OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Infections; Pseudomonas Infections; Cystic Fibrosis; Fibrosis
Intervention: azithromycin; placebo; Tobramycin solution for inhalation
Intervention description: 3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months; 3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months; 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
Intervention MeSH terms: Azithromycin; Tobramycin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 221.0
Sex: All
Minimum age: 6 Months
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Cystic fibrosis (CF); Azithromycin; Tobramycin solution for inhalation (TIS); Pseudomonas aeruginosa (Pa); Early Pseudomonas aeruginosa infection; Pulmonary exacerbation; Standardized anti-pseudomonal therapy

Summary:

      The purpose of this trial is to compare the effects of treatment with tobramycin solution for
      inhalation (TIS) with and without azithromycin in people with cystic fibrosis (CF) age 6
      months to 18 years who have early isolation of Pseudomonas aeruginosa (Pa) from a respiratory
      culture. Specimens of blood and sputum or throat swabs will be taken during the study along
      with pulmonary function testing. Participants will receive initial treatment with TIS
      followed additional treatment with TIS if quarterly respiratory cultures are positive for Pa
      in addition to either azithromycin or placebo for 18 months.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥ 6 months to ≤ 18 years

          -  Documentation of a CF diagnosis as evidenced by one or more clinical features
             consistent with the CF phenotype or positive CF Newborn Screening result for
             immunoreactive trypsinogen (IRT) IRT/DNA or IRT/IRT and one or more of the following
             criteria:

          -  sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative by pilocarpine
             iontophoresis test (QPIT)

          -  two well-characterized mutations in the cystic fibrosis transmembrane conductive
             regulator (CFTR) gene

          -  Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride
             solution and isoproteronol of less than - 5 mV)

          -  Documented new positive oropharyngeal, sputum or lower respiratory tract culture for
             Pa within 30 days of the Baseline Visit (Visit 1), defined as: a) first lifetime
             documented Pa positive culture; or b) Pa recovered after at least a two-year history
             of Pa negative respiratory cultures (≥ 1 culture/ year)

          -  Clinically stable with no evidence of any significant respiratory symptoms at the
             Baseline Visit that would require administration of intravenous anti- pseudomonal
             antibiotics, oxygen supplementation, and/or hospitalization as determined by the study
             physician

          -  Written informed consent obtained from participant or participant's legal
             representative (and assent when applicable) and ability for participant to comply with
             the requirements of the study

        Exclusion Criteria:

          -  Macrolide antibiotic use within 30 days of the Baseline Visit

          -  Initiation of current course of treatment with TIS >14 days prior to Baseline Visit

          -  Weight <6.0 kg at the Baseline Visit

          -  History of aminoglycoside hypersensitivity or adverse reaction to inhaled
             aminoglycoside

          -  History of azithromycin hypersensitivity or adverse reaction to azithromycin or
             allergy to macrolide antibiotics

          -  History of positive respiratory culture for Non-tuberculous mycobacteria (NTM) or
             Burkholderia cepacia complex within 2 years of the Baseline Visit

          -  History of unresolved, abnormal renal function (defined as serum creatinine greater
             than 1.5 times the upper limit of normal for age).

          -  History of unresolved, abnormal liver function tests (defined as alanine
             aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 4 times
             the upper limit of normal range) or history of portal hypertension

          -  History of unresolved, abnormal neutropenia (ANC ≤ 1000)

          -  Abnormal ECG test at the Baseline Visit defined as a QT interval corrected (QTc) (B)
             of ≥460 msec or history of ventricular arrhythmia

          -  History of abnormal hearing sensitivity defined as hearing threshold levels >25 dB HL
             (decibels Hearing Level) for visual reinforcement audiometry (VRA) at any frequency
             (500-4000Hz) or >20 Decibels Hearing Level (dBHL) for play or standard audiometry at
             any two frequencies (500-8000Hz) in either ear, not associated with middle ear disease
             (including infection) or a flat (Type B) tympanogram

          -  New initiation of chronic therapy (greater than 21 days) with drugs known to prolong
             QT interval (refer to Appendix III) within 30 days prior to the Baseline Visit or
             coadministration of nelfinavir or oral anticoagulants

          -  Positive serum or urine pregnancy test at the Baseline Visit (to be performed on all
             females of child-bearing potential) or for females of child bearing potential:
             pregnant, breastfeeding, or unwilling to use barrier contraception during
             participation in the study

          -  Administration of any investigational drug within 30 days prior to the Baseline Visit

          -  Presence of a condition or abnormality (e.g., pre-existing heart disease) that in the
             opinion of the site investigator would compromise the safety of the participant or the
             quality of the data