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Clinical Trial Results:
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)

Summary
EudraCT number	2015-000395-97
Trial protocol	Outside EU/EEA
Global end of trial date	19 Jun 2009

Results information
Results version number	v1(current)
This version publication date	22 Mar 2016
First version publication date	05 Aug 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GS-US-205-0117

ISRCTN number

US NCT number

NCT00712166

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences, Inc.

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com

Scientific contact

Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

19 Jun 2009

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Jun 2009

Was the trial ended prematurely?

Main objective of the trial

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.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Jun 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

United States: 145

Worldwide total number of subjects

157

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

Screening details

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.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Data analyst

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo to match AZLI self administered 3 times daily (TID) for the duration of the study.

Arm type

Placebo

Investigational medicinal product name

Placebo to match AZLI

Investigational medicinal product code

Other name

Pharmaceutical forms

Nebuliser solution

Routes of administration

Inhalation use

Dosage and administration details

Placebo to match AZLI (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) administered using an eFlow nebulizer

AZLI

Arm description

Participants received AZLI self administered 3 times daily for the duration of the study.

Arm type

Experimental

Investigational medicinal product name

Aztreonam for inhalation solution

Investigational medicinal product code

Other name

AZLI, Cayston®

Pharmaceutical forms

Nebuliser solution

Routes of administration

Inhalation use

Dosage and administration details

AZLI (75 mg aztreonam and 52.5 mg lysine monohydrate reconstituted in diluent [0.17% saline] with a pH of 4.4 to 5.4, and osmolality 350 to 550 mOsmol/kg) administered using an eFlow nebulizer

Number of subjects in period 1	Placebo	AZLI
Started	81	76
Completed	81	75
Not completed	0	1
Noncompliance	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received placebo to match AZLI self administered 3 times daily (TID) for the duration of the study.

Reporting group title

AZLI

Reporting group description

Participants received AZLI self administered 3 times daily for the duration of the study.

Reporting group values	Placebo	AZLI	Total
Number of subjects	81	76	157
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	18.9 ( 9.11 )	19.5 ( 9.07 )	-
Gender categorical
Units: Subjects
Female	37	30	67
Male	44	46	90

End points

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Reporting group title

Placebo

Reporting group description

Participants received placebo to match AZLI self administered 3 times daily (TID) for the duration of the study.

Reporting group title

AZLI

Reporting group description

Participants received AZLI self administered 3 times daily for the duration of the study.

Primary: Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

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End point title

Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

End point 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. 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).

End point type

Primary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	81	75
Units: Units on a scale
least squares mean (standard error)	1.41 ( 1.64 )	3.22 ( 1.71 )

Difference in change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.433 ^[1]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.83

upper limit

6.44

Notes
[1] - 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.

Secondary: Change from baseline in CFQ-R RSS score at Day 14

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End point title

Change from baseline in CFQ-R RSS score at Day 14

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 14

End point values	Placebo	AZLI
Number of subjects analysed	81	75
Units: Units on a scale
least squares mean (standard error)	0.28 ( 1.56 )	3.65 ( 1.63 )

Difference in change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.133 ^[3]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

3.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

7.78

Notes
[2] - Intergroup analysis of change from baseline in RSS score.
[3] - No adjustments were made for multiple comparisons.

Secondary: Change from baseline in CFQ-R RSS score at Day 42

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End point title

Change from baseline in CFQ-R RSS score at Day 42

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 42

End point values	Placebo	AZLI
Number of subjects analysed	81	75
Units: Units on a scale
least squares mean (standard error)	2.91 ( 1.65 )	3.02 ( 1.72 )

Difference in change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.965 ^[5]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.56

upper limit

4.76

Notes
[4] - Intergroup analysis of change from baseline in RSS score.
[5] - No adjustments were made for multiple comparisons.

Secondary: Change From Baseline in CFQ-R Physical Functioning Domain Score

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End point title

Change From Baseline in CFQ-R Physical Functioning Domain Score

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	80	76
Units: Units on a scale
least squares mean (standard error)	-0.69 ( 1.53 )	1.79 ( 1.57 )

Difference in change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.256 ^[7]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.47

Confidence interval

level

95%

sides

2-sided

lower limit

-1.81

upper limit

6.76

Notes
[6] - Intergroup analysis of change from baseline in physical domain score.
[7] - No adjustments were made for multiple comparisons.

Secondary: Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

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End point title

Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 42

End point values	Placebo	AZLI
Number of subjects analysed	81	76
Units: Participants	21	19

Difference in antibiotic use

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

> 0.999 ^[9]

Method

Fisher exact

Confidence interval

Notes
[8] - Intergroup analysis of nonprotocol-specified antipseudomonal antibiotic use.
[9] - No adjustments were made for multiple comparisons.

Secondary: Number of participants hospitalized during study

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End point title

Number of participants hospitalized during study

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 42

End point values	Placebo	AZLI
Number of subjects analysed	81	76
Units: Participants	3	8

Difference in hospitalization rate

Statistical analysis description

Null hypothesis was there was no difference between 75 mg AZLI TID and placebo treatment groups in proportion of participants hospitalized.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.122 ^[11]

Method

Fisher exact

Confidence interval

Notes
[10] - Intergroup analysis of hospitalization rate.
[11] - No adjustments were made for multiple comparisons.

Secondary: Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

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End point title

Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	31	37
Units: Log10 PA CFUs/gram of sputum
least squares mean (standard error)	-0.14 ( 0.36 )	-1.35 ( 0.36 )

Difference in change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.016 ^[13]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

-0.23

Notes
[12] - Intergroup analysis of change from baseline.
[13] - No adjustments were made for multiple comparisons.

Secondary: Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

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End point title

Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

End point 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. 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 postbaseline 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.

End point type

Secondary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	81	76
Units: Percent change from baseline
least squares mean (standard error)	-2.45 ( 0.82 )	0.29 ( 0.85 )

Difference in relative change from baseline

Statistical analysis description

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.

Comparison groups

Placebo v AZLI

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.021 ^[15]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

5.04

Notes
[14] - Intergroup analysis of relative change from baseline.
[15] - No adjustments were made for multiple comparisons.

Secondary: Number of participants testing positive for other respiratory pathogens

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End point title

Number of participants testing positive for other respiratory pathogens

End point 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. 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.

End point type

Secondary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	81	76
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 analyses for this end point

Secondary: The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

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End point title

The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

End point 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. Analysis based on ITT population (all participants who received at least part of one dose of AZLI or placebo). Baseline and Day 28 MIC50 were ≤ 1 in the Placebo Group, and baseline MIC50 was ≤ 1 in the AZLI Group.

End point type

Secondary

End point timeframe

Day 0 to Day 28

End point values	Placebo	AZLI
Number of subjects analysed	81	76
Units: μg/mL
Baseline MIC50	1	1
Day 28 MIC50	1	4
Baseline MIC90	16	8
Day 28 MIC90	16	32

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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 additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

11.1

Reporting group title

Placebo

Reporting group description

Participants received placebo to match AZLI self administered 3 times daily (TID) for the duration of the study.

Reporting group title

AZLI

Reporting group description

Participants received AZLI self administered 3 times daily for the duration of the study.

Serious adverse events	Placebo	AZLI
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 81 (3.70%)	9 / 76 (11.84%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Investigations
Pulmonary function test decreased
subjects affected / exposed	1 / 81 (1.23%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breath sounds abnormal
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 81 (2.47%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 81 (1.23%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 81 (1.23%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 81 (1.23%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 81 (1.23%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 81 (1.23%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 81 (1.23%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonas bronchitis
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Malnutrition
subjects affected / exposed	0 / 81 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	AZLI
Total subjects affected by non serious adverse events
subjects affected / exposed	58 / 81 (71.60%)	53 / 76 (69.74%)
Investigations
Pulmonary function test decreased
subjects affected / exposed	8 / 81 (9.88%)	6 / 76 (7.89%)
occurrences all number	8	6
Nervous system disorders
Headache
subjects affected / exposed	10 / 81 (12.35%)	14 / 76 (18.42%)
occurrences all number	12	17
Sinus headache
subjects affected / exposed	3 / 81 (3.70%)	5 / 76 (6.58%)
occurrences all number	4	8
Dizziness
subjects affected / exposed	1 / 81 (1.23%)	5 / 76 (6.58%)
occurrences all number	2	6
General disorders and administration site conditions
Fatigue
subjects affected / exposed	10 / 81 (12.35%)	6 / 76 (7.89%)
occurrences all number	11	7
Pyrexia
subjects affected / exposed	7 / 81 (8.64%)	5 / 76 (6.58%)
occurrences all number	8	6
Chest pain
subjects affected / exposed	2 / 81 (2.47%)	4 / 76 (5.26%)
occurrences all number	2	4
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	9 / 81 (11.11%)	3 / 76 (3.95%)
occurrences all number	9	3
Abdominal pain
subjects affected / exposed	9 / 81 (11.11%)	1 / 76 (1.32%)
occurrences all number	9	1
Abdominal pain upper
subjects affected / exposed	3 / 81 (3.70%)	5 / 76 (6.58%)
occurrences all number	5	6
Nausea
subjects affected / exposed	6 / 81 (7.41%)	2 / 76 (2.63%)
occurrences all number	6	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	30 / 81 (37.04%)	32 / 76 (42.11%)
occurrences all number	32	35
Productive cough
subjects affected / exposed	13 / 81 (16.05%)	18 / 76 (23.68%)
occurrences all number	13	18
Nasal congestion
subjects affected / exposed	15 / 81 (18.52%)	13 / 76 (17.11%)
occurrences all number	15	13
Oropharyngeal pain
subjects affected / exposed	11 / 81 (13.58%)	12 / 76 (15.79%)
occurrences all number	12	12
Rhinorrhoea
subjects affected / exposed	12 / 81 (14.81%)	8 / 76 (10.53%)
occurrences all number	12	10
Respiratory tract congestion
subjects affected / exposed	6 / 81 (7.41%)	11 / 76 (14.47%)
occurrences all number	6	11
Rales
subjects affected / exposed	5 / 81 (6.17%)	7 / 76 (9.21%)
occurrences all number	5	7
Dyspnoea
subjects affected / exposed	4 / 81 (4.94%)	7 / 76 (9.21%)
occurrences all number	5	7
Postnasal drip
subjects affected / exposed	7 / 81 (8.64%)	3 / 76 (3.95%)
occurrences all number	7	3
Wheezing
subjects affected / exposed	5 / 81 (6.17%)	5 / 76 (6.58%)
occurrences all number	5	5
Chest discomfort
subjects affected / exposed	2 / 81 (2.47%)	6 / 76 (7.89%)
occurrences all number	2	6
Sputum discoloured
subjects affected / exposed	5 / 81 (6.17%)	3 / 76 (3.95%)
occurrences all number	5	4
Pleuritic pain
subjects affected / exposed	0 / 81 (0.00%)	4 / 76 (5.26%)
occurrences all number	0	4
Infections and infestations
Rhinitis
subjects affected / exposed	4 / 81 (4.94%)	5 / 76 (6.58%)
occurrences all number	4	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 81 (0.00%)	6 / 76 (7.89%)
occurrences all number	0	6

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

There were no limitations affecting the analysis or results.

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Clinical trials

Clinical Trial Results:
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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

Primary: Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

Secondary: Change from baseline in CFQ-R RSS score at Day 14

Secondary: Change from baseline in CFQ-R RSS score at Day 14

Secondary: Change from baseline in CFQ-R RSS score at Day 42

Secondary: Change from baseline in CFQ-R RSS score at Day 42

Secondary: Change From Baseline in CFQ-R Physical Functioning Domain Score

Secondary: Change From Baseline in CFQ-R Physical Functioning Domain Score

Secondary: Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

Secondary: Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

Secondary: Number of participants hospitalized during study

Secondary: Number of participants hospitalized during study

Secondary: Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

Secondary: Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

Secondary: Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

Secondary: Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

Secondary: Number of participants testing positive for other respiratory pathogens

Secondary: Number of participants testing positive for other respiratory pathogens

Secondary: The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

Secondary: The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

Primary: Change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory symptoms scale (RSS) score at Day 28

Secondary: Change from baseline in CFQ-R RSS score at Day 14

Secondary: Change from baseline in CFQ-R RSS score at Day 14

Secondary: Change from baseline in CFQ-R RSS score at Day 42

Secondary: Change from baseline in CFQ-R RSS score at Day 42

Secondary: Change From Baseline in CFQ-R Physical Functioning Domain Score

Secondary: Change From Baseline in CFQ-R Physical Functioning Domain Score

Secondary: Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

Secondary: Number of participants using additional (nonprotocol-specified) antipseudomonal antibiotics during study

Secondary: Number of participants hospitalized during study

Secondary: Number of participants hospitalized during study

Secondary: Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

Secondary: Change from baseline in Log10 Pseudomonas aeruginosa (PA) colony forming units (CFUs) in sputum at Day 28

Secondary: Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

Secondary: Relative change from baseline in forced expiratory volume in 1 second (FEV1) percent predicted

Secondary: Number of participants testing positive for other respiratory pathogens

Secondary: Number of participants testing positive for other respiratory pathogens

Secondary: The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

Secondary: The Minimum Concentrations of Aztreonam that Inhibit 50% and 90% of all PA Isolates (MIC50 and MIC90, respectively)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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)