OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Infections; Pseudomonas Infections; Cystic Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Cystic fibrosis (CF) lung disease begins in the first few months of life and follows a course
      of recurrent lower airway bacterial infection and inflammation and progression of disease
      over years and decades at a variable pace. With the development of chronic lung infection,
      obstructive disease progressively worsens, ultimately leading to respiratory failure.
      Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the CF lower airways,
      and its acquisition early in life is associated with a pro-inflammatory effect, lower lung
      function, poor nutritional outcomes, and decreased survival.

      Pseudomonas aeruginosa (Pa) infection of the cystic fibrosis (CF) airway typically proceeds
      from early infection to chronic infection. Although some studies have shown that a minority
      of individuals with CF spontaneously clear early Pseudomonas aeruginosa (Pa) infection, data
      from multiple studies suggest that antibiotics are superior to no treatment in clearing
      Pseudomonas aeruginosa (Pa) from respiratory cultures. Understanding the transition period
      from early to chronic Pseudomonas aeruginosa (Pa) infection is thus of critical importance in
      identifying strategies to prevent this progression.

      The study will assess the clinical and microbiologic efficacy and safety of azithromycin
      given three times weekly in combination with standardized tobramycin solution for inhalation
      (TIS) therapy among children with early Pseudomonas aeruginosa (Pa). TIS therapy is defined
      as an initial eradication treatment with 1-2 courses of 28 days TIS and subsequent 28 day
      treatments only at times a quarterly respiratory culture is positive for Pseudomonas
      aeruginosa (Pa). Eligible participants will be randomized within one month of their
      Pseudomonas aeruginosa (Pa) positive culture to receive one of the following two treatment
      strategies for 18 months: (1) oral placebo in addition to standardized TIS therapy, or (2)
      oral azithromycin in addition to standardized TIS therapy.

      At the first study visit, participants will undergo a physical examination and a review of
      their medical history. Lung function will be measured via spirometry (in children greater
      than four years of age who are able to perform spirometry), electrocardiogram (ECG) testing
      will be conducted, and hearing ability will be measured via audiometry. Blood will be drawn
      for laboratory tests and a specimen will be obtained for a respiratory culture before
      randomization and study drug dispensing occurs. Subsequent study visits will take place at
      Day 21, Weeks 13, 26, 39, 52, 65, and 78. At each visit, participants will undergo a physical
      examination, a spirometry test (as appropriate), a respiratory specimen for Pseudomonas
      aeruginosa (Pa) culture will be collected and study drug will be dispensed (except at Week
      78). Participants will complete self-report or parent-completed respiratory symptom
      questionnaires and signs and symptoms evaluations will be performed at all visits. Repeat
      hearing and laboratory tests will be performed at Weeks 39 and 78 and ECG testing will be
      repeated at Day 21 and Week 78. Participants will be required to maintain a medication diary
      throughout the study.
    

Intervention name(s): azithromycin; placebo; Tobramycin solution for inhalation
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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
Other intervention name(s): TIS
Intervention MeSH terms: Azithromycin; Tobramycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cystic fibrosis (CF); Azithromycin; Tobramycin solution for inhalation (TIS); Pseudomonas aeruginosa (Pa); Early Pseudomonas aeruginosa infection; Pulmonary exacerbation; Standardized anti-pseudomonal therapy