Prevention of Bronchiectasis in Infants With Cystic Fibrosis
Condition: Cystic Fibrosis; Bronchiectasis
MeSH terms: Cystic Fibrosis; Bronchiectasis; Fibrosis
Study type: Interventional
Phase: Phase 3

Summary: 
      The general aim of this project is to conduct a randomized, double-blind, placebo-controlled
      clinical trial of azithromycin to determine whether treatment from infancy is safe and will
      prevent the onset of bronchiectasis. One hundred and thirty infants will be recruited from CF
      clinics in Australia and New Zealand and treated from 3 months to three years of age. The
      primary outcome will be the proportion with radiologically-defined bronchiectasis at 3 years
      of age. Safety and mechanistic evaluations will also be undertaken.
    

Detailed description: 
      SYNOPSIS OF PROTOCOL

      Title Multi-centre randomized placebo-controlled study of azithromycin in the primary
      prevention of radiologically-defined bronchiectasis in infants with Cystic Fibrosis

      Clinical Phase Phase 3

      Protocol Number: AZI001

      TGA Reference Number:

      Protocol Co-Chairs: Peter D. Sly & Stephen M. Stick Microbiology Consultant: Lisa Saiman CT
      Consultant: Harm Tiddens Statistical Consultant: Robert S Ware

      Study Design Randomized, double-blind parallel groups. Participants will be randomized into
      one of the following 2 groups on a 1:1 ratio with 65 participants per group;

      Group A: 10 mg/kg (as 200mg/5ml) azithromycin three times weekly for three years added to
      standard CF therapy.

      Group B: matched placebo three times weekly for three years added to standard CF therapy.

      Accrual Objective 130 children

      Accrual Period 24 months

      Study Duration 36 months

      Countries: Australia and New Zealand

      Sites: Brisbane Au, Sydney, Au, Melbourne Au, Adelaide Au, Perth Au,Auckland Nz, Christchurch
      Nz.

      Primary Endpoint The primary endpoints are the proportion of children with
      radiologically-defined bronchiectasis at age 3 years, and the proportion of lung tissue
      affected by disease at age 3 years.

      Secondary Endpoints

        -  The extent and severity of bronchiectasis at age 3 years

        -  The volume of trapped gas at age 3 years

        -  CF-related quality of life

        -  Time to first pulmonary exacerbation

        -  Proportion of participants experiencing a pulmonary exacerbation

        -  Number of courses of inhaled or oral antibiotics

        -  Number of days of inhaled antibiotics

        -  Incidence of hospitalizations/Accident and Emergency department (A&E) visits for an
           acute respiratory exacerbation

        -  Number of days hospitalized for an acute respiratory exacerbation

        -  Number of days if intravenous antibiotics

        -  Body mass index at 3 years of age.

      Exploratory Endpoints

        -  Markers of neutrophilic inflammation

        -  Markers of oxidative stress

        -  Composition of airway flora

      Safety Endpoints

        -  Proportion of participants growing P. aeruginosa in BAL

        -  Age of acquisition of P. aeruginosa in BAL

        -  Emergence of macrolide-resistant S. aureus, small colony variant S. aureus and
           non-tuberculous mycobacteria (NTM)

        -  Treatment-related adverse events

        -  Haematology and clinical chemistry

      Inclusion Criteria Participants who meet all of the following criteria are eligible for
      enrolment as study participants:

        1. Children of either sex with a diagnosis of CF following detection via New Born Screening
           (NBS) for cystic fibrosis

        2. Participants who, in the opinion of the Investigator, are able to comply with the
           protocol for its duration

        3. Written informed consent signed and dated by parent/legal guardian according to local
           regulations

      Exclusion Criteria Participants who meet any of these criteria are not eligible for enrolment
      as trial participants:

        1. Born <30 weeks gestation

        2. Prolonged mechanical ventilation in the first 3 months of life

        3. Participation in another randomized controlled trial within the 3 months preceding
           inclusion in this study

        4. A significant medical disease or condition other than CF that is likely to interfere
           with the child's ability to complete the entire protocol

        5. Previous major surgery except for meconium ileus

        6. Macrolide hypersensitivity

      Treatment Description ZITHROMAX® (azithromycin)

      Study Procedures The study participants will be stratified by investigational site and
      randomly assigned to either azithromycin or placebo for three years.

      Statistical Considerations Participants will be randomized in blocks to the treatment group
      or the placebo group using a one-to-one ratio. Randomization will be stratified by study
      site. This will ensure an approximately equal allocation to each group within each site.

      Interim Analyses Interim analyses will occur when the first 50% of children (n=33 per group
      have completed the 12 month CT and when all subjects have completed the 12 month CT. Interim
      analyses will determine safety or success (unethical to continue).

      Stopping Rules Study enrolment may be stopped if any of the following events occur:

        -  Death of a participant that is related to study treatment.

        -  The trial meets the definition of futility or success at either of the planned interim
           analyses
    

Intervention name(s): Azithromycin; Placebo control
Intervention type(s): Drug; Drug
Intervention description(s): azithromycin will be given as a liquid preparation at a dose of 10 mg/kg three times per week from three months of age until three years of age; inert liquid preparation will be given three times per week from three months of age to three years of age
Other intervention name(s): Zithromax
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: double blind placebo controlled randomised clinical trial; azithromycin; infant; pediatric; cystic fibrosis; bronchiectasis