organ Class (SOC) and preferred term.
 
Arm/Group Title AZLI (75 mg TID) TIS (300 mg BID)
Hide Arm/Group Description AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer. TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor.
All-Cause Mortality
AZLI (75 mg TID) TIS (300 mg BID)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
AZLI (75 mg TID) TIS (300 mg BID)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   42/136 (30.88%)      44/132 (33.33%)    
Cardiac disorders     
Atrial Fibrillation  0/136 (0.00%)  0 1/132 (0.76%)  1
Cyanosis  0/136 (0.00%)  0 1/132 (0.76%)  1
Ear and labyrinth disorders     
Vertigo  0/136 (0.00%)  0 1/132 (0.76%)  1
Gastrointestinal disorders     
Abdominal Discomfort  1/136 (0.74%)  1 0/132 (0.00%)  0
Abdominal Distention  0/136 (0.00%)  0 2/132 (1.52%)  2
Abdominal Pain  5/136 (3.68%)  5 1/132 (0.76%)  1
Constipation  1/136 (0.74%)  1 0/132 (0.00%)  0
Nausea  1/136 (0.74%)  1 0/132 (0.00%)  0
Vomiting  4/136 (2.94%)  4 0/132 (0.00%)  0
General disorders     
Chest Discomfort  1/136 (0.74%)  1 0/132 (0.00%)  0
Chest Pain  3/136 (2.21%)  3 2/132 (1.52%)  2
Chills  1/136 (0.74%)  1 0/132 (0.00%)  0
Exercise Tolerance Decreased  6/136 (4.41%)  6 3/132 (2.27%)  3
Fatigue  1/136 (0.74%)  1 3/132 (2.27%)  3
Malaise  1/136 (0.74%)  1 0/132 (0.00%)  0
Oedema Peripheral  0/136 (0.00%)  0 2/132 (1.52%)  2
Pain  2/136 (1.47%)  2 0/132 (0.00%)  0
Pyrexia  11/136 (8.09%)  13 8/132 (6.06%)  10
Infections and infestations     
Catheter Related Infection  1/136 (0.74%)  1 0/132 (0.00%)  0
Systemic Candida  1/136 (0.74%)  1 0/132 (0.00%)  0
Injury, poisoning and procedural complications     
Alcohol Poisoning  1/136 (0.74%)  1 0/132 (0.00%)  0
Feeding Tube Complication  1/136 (0.74%)  1 0/132 (0.00%)  0
Investigations     
Body Temperature Increased  0/136 (0.00%)  0 1/132 (0.76%)  1
Breath Sounds Abnormal  1/136 (0.74%)  1 1/132 (0.76%)  1
C-Reactive Protein Increased  1/136 (0.74%)  1 0/132 (0.00%)  0
Forced Expiratory Volume Decreased  3/136 (2.21%)  3 0/132 (0.00%)  0
Glycosylated Haemoglobin Increased  0/136 (0.00%)  0 1/132 (0.76%)  1
Oxygen Saturation Decreased  0/136 (0.00%)  0 1/132 (0.76%)  2
Pulmonary Function Test Decreased  5/136 (3.68%)  5 4/132 (3.03%)  4
Weight Decreased  1/136 (0.74%)  1 2/132 (1.52%)  2
Metabolism and nutrition disorders     
Decreased Appetite  3/136 (2.21%)  3 2/132 (1.52%)  2
Diabetes Mellitus Inadequate Control  2/136 (1.47%)  3 0/132 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Joint Swelling  0/136 (0.00%)  0 1/132 (0.76%)  1
Muscle Spasms  1/136 (0.74%)  1 0/132 (0.00%)  0
Pain in Extremity  0/136 (0.00%)  0 1/132 (0.76%)  1
Nervous system disorders     
Coma  1/136 (0.74%)  1 0/132 (0.00%)  0
Headache  1/136 (0.74%)  1 1/132 (0.76%)  1
Lethargy  1/136 (0.74%)  2 0/132 (0.00%)  0
Poor Quality Sleep  1/136 (0.74%)  1 0/132 (0.00%)  0
Sinus Headache  1/136 (0.74%)  1 0/132 (0.00%)  0
Psychiatric disorders     
Insomnia  1/136 (0.74%)  1 0/132 (0.00%)  0
Renal and urinary disorders     
Anuria  0/136 (0.00%)  0 1/132 (0.76%)  1
Respiratory, thoracic and mediastinal disorders     
Cough  27/136 (19.85%)  31 26/132 (19.70%)  30
Dyspnoea  10/136 (7.35%)  13 15/132 (11.36%)  17
Dyspnoea Exertional  1/136 (0.74%)  1 1/132 (0.76%)  1
Haemoptysis  5/136 (3.68%)  6 3/132 (2.27%)  4
Hypoxia  1/136 (0.74%)  1 0/132 (0.00%)  0
Lung Infiltration  0/136 (0.00%)  0 1/132 (0.76%)  1
Nasal Congestion  1/136 (0.74%)  2 0/132 (0.00%)  0
Nasal Mucosal Disorder  1/136 (0.74%)  1 0/132 (0.00%)  0
Oropharyngeal Pain  4/136 (2.94%)  4 0/132 (0.00%)  0
Pleuritic Pain  0/136 (0.00%)  0 2/132 (1.52%)  2
Productive Cough  16/136 (11.76%)  21 23/132 (17.42%)  29
Rales  2/136 (1.47%)  2 3/132 (2.27%)  3
Respiratory Tract Congestion  1/136 (0.74%)  1 3/132 (2.27%)  3
Rhinorrhoea  3/136 (2.21%)  3 0/132 (0.00%)  0
Rhonchi  1/136 (0.74%)  1 0/132 (0.00%)  0
Sinus Congestion  1/136 (0.74%)  1 0/132 (0.00%)  0
Sputum Discoloured  2/136 (1.47%)  2 1/132 (0.76%)  1
Tachypnoea  1/136 (0.74%)  1 2/132 (1.52%)  2
Wheezing  3/136 (2.21%)  3 5/132 (3.79%)  5
Vascular disorders     
Hyperaemia  0/136 (0.00%)  0 1/132 (0.76%)  1
Vein Disorder  0/136 (0.00%)  0 1/132 (0.76%)  1
1
Term from vocabulary, MedDRA (11.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AZLI (75 mg TID) TIS (300 mg BID)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   128/136 (94.12%)      127/132 (96.21%)    
Gastrointestinal disorders     
Abdominal Pain  15/136 (11.03%)  8/132 (6.06%) 
Diarrhoea  4/136 (2.94%)  12/132 (9.09%) 
Nausea  13/136 (9.56%)  10/132 (7.58%) 
Vomiting  12/136 (8.82%)  14/132 (10.61%) 
General disorders     
Chest Discomfort  13/136 (9.56%)  13/132 (9.85%) 
Chest Pain  6/136 (4.41%)  8/132 (6.06%) 
Exercise Tolerance Decreased  20/136 (14.71%)  24/132 (18.18%) 
Fatigue  23/136 (16.91%)  22/132 (16.67%) 
Pain  9/136 (6.62%)  4/132 (3.03%) 
Pyrexia  34/136 (25.00%)  36/132 (27.27%) 
Investigations     
Breath Sounds Abnormal  7/136 (5.15%)  14/132 (10.61%) 
Forced Expiratory Volume Decreased  7/136 (5.15%)  5/132 (3.79%) 
Pulmonary Function Test Decreased  6/136 (4.41%)  15/132 (11.36%) 
Metabolism and nutrition disorders     
Decreased Appetite  17/136 (12.50%)  17/132 (12.88%) 
Musculoskeletal and connective tissue disorders     
Arthalgia  10/136 (7.35%)  2/132 (1.52%) 
Back Pain  7/136 (5.15%)  4/132 (3.03%) 
Myalgia  9/136 (6.62%)  6/132 (4.55%) 
Nervous system disorders     
Headache  28/136 (20.59%)  27/132 (20.45%) 
Respiratory, thoracic and mediastinal disorders     
Cough  92/136 (67.65%)  95/132 (71.97%) 
Dysphonia  5/136 (3.68%)  8/132 (6.06%) 
Dyspnoea  26/136 (19.12%)  28/132 (21.21%) 
Haemoptysis  30/136 (22.06%)  20/132 (15.15%) 
Nasal Congestion  29/136 (21.32%)  26/132 (19.70%) 
Oropharyngeal Pain  34/136 (25.00%)  37/132 (28.03%) 
Productive Cough  63/136 (46.32%)  67/132 (50.76%) 
Rales  29/136 (21.32%)  32/132 (24.24%) 
Respiratory Tract Congestion  15/136 (11.03%)  16/132 (12.12%) 
Rhinitis  4/136 (2.94%)  7/132 (5.30%) 
Rhinorrhoea  24/136 (17.65%)  33/132 (25.00%) 
Sinus Congestion  3/136 (2.21%)  8/132 (6.06%) 
Wheezing  13/136 (9.56%)  15/132 (11.36%) 
1
Term from vocabulary, MedDRA (11.1)
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.

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.

Results Point of Contact
Name/Title: Mark Bresnik, MD, Director, Clinical Research
Organization: Gilead Sciences, Inc.
Phone: (650) 522-5934
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Mark Bresnik, MD/Medical Monitor, GSI
ClinicalTrials.gov Identifier: NCT00757237     History of Changes
Other Study ID Numbers: GS-US-205-0110
First Submitted: September 22, 2008
First Posted: September 23, 2008
Results First Submitted: April 8, 2011
Results First Posted: July 4, 2011
Last Update Posted: July 4, 2011