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.

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

Inclusion Criteria:

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:

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