Title
International Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis Patients With P. Aeruginosa
A Phase 3, Double-Blind, Multicenter, Multinational, Randomized, Placebo-Controlled Trial Evaluating Aztreonam Lysinate for Inhalation in Cystic Fibrosis Patients With Pulmonary Pseudomonas Aeruginosa (AIR-CF1)
Phase
Phase 3Lead Sponsor
Gilead SciencesStudy Type
InterventionalStatus
Completed Results PostedIndication/Condition
Cystic FibrosisIntervention/Treatment
azlocillin ...Study Participants
166The 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) and lung infection due to Pseudomonas aeruginosa (PA).
CF patients often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called Pseudomonas aeruginosa (PA). Treatment with antibiotics can stop or slow down the growth of the bacteria. The antibiotics may be given by mouth, intravenously (IV), or by inhalation as a mist. The purpose of this study was to evaluate the safety and efficacy of AZLI, an investigational formulation of the antibiotic aztreonam and administered TID using the PARI eFlow® electronic nebulizer, in CF patients with PA.
In this study, participant eligibility was assessed at a screening visit 7 to 14 days prior to the baseline visit (Day 0). Those participants who continued to meet eligibility criteria at Day 0 were randomized and began a 28-day course of blinded study treatment (AZLI TID or placebo TID). Participants returned for clinic visits at Day 14, an end of treatment visit at Day 28, and a follow-up visit 14 days after the last dose of study drug (Day 42).
Inclusion Criteria: Documentation of CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria: Sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT); Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or Abnormal nasal potential difference. PA present in expectorated sputum or throat swab culture at Screening. FEV1 between (and including) 25% and 75% predicted at Screening. Negative pregnancy test at Screening. Ability to perform reproducible pulmonary function tests. Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening. Ability to provide written informed consent. Exclusion Criteria: Administration of antipseudomonal antibiotics by inhalation, IV, or oral routes (including azithromycin) within 14 days of Screening. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day. History of sputum or throat swab culture yielding Burkholderia cepacia in the previous 2 years. History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night. Administration of any investigational drug or use of any investigational device within 28 days of Screening and within 6 half-lives of the investigational drug (whichever was longer). Known local or systemic hypersensitivity to monobactam antibiotics. Inability to tolerate short-acting bronchodilator use at least three times daily. Changes in protocol-permitted antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days prior to Screening or between Screening and the next visit. Changes in physiotherapy technique or schedule within 7 days prior to Screening or between Screening and the next visit. History of lung transplantation. A chest x-ray indicating abnormal findings at Screening or within the previous 90 days. Abnormal renal or hepatic function at Screening. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with participant treatment, assessment, or compliance with the protocol. Use of aerosolized hypertonic saline (except for sputum induction) during the 14 days preceding Visit 1.
| Event Type | Organ System | Event Term | Placebo TID | 75 mg AZLI TID |
|---|
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R respiratory symptoms scale (RSS; range of scores: 0-100; higher scores indicate fewer symptoms).
Details of all hospitalizations, including the dates of admission and discharge, were recorded on the SAE eCRF.
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms).
The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms).
Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. The percent change from baseline in forced expiratory volume (liters) in one second (FEV1) was determined at Day 28.
Sputum samples were collected at all participant visits of the study for analysis of microbiology endpoints. Sputum samples were processed for qualitative and quantitative culture of PA (each morphotype). Due to the skewness of the distribution of CFU data, the data were transformed using the base 10 logarithm, in an attempt to normalize the data and allow for parametric tests, before calculating changes. To account for zero values, 1 was added to each CFU measurement before being transformed. Any CFU data values where PA was not isolated from a valid culture were set to zero.
Use of IV and inhaled antipseudomonal antibiotics was compiled from data recorded on the Concomitant Medications eCRF.
PA isolates from sputum samples (collected at all visits) were assessed for their susceptibility to aztreonam. MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism). MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism). MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis.
Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans.
PA isolates from sputum samples (collected at all visits) were assessed for their susceptibility to aztreonam. MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism). MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism). MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis.
