Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis and Chronic Burkholderia Species Infection
Condition: Cystic Fibrosis; Burkholderia Infections
MeSH terms: Infections; Communicable Diseases; Burkholderia Infections; Cystic Fibrosis; Fibrosis
Intervention: AZLI; Placebo
Intervention description: Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.; Placebo to match AZLI (lactose and sodium chloride) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 102.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
Keywords: Cystic Fibrosis; Aztreonam Lysine; lung infection; Burkholderia; CFQ-R; inhaled antibiotic

Summary:

      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.
    

Eligibility criteria:

        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