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Study of Aztreonam for Inhalation in Children With Cystic Fibrosis and New Infection of the Airways by Pseudomonas Aeruginosa Bacteria (ALPINE 2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03219164
Recruitment Status : Terminated (Study was terminated early by sponsor due to the challenges and risks introduced by Coronavirus disease 2019 (COVID-19) pandemic.)
First Posted : July 17, 2017
Results First Posted : May 16, 2022
Last Update Posted : June 14, 2022
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Pseudomonas Aeruginosa Respiratory Tract Infection/Colonization
Cystic Fibrosis
Interventions Drug: AZLI
Drug: Placebo
Enrollment 149
Recruitment Details Participants were enrolled at study sites in Europe, Israel, and the United States. The first participant was screened on 28 November 2017. The last study visit occurred on 23 September 2021.
Pre-assignment Details 149 participants were screened.
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Hide Arm/Group Description 75 milligrams per milliliter (mg/ml) of aztreonam was administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received aztreonam for inhalation solution (AZLI) and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. 75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
Period Title: Overall Study
Started 74 75
Completed 49 57
Not Completed 25 18
Reason Not Completed
Study Terminated by Sponsor             16             12
Withdrew Consent by Parent/Guardian             5             4
Lost to Follow-up             1             1
Adverse Event             1             0
Non-Compliance with Study Drug             1             0
Protocol Violation             0             1
Withdrew Assent             1             0
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days Total
Hide Arm/Group Description 75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. 75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. Total of all reporting groups
Overall Number of Baseline Participants 74 75 149
Hide Baseline Analysis Population Description
Safety Analysis Set included participants who were randomized and received at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 74 participants 75 participants 149 participants
7.3  (5.34) 6.5  (4.91) 6.9  (5.13)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 74 participants 75 participants 149 participants
Female
35
  47.3%
33
  44.0%
68
  45.6%
Male
39
  52.7%
42
  56.0%
81
  54.4%
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Ethnicity Number Analyzed 74 participants 75 participants 149 participants
Not Hispanic or Latino
66
  89.2%
65
  86.7%
131
  87.9%
Hispanic or Latino
8
  10.8%
9
  12.0%
17
  11.4%
Not Permitted
0
   0.0%
1
   1.3%
1
   0.7%
[1]
Measure Description: Not Permitted = collection of ethnicity information not allowed by local regulations.
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 74 participants 75 participants 149 participants
American Indian or Alaska Native
1
   1.4%
0
   0.0%
1
   0.7%
Asian
1
   1.4%
1
   1.3%
2
   1.3%
Black or African American
1
   1.4%
0
   0.0%
1
   0.7%
White
69
  93.2%
73
  97.3%
142
  95.3%
Other
2
   2.7%
1
   1.3%
3
   2.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 74 participants 75 participants 149 participants
United Kingdom 16 17 33
United States 16 16 32
Spain 6 14 20
Italy 8 4 12
France 6 5 11
Denmark 4 5 9
Israel 4 4 8
Austria 4 3 7
Germany 4 3 7
Greece 3 1 4
Belgium 3 0 3
Netherlands 0 3 3
1.Primary Outcome
Title Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group
Hide Description [Not Specified]
Time Frame 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group and Weeks 4 to 8 for the 28 Day treatment group)
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable Analysis Set included participants who completed study drug with at least 75% compliance, did not use any anti-PA antibiotics while on study treatment with AZLI.
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Hide Arm/Group Description:
75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
Overall Number of Participants Analyzed 68 71
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
55.9
(43.3 to 67.9)
63.4
(51.1 to 74.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI 14 Days + Placebo 14 Days, AZLI 28 Days
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of the 14-day treatment regimen was claimed if the lower bound of 1-sided 97.5% confidence limit of the treatment difference (14-day course group vs 28-day course group) was above the noninferiority margin of -20%.
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value -8.0
Confidence Interval (2-Sided) 95%
-24.6 to 8.6
Estimation Comments The difference in percentage between treatment groups, and the associated 95% CIs were constructed based on stratum-adjusted Mantel-Haenszel method using age as stratification factor.
2.Secondary Outcome
Title Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period
Hide Description The primary eradication was achieved when all cultures through 28 days post AZLI treatment were PA negative. Recurrence after PA eradication was defined as first positive PA culture result in participant who successfully met primary endpoint and had no PA-positive culture from local lab at Week 4 through Week 6 for AZLI 14 Days group or through Week 8 for AZLI 28 Days group.
Time Frame Last dose date of AZLI up to Week 112
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Evaluable Analysis Set were analyzed.
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Hide Arm/Group Description:
75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
Overall Number of Participants Analyzed 68 71
Median (Inter-Quartile Range)
Unit of Measure: months
19.3 [1] 
(10.5 to NA)
NA [1] 
(4.9 to NA)
[1]
Not Available as the calculated percentiles of event rate were not reached.
3.Secondary Outcome
Title Percentage of Participants With PA-negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs Historical Pooled Data for PA Eradication at 28 Days Post-Treatment in Participants Treated With Tobramycin Nebulizer Solution (TNS)
Hide Description [Not Specified]
Time Frame 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group)
Hide Outcome Measure Data
Hide Analysis Population Description
AZLI 14 Day treatment group: Evaluable Analysis Set. No data was collected for the AZLI 28 Day treatment group for this outcome measure.
Arm/Group Title AZLI 14 Days + Placebo 14 Days
Hide Arm/Group Description:
75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
Overall Number of Participants Analyzed 68
Measure Type: Number
Unit of Measure: percentage of participants
55.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZLI 14 Days + Placebo 14 Days
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Other Statistical Analysis The historical pooled data from published results for the percentage of participants with successful PA eradication at 28 days post-treatment with TNS was estimated to be 77%.
4.Secondary Outcome
Title Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period
Hide Description

In ELITE study (NCT00391976), participants with cystic fibrosis who had early PA infection received TNS. Published criteria for efficacy analysis population in ELITE study included:

  • Participants must be ≥ 6 months at randomization
  • No history of positive anti-PA antibody (no anti-PA immunoglobulin G [IgG] antibody interpretation at Screening/Baseline) on record
  • Did not use anti-pseudomonal antibiotics through 28 days after completion of active treatment and within 2 years of Screening
  • Non-missing PA culture result at 28 days after last dose of AZLI
  • PA negative through 28 days after completion of active treatment
  • No important protocol deviation related to compliance with study drug administration
  • Documented new onset of positive respiratory tract culture for PA within 30 days of Screening defined as either first lifetime documented PA-positive culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year).
Time Frame Last dose date of AZLI up to Week 112
Hide Outcome Measure Data
Hide Analysis Population Description
ELITE Study Matching Analysis Set included participants from Evaluable Analysis Set (who did not meet evaluability criteria due to < 75% compliance, use of anti-PA antibiotics while on AZLI treatment, missing PA culture result during initial eradication phase) who also satisfied the published criteria for efficacy analysis population in ELITE study.
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Hide Arm/Group Description:
75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
Overall Number of Participants Analyzed 23 25
Median (Inter-Quartile Range)
Unit of Measure: months
19.3 [1] 
(10.5 to NA)
15.2 [1] 
(4.7 to NA)
[1]
Not Available as the calculated percentiles of event rate were not reached.
Time Frame Adverse Events: First dose date up to 28 days plus 30 days; All-Cause Mortality: Randomization up to 112 weeks
Adverse Event Reporting Description

Adverse Events: Safety Analysis Set included participants who were randomized and received at least one dose of study drug.

All-Cause Mortality: Intent-To-Treat Analysis Set included all participants who were randomized in the study.
 
Arm/Group Title AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Hide Arm/Group Description 75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. 75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece.
All-Cause Mortality
AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Affected / at Risk (%) Affected / at Risk (%)
Total   0/74 (0.00%)   0/75 (0.00%) 
Hide Serious Adverse Events
AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Affected / at Risk (%) Affected / at Risk (%)
Total   5/74 (6.76%)   4/75 (5.33%) 
Congenital, familial and genetic disorders     
Cystic fibrosis † 1  1/74 (1.35%)  0/75 (0.00%) 
Gastrointestinal disorders     
Constipation † 1  1/74 (1.35%)  0/75 (0.00%) 
Subileus † 1  1/74 (1.35%)  0/75 (0.00%) 
Infections and infestations     
Abscess † 1  0/74 (0.00%)  1/75 (1.33%) 
Infective pulmonary exacerbation of cystic fibrosis † 1  1/74 (1.35%)  0/75 (0.00%) 
Pseudomonas infection † 1  1/74 (1.35%)  1/75 (1.33%) 
Upper respiratory tract infection † 1  0/74 (0.00%)  1/75 (1.33%) 
Investigations     
Pseudomonas test positive † 1  1/74 (1.35%)  0/75 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Bronchial obstruction † 1  0/74 (0.00%)  1/75 (1.33%) 
1
Term from vocabulary, MedDRA (24.1)
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AZLI 14 Days + Placebo 14 Days AZLI 28 Days
Affected / at Risk (%) Affected / at Risk (%)
Total   28/74 (37.84%)   22/75 (29.33%) 
Gastrointestinal disorders     
Diarrhoea † 1  5/74 (6.76%)  1/75 (1.33%) 
General disorders     
Pyrexia † 1  4/74 (5.41%)  6/75 (8.00%) 
Infections and infestations     
Influenza † 1  1/74 (1.35%)  5/75 (6.67%) 
Rhinitis † 1  5/74 (6.76%)  0/75 (0.00%) 
Upper respiratory tract infection † 1  4/74 (5.41%)  3/75 (4.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  12/74 (16.22%)  11/75 (14.67%) 
1
Term from vocabulary, MedDRA (24.1)
†
Indicates events were collected by systematic assessment
The study was terminated early due to Coronavirus disease 2019 (COVID-19) pandemic. At the time of study termination, all evaluable participants completed the initial eradication period and provided data for the primary analysis.
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
Layout table for Results Point of Contact information
Name/Title: Gilead Clinical Study Information Center
Organization: Gilead Sciences
Phone: 1-833-445-3230 (GILEAD-0)
EMail: GileadClinicalTrials@gilead.com
Layout table for additonal information
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03219164    
Other Study ID Numbers: GS-US-205-1850
2016-002749-42 ( EudraCT Number )
First Submitted: July 13, 2017
First Posted: July 17, 2017
Results First Submitted: March 2, 2022
Results First Posted: May 16, 2022
Last Update Posted: June 14, 2022