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

• AZLI (Drug), also known as Cayston®, Aztreonam: Administered via the PARI Altera® Nebulizer System. Participants < 2 years will receive via the SmartMask® Baby, 2 to < 6 years via the SmartMask Kids® and > 6 years via the nebulizer mouthpiece.
• Placebo (Drug): Administered via the PARI Altera® Nebulizer System. Participants < 2 years will receive via the SmartMask® Baby, 2 to < 6 years via the SmartMask Kids® and > 6 years via the nebulizer mouthpiece.

Primary outcomes

• 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 [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)]

Secondary outcomes

• Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period [Last dose date of AZLI up to Week 112]: 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.
• 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) [28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group)]
• 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 [Last dose date of AZLI up to Week 112]: 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).

Sex: All, ages: 3 Months to 18 Years

Key Inclusion Criteria:

* Diagnosis of cystic fibrosis (CF) as determined by the 2008 CF Consensus Conference criteria: Sweat chloride level ≥ 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis; or a genotype with 2 identifiable mutations consistent with CF; or an abnormal nasal transepithelial potential difference (NPD), and 1 or more clinical features consistent with CF
* 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)
* Forced expiratory volume in one second (FEV1) ≥ 80% predicted (for subjects ≥ 6 years of age who can reliably perform spirometry assessments)
* Clinically stable with no evidence of acute significant respiratory symptoms that would require administration of intravenous (IV) antipseudomonal antibiotics, oxygen supplementation, or hospitalization

Key Exclusion Criteria:

* Use of IV or inhaled antipseudomonal antibiotics within 2 years of screening
* Use of oral antipseudomonal antibiotics for a respiratory event within 30 days of study entry (screening visit)
* History of intolerance to inhaled short acting β2 agonists
* History of lung transplantation
* Current requirement for daily continuous oxygen supplementation or requirement of more than 2 L/minute at night
* Hospitalization for a respiratory event within 30 days prior to screening
* Changes in bronchodilator, corticosteroid, dornase alfa, or hypertonic saline medications within 7 days prior to screening.
* Significant changes (per investigators discretion) in physiotherapy technique or schedule within 7 days prior to screening
* Abnormal renal or hepatic function results at most recent test within the previous 12 months, defined as Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN), or Serum creatinine > 2 times ULN for age
* Presence of a condition or abnormality that would compromise the subject's safety or the quality of the study data, in the opinion of the Investigator
* Known hypersensitivity to aztreonam, its metabolites, or formulation excipients in AZLI
* Respiratory cultures performed within 24 months prior to screening that are positive for ANY Burkholderia spp. or Non-tuberculous mycobacteria (NTM)

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Participant flow

Outcome results

• 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 (Primary), Number, percentage of participants: AZLI 14 Days + Placebo 14 Days 55.9 (43.3 to 67.9); AZLI 28 Days 63.4 (51.1 to 74.5)
• Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period (Secondary), Median, months: AZLI 14 Days + Placebo 14 Days 19.3 (10.5 to NA); AZLI 28 Days NA (4.9 to NA)
• 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) (Secondary), Number, percentage of participants: AZLI 14 Days + Placebo 14 Days 55.9
• 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 (Secondary), Median, months: AZLI 14 Days + Placebo 14 Days 19.3 (10.5 to NA); AZLI 28 Days 15.2 (4.7 to NA)

Adverse events

Time frame: Adverse Events: First dose date up to 28 days plus 30 days; All-Cause Mortality: Randomization up to 112 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: 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.

• Results publication: Gilchrist FJ, Bui S, Gartner S, McColley SA, Tiddens H, Ruiz G, Stehling F, Alani M, Gurtovaya O, Bresnik M, Watkins TR, Frankovic B, Skov M; ALPINE2 study investigators. ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis. J Cyst Fibros. 2024 Jan;23(1):80-86. doi: 10.1016/j.jcf.2023.06.008. Epub 2023 Jul 15. PMID 37455237

• Study Protocol (PDF, 2020-04-15)
• Statistical Analysis Plan (PDF, 2021-12-01)

• Gilead Study Director, Study director, Gilead Sciences

NIH grants: 2016