Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis and Chronic Burkholderia Species Infection

Phase 3b Randomized, Double-Blind, Placebo-Controlled Two-Part Trial to Assess the Safety and Efficacy of Continuous Aztreonam for Inhalation Solution (AZLI) in Subjects With Cystic Fibrosis (CF) and Chronic Burkholderia Species Infection

The purpose of this research study was to determine if an experimental drug called Aztreonam for Inhalation Solution (AZLI) was safe and effective to treat Burkholderia lung infections in patients with cystic fibrosis (CF).

Spirometry was used to assess pulmonary function, and the revised Cystic Fibrosis Questionnaire (CFQ-R) was used to assess quality of life. The CFQ-R is a validated, patient-reported outcome tool used to measure health-related quality of life for children and adults with CF.

The study consisted of a 24-week randomized phase, and a 24-week open-label phase. Primary and secondary efficacy analyses were conducted for the 24-week randomized phase only. Safety data were collected for both the randomized and open-label phases.

Inclusion Criteria:

1. Male or female ≥ 6 years of age

2. Subjects with CF as diagnosed by one of the following:

   • Documented sweat chloride ≥ 60 milliequivalent (mEq)/L by quantitative pilocarpine iontophoresis test
   • Documented sweat sodium ≥ 60 mmol/L
   • Two well-characterized genetic mutations in the CF transmembrane conductance regulator (CFTR) gene
   • Abnormal nasal potential difference (NPD) with accompanying symptoms characteristic of CF

3. Chronic infection with Burkholderia spp. defined by:

   • One sputum (or bronchoalveolar lavage) culture positive for Burkholderia spp. within 6 months prior to baseline assessment,
   • At least 50% of sputum (or bronchoalveolar lavage) cultures collected at least one month apart over the previous 12 months prior to baseline assessment positive for Burkholderia spp. (minimum of 2 positive cultures), and
   • At least one positive sputum (or bronchoalveolar lavage) culture (obtained at any point in time) confirmed to be Burkholderia spp. by the Cystic Fibrosis Foundation (CFF) Burkholderia cepacia Research Laboratory and Repository at the University of Michigan (or equivalent Canadian reference laboratory).

4. Concomitant aerosolized antibiotic treatment: subjects receiving intermittent (alternating month on/month off) aerosolized antibiotic treatment were eligible, but must have been at least 1 week into their off-treatment cycle at the time of baseline assessment. Subjects receiving continuous aerosolized antibiotic treatment were eligible without restriction on their aerosolized antibiotic treatment.

5. Chest radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) (most recent, obtained within 90 days of screening) without significant acute findings (eg, infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax), and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) were allowed.

6. Subjects (and parent/guardian as required) must have been able to provide written informed consent/assent prior to any study-related procedures,

7. Ability to perform reproducible pulmonary function tests

8. Sexually active females of childbearing potential must have agreed to use a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of study drug. A highly effective method of birth control was defined as a method that would result in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), or a vasectomized partner.

Exclusion Criteria:

1. Administration of any investigational drug or use of any investigational device within 28 days of randomization/baseline and within six half-lives of the investigational drug (whichever is longer)

2. Administration of AZLI treatment within the 28 days prior to randomization/baseline

3. Known local or systemic hypersensitivity to monobactam antibiotics

4. History of lung transplantation

5. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as:

   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of the normal range (ULN)
   • Serum creatinine > 2 times ULN

6. Known portal hypertension or complications of CF hepatopathy

7. Positive urine pregnancy test (confirmed by serum pregnancy test) at screening; all women of childbearing potential were tested

8. Any female of childbearing potential who was lactating or not practicing a highly effective method of birth control as defined in the protocol

9. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with subject treatment, assessment or compliance with the protocol