Prevention of Bronchiectasis in Infants With Cystic Fibrosis (COMBATCF)

A Phase 3 Multi-centre Randomised Placebo-controlled Study of Azithromycin in the Primary Prevention of Radiologically-defined Bronchiectasis in Infants With Cystic Fibrosis.

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.

Study Overview

• Status: Completed
• Conditions: Bronchiectasis; Cystic Fibrosis
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo control

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

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Sydney Children's Hospital
    • Sydney, New South Wales, Australia
      • Westmead Children's Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
    • Brisbane, Queensland, Australia
      • Royal Children's Hospital
    • Brisbane, Queensland, Australia
      • Mater Children's Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Women's and Children's Hospital
  • Victoria
    • Melbourne, Victoria, Australia
      • Royal Children's Hospital
    • Melbourne, Victoria, Australia
      • Monash Medical Centre
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Perth Children's Hospital
• New Zealand
  • Auckland, New Zealand
    • Starship Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: azithromycin liquid preparation; azithromycin will be given at a dose of 10mg/kg given three times per week from three months of age to three years of age	Drug: Azithromycin; 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; Other Names: Zithromax
Active Comparator: inert liquid preparation; inert liquid preparation will be given three times per week from three months of age to three years of age	Drug: Placebo control; inert liquid preparation will be given three times per week from three months of age to three years of age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of children with radiologically-defined bronchiectasis	bronchiectasis will be determined from a low dose volumetric chest computed tomography scan performed at 3 years of age	at three years of age
The proportion of lung tissue affected by disease	Percentage of diseased lung will be determined from a low dose volumetric chest computed tomography scan performed at 3 years of age	at three years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
extent and severity of bronchiectasis	bronchiectasis will be determined from a low dose volumetric chest computed tomography scan performed at 3 years of age	at three years of age
CF-related quality of life	Quality of life questionnaire to be measured at 3 years	at three years of age
time to first pulmonary exacerbation	pulmonary exacerbation will be defined using a standardized instrument	over the first three years of life
proportion of participants experiencing a pulmonary exacerbation	pulmonary exacerbation will be defined using a standardized instrument	over the first three years of life
body mass index	body mass index will be calcualted from hieight and weight measurements taken at 3 years of age.	at three years of age
Proportion of participants growing Pseudomonas aeruginosa in bronchoalveolar lavage	bronchoalveolar lavage will be performed at 3 months, 1 year and 3 years of age	over the first three years of life
age of acquisition of Pseudomonas aeruginosa		over the first three years of life
Emergence of macrolide-resistant Staphylococcus aureus, small colony variant Staphylococcal aureus and non-tuberculous mycobacterium		over the first three years of life
Volume of trapped gas at age 3 years	air trapping will be determined from a low dose volumetric chest computed tomography scan performed at 3 years of age	at 3 years

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: Telethon Kids Institute
• Investigators: Study Chair: Peter D Sly, MMBS MD DSc, The University of Queensland; Study Chair: Stephen M Stick, MBBChir PhD, Telethon Kids Institute

Publications and helpful links

General Publications

• Douglas TA, Brennan S, Gard S, Berry L, Gangell C, Stick SM, Clements BS, Sly PD. Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis. Eur Respir J. 2009 Feb;33(2):305-11. doi: 10.1183/09031936.00043108. Epub 2008 Nov 14.
• Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST-CF). Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med. 2009 Jul 15;180(2):146-52. doi: 10.1164/rccm.200901-0069OC. Epub 2009 Apr 16.
• Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, Robinson P, Robertson C, Sly PD; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr. 2009 Nov;155(5):623-8.e1. doi: 10.1016/j.jpeds.2009.05.005. Epub 2009 Jul 19.
• Stick SM, Foti A, Ware RS, Tiddens HAWM, Clements BS, Armstrong DS, Selvadurai H, Tai A, Cooper PJ, Byrnes CA, Belessis Y, Wainwright C, Jaffe A, Robinson P, Saiman L, Sly PD; COMBAT CF Study Group. The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial. Lancet Respir Med. 2022 Aug;10(8):776-784. doi: 10.1016/S2213-2600(22)00165-5. Epub 2022 Jun 2.

Helpful Links

• The Australia Respiratory Early Surveillance Team for Cystic Fibrosis
• Telethon Institute for Child Health Research

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: December 23, 2010
• First Submitted That Met QC Criteria: January 4, 2011
• First Posted (Estimate): January 5, 2011

Study Record Updates

• Last Update Posted (Actual): September 16, 2021
• Last Update Submitted That Met QC Criteria: September 8, 2021
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: pediatric; cystic fibrosis; infant; bronchiectasis; azithromycin; double blind placebo controlled randomised clinical trial
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Bronchial Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Bronchiectasis; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: AZI001; STICK10K0 (Other Grant/Funding Number: Cystif Fibrosis Foundation Therapeutics, INc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol; Clinical Study Report (CSR)