Aztreonam Lysine for Pseudomonas Infection Eradication Study (ALPINE)

• ClinicalTrials.gov Identifier: NCT01375049
• Recruitment Status: Completed
• First Posted: June 17, 2011
• Results First Posted: July 1, 2014
• Last Update Posted: July 17, 2014
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cystic Fibrosis
• Intervention: Drug: Aztreonam for Inhalation Solution (AZLI)
• Enrollment: 105

Participant Flow

Recruitment Details	Participants were enrolled at a total of 46 study sites in the United States and Europe. The first participant was screened on 04 October 2011. The last participant observation occurred on 29 May 2013.
Pre-assignment Details	109 participants were screened; 105 participants were enrolled and treated, and comprise the Safety Analysis Set and the Full Analysis Set.

Arm/Group Title	AZLI
Arm/Group Description	Participants received one 28-day course of Aztreonam for Inhalation Solution (AZLI), then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Period Title: Overall Study
Started	105
Completed	55
Not Completed	50
Reason Not Completed
Adverse Event	2
Lost to Follow-up	1
Withdrawal by Subject	2
Protocol-Specified Withdrawal Criteria	45

Baseline Characteristics

Arm/Group Title		AZLI
Arm/Group Description		Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Baseline Participants		105
Baseline Analysis Population Description		Safety Analysis Set: participants who received at least 1 dose of study drug
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	105 participants
		6.26 (4.743)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	105 participants
3 months to < 2 years		24
≥ 2 years to < 6 years		25
≥ 6 years to < 18 years		56
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	105 participants
	Female	47 44.8%
	Male	58 55.2%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	105 participants
Asian		1
Black or African Heritage		1
White		99
Other		2
Not Permitted to be Recorded		2
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	105 participants
Hispanic		5
Not Hispanic		93
Not Permitted to be Recorded		7
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	105 participants
France		12
United States		56
Spain		6
Poland		3
Belgium		11
Austria		3
Netherlands		5
Germany		4
Italy		5
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	105 participants
		24.8 (15.69)
Height; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	105 participants
		113.9 (33.02)
BMI; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	105 participants
		17.1 (2.57)
Presence of Pseudomonas aeruginosa (PA) [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	105 participants
Present at baseline		45
Absent at baseline		57
		[1] Measure Description: Of the 105 participants in the safety analysis set, 3 participants did not provide baseline samples (ie, oropharyngeal swab sample). All participants had a positive PA culture within 30 days of baseline.

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Evaluable Analysis Set)
Description	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Evaluable Analysis Set.
Time Frame	Day 28 to Day 196

Outcome Measure Data

Analysis Population Description

Evaluable Analysis Set

Arm/Group Title	AZLI - Evaluable Analysis Set
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer. The Evaluable Analysis Set consists of participants who completed study drug and did not receive an additional antipseudomonal antibiotic during the 28-day AZLI treatment course, and either completed the study through Day 196 with PA-negative cultures at every visit without the use of additional antipseudomonal antibiotics from Day 28 through Day 196 or had evidence of a positive PA-positive culture from Day 28 through Day 196.
Overall Number of Participants Analyzed	79
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	58.2; (47.4 to 69.1)

2. Primary Outcome

Title	Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Sensitivity Analysis Set)
Description	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Sensitivity Analysis Set.
Time Frame	Day 28 to Day 196

Outcome Measure Data

Analysis Population Description

Sensitivity Analysis Set

Arm/Group Title	AZLI - Sensitivity Analysis Set
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer. The Sensitivity Analysis Set consists of participants who completed study drug and did not receive an additional antipseudomonal antibiotic during the 28-day AZLI treatment course, and either completed the study through Day 196 with PA-negative cultures at every visit without the use of additional antipseudomonal antibiotics from Day 28 through Day 196 or had evidence of a PA-positive culture from Day 28 through Day 196 or used any additional antipseudomonal antibiotics from Day 28 through Day 196.
Overall Number of Participants Analyzed	98
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	46.9; (37.1 to 56.8)

3. Secondary Outcome

Title	Change From Baseline in FEV1% Predicted
Description	Spirometry assessments were performed only in participants ≥ 6 years of age. Forced expiratory volume in 1 second (FEV1) % predicted was defined as FEV1 of the participant divided by the average FEV1 in the population for any person of similar age, sex and body composition.
Time Frame	Baseline to Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Participants in the Sensitivity Analysis Set ≥ 6 years of age with available data for this assessment were analyzed.

Arm/Group Title	AZLI - Met Primary Efficacy Endpoint	AZLI - Did Not Meet Primary Efficacy Endpoint
Arm/Group Description:	This group included participants who met the primary efficacy endpoint, defined as having PA-negative cultures at all time points after cessation of active treatment through Day 196. Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.	This group included participants who did not meet the primary efficacy endpoint, defined as having any PA-positive culture at Day 28 through Day 196 or having used anti-PA antibiotics through Day 196. Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	25	27
Mean (Standard Deviation); Unit of Measure: percentage of FEV1% predicted
Change at Day 28 (n=25 [met], 26 [did not meet])	-0.23 (10.373)	-0.38 (12.347)
Change at Day 56 (n=25 [met], 26 [did not meet])	-0.20 (10.949)	-4.24 (7.513)
Change at Day 112 (n=25 [met], 19 [did not meet])	0.32 (9.830)	-5.10 (7.948)
Change at Day 196 (n=25 [met], 8 [did not meet])	-2.47 (8.895)	-8.85 (11.510)

4. Secondary Outcome

Title	Change From Baseline in CFQ-R RSS Score
Description	Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) only in participants ≥ 6 years of age. The range of scores (units) is 0 to 100 with higher scores indicating fewer symptoms.
Time Frame	Baseline to Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Participants in the Sensitivity Analysis Set ≥ 6 years of age with available data for this assessment were analyzed.

Arm/Group Title	AZLI - Met Primary Efficacy Endpoint	AZLI - Did Not Meet Primary Efficacy Endpoint
Arm/Group Description:	This group included participants who met the primary efficacy endpoint, defined as having PA-negative cultures at all time points after cessation of active treatment through Day 196. Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.	This group included participants who did not meet the primary efficacy endpoint, defined as having any PA-positive culture at Day 28 through Day 196 or having used anti-PA antibiotics through Day 196. Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	25	31
Mean (Standard Deviation); Unit of Measure: units on a scale
Change at Day 28 (n=24 [met], 29 [did not meet])	8.33 (15.883)	5.36 (8.937)
Change at Day 56 (n=24 [met], 27 [did not meet])	6.37 (16.433)	6.17 (11.040)
Change at Day 112 (n=24 [met], 21 [did not meet])	5.79 (14.397)	1.46 (14.636)
Change at Day 196 (n=24 [met], 10 [did not meet])	6.13 (18.002)	5.83 (9.663)

5. Secondary Outcome

Title	Percentage of Participants With PA-negative Cultures
Description	The percentage of participants with a PA-negative culture was summarized at each visit.
Time Frame	Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set who completed study drug and did not receive an additional antipseudomonal antibiotic during the 28-day AZLI treatment course were included in the analysis at all time points.

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	101
Measure Type: Number; Unit of Measure: percentage of participants
Day 28	89.1
Day 56	75.2
Day 112	63.4
Day 196	47.5

6. Secondary Outcome

Title	Use of Additional (Non-study) Antipseudomonal Antibiotics
Description	The percentage of participants who used additional (non-study) antipseudomonal antibiotics (an indication of PA exacerbation) while on treatment and posttreatment was summarized.
Time Frame	Baseline to Day 196

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	105
Measure Type: Number; Unit of Measure: percentage of participants
On-treatment	1.9
Posttreatment	43.8

7. Secondary Outcome

Title	Change From Baseline in Weight
Description	[Not Specified]
Time Frame	Baseline to Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	105
Mean (Standard Deviation); Unit of Measure: kg
Change at Day 28 (On-Treatment, n = 104)	0.3 (0.70)
Change at Day 56 (Posttreatment, n = 101)	0.5 (0.72)
Change at Day 112 (Posttreatment, n = 90)	0.8 (1.02)
Change at Day 196 (Posttreatment, n = 69)	1.5 (3.8)

8. Secondary Outcome

Title	Change From Baseline in Height
Description	[Not Specified]
Time Frame	Baseline to Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	105
Mean (Standard Deviation); Unit of Measure: cm
Change at Day 28 (On-Treatment, n = 104)	0.6 (0.87)
Change at Day 56 (Posttreatment, n = 101)	1.4 (1.27)
Change at Day 112 (Posttreatment, n = 90)	2.6 (2.00)
Change at Day 196 (Posttreatment, n = 69)	4.5 (2.86)

9. Secondary Outcome

Title	Change From Baseline in Body Mass Index (BMI)
Description	[Not Specified]
Time Frame	Baseline to Days 28, 56, 112, and 196

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	105
Mean (Standard Deviation); Unit of Measure: kg/m^2
Change at Day 28 (On-Treatment, n = 104)	0.1 (0.57)
Change at Day 56 (Posttreatment, n = 101)	0.1 (0.71)
Change at Day 112 (Posttreatment, n = 90)	0.0 (0.97)
Change at Day 196 (Posttreatment, n = 69)	0.0 (0.93)

10. Secondary Outcome

Title	Pharmacokinetics (PK) Peak and Trough Plasma Concentrations of Aztreonam
Description	The plasma concentration of aztreonam for participants < 6 years of age was obtained 1 hour after the first dose of AZLI on Day 1 and immediately prior to the last dose of AZLI on Day 28.
Time Frame	Day 1 (1 hour postdose) and Day 28 (immediately prior to dosing)

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set < 6 years of age with evaluable PK profiles were analyzed.

Arm/Group Title	AZLI
Arm/Group Description:	Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
Overall Number of Participants Analyzed	49
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 1 (1 hour postdose, n = 40)	578 (560.0)
Day 28 (immediately prior to dosing, n = 43)	125 (166.3)

Adverse Events

Time Frame	Baseline to Day 28 plus 30 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	AZLI
Arm/Group Description	Treatment-emergent adverse events and treatment-emergent serious adverse events were collected from Baseline through Day 28 plus 30 days. Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.
All-Cause Mortality
	AZLI
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	AZLI
	Affected / at Risk (%)
Total	8/105 (7.62%)
Hepatobiliary disorders
Hepatitus acute † 1	1/105 (0.95%)
Infections and infestations
Infectious mononucleosis † 1	1/105 (0.95%)
Pseudomonas infection † 1	2/105 (1.90%)
Viral infection † 1	1/105 (0.95%)
Investigations
Pseudomonas test positive † 1	1/105 (0.95%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/105 (0.95%)
Lung disorder † 1	1/105 (0.95%)
Skin and subcutaneous tissue disorders
Rash † 1	1/105 (0.95%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	AZLI
	Affected / at Risk (%)
Total	66/105 (62.86%)
Gastrointestinal disorders
Diarrhoea † 1	7/105 (6.67%)
Vomiting † 1	7/105 (6.67%)
General disorders
Pyrexia † 1	15/105 (14.29%)
Infections and infestations
Rhinitis † 1	8/105 (7.62%)
Investigations
Pseudomonas test positive † 1	20/105 (19.05%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	42/105 (40.00%)
Rhinorrhoea † 1	10/105 (9.52%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.0

Limitations and Caveats

[Not Specified]

More Information

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 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: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.
• EMail: ClinicalTrialDisclosures@gilead.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tiddens HA, De Boeck K, Clancy JP, Fayon M, H G M A, Bresnik M, Derchak A, Lewis SA, Oermann CM; ALPINE study investigators. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros. 2015 Jan;14(1):111-9. doi: 10.1016/j.jcf.2014.06.003. Epub 2014 Aug 1.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01375049
• Other Study ID Numbers: GS-US-205-0162
• First Submitted: June 15, 2011
• First Posted: June 17, 2011
• Results First Submitted: May 29, 2014
• Results First Posted: July 1, 2014
• Last Update Posted: July 17, 2014