Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis Patients With P. Aeruginosa

Phase 3

Completed

Conditions: Cystic Fibrosis

Interventions: Drug: Placebo two times a day (BID)/three times a day (TID)
Drug: AZLI 75 mg two times a day (BID)/three times a day (TID)

Registration Number: NCT00104520

Lead Sponsor: Gilead Sciences

Brief Summary: The purpose of this study was to evaluate the safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).

Detailed Description: Patients with CF often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called 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 aztreonam for inhalation solution (AZLI), an investigational formulation of the antibiotic administered using the eFlow® Electronic Nebulizer by PARI GmbH, in CF patients with PA.

In this study, participants were screened for eligibility at Visit 1 (Day -42) and returned to the center for Visit 2 after a 14-day evaluation period. At Visit 2 (Day -28), participants began a 28-day course of open-label Tobramycin Inhalation Solution (TIS). At Visit 3 (Day 0), following completion of the 28-day course of TIS, participants began randomized, blinded treatment with either AZLI twice a day (BID) or three times a day (TID) or placebo BID or TID, and continued treatment for a total of 28 days, with a clinic visit at Day 14 (Visit 4) and at the end of treatment (Visit 5 \[Day 28\]). Participants returned for visits every 2 weeks for 8 weeks after the end of the blinded treatment (Visits 6 to 9 \[Days 42 to 84\]).

Two hundred and forty-seven participants were treated in the TIS phase of this study. Two hundred and eleven subjects completed the TIS phase and were treated in the placebo-controlled phase with study drug (AZLI or placebo).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 211

Inclusion Criteria

CF as diagnosed by:
1. Documented sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test; or
2. Two well-characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or
3. Abnormal nasal potential difference with accompanying symptoms characteristic of CF.
PA present in expectorated sputum or throat swab culture at Screening.
Participants must have received three or more courses of TIS within the previous 12 months.
Participants on chronic azithromycin must have had no change in regimen in the previous 3 months and must have had a need for TIS and/or additional antipseudomonal therapy since initiation of azithromycin.
Forced expiratory volume in 1 second (FEV1) between (and including) 25% and 75% predicted at Screening.
Ability to perform reproducible pulmonary function tests.
Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening.

Exclusion Criteria

Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day.
History of sputum or throat culture swab yielding Burkholderia cepacia in the past 2 years.
History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night.
Administration of any investigational drug or device within 28 days of Screening (Visit 1) or within 6 half-lives of the investigational drug (whichever was longer).
Known local or systemic hypersensitivity to monobactam antibiotics.
Inability to tolerate inhalation of a short acting Beta-2 agonist.
Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days before Screening or between Screening and the next visit.
Changes in physiotherapy technique or schedule within 7 days before 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 or serum chemistry at Screening (aspartate aminotransferase [AST], alanine aminotransferase [ALT] greater than 5 times the upper limit of normal range; Creatinine greater than 2 times the upper limit of normal range).
Positive pregnancy test at Screening.
Female of childbearing potential who was lactating or in the opinion of the investigator was not practicing acceptable birth control.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo (pooled two times a day [BID]/three times a day [TID])	Placebo two times a day (BID)/three times a day (TID)	-
AZLI (pooled two times a day [BID]/three times a day [TID])	AZLI 75 mg two times a day (BID)/three times a day (TID)	-

Primary Outcome Measures

Name	Time	Method
Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics	Day 0 to Day 84 (end of study)	The primary endpoint was time to need for a course of inhaled or IV antipseudomonal antibiotics with documented physician assessment of need for antibiotics. Antipseudomonal Antibiotic need was documented based on the presence of at least one of the following four symptoms predictive of pulmonary exacerbation: decreased exercise tolerance, increased cough, increased sputum / chest congestion, decreased appetite, or other.

Secondary Outcome Measures

Name	Time	Method
Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score	Day 0 to Day 28	The CFQ-R was administered at Day -28, baseline, Day 14, Day 28, and Day 84 (end of study). The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms).
Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L)	Day 0 to Day 28	Spirometry was performed at each visit. FEV1 was recorded according to American Thoracic Society (ATS) guidelines. FEV1(L) is the measurement of the volume of air (expressed in liters) exhaled in 1 second. The percent change in this parameter from Day 0 to Day 28 was determined for each treatment group.
Number of Hospitalization Days	Day 0 to Day 84	Details of all hospitalizations, including the dates of admission and discharge, were recorded on the electronic case report form (eCRF).
Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum	Day 0 to 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.

Trial Locations

Locations (56): Phoenix Children's Hospital
🇺🇸
Phoenix, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
University of California, San Diego
🇺🇸
La Jolla, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Kaiser Permanente Medical Care Program
🇺🇸
Oakland, California, United States
Children's Hospital, Orange Co.
🇺🇸
Orange, California, United States
Stanford University Hospital and Medical Center
🇺🇸
Palo Alto, California, United States
UC Davis Medical Center
🇺🇸
Sacramento, California, United States
Children's Hospital
🇺🇸
Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
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Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States