Prevention of Bronchiectasis in Infants With Cystic Fibrosis

NCT ID: NCT01270074

Last Updated: 2021-09-16

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

130 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-04-30

Study Completion Date

2021-03-31

Brief Summary

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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

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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

Conditions

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Cystic Fibrosis Bronchiectasis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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

Group Type EXPERIMENTAL

Azithromycin

Intervention Type DRUG

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

inert liquid preparation will be given three times per week from three months of age to three years of age

Group Type ACTIVE_COMPARATOR

Placebo control

Intervention Type DRUG

inert liquid preparation will be given three times per week from three months of age to three years of age

Interventions

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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

Intervention Type DRUG

Placebo control

inert liquid preparation will be given three times per week from three months of age to three years of age

Intervention Type DRUG

Other Intervention Names

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Zithromax

Eligibility Criteria

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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
Minimum Eligible Age

6 Weeks

Maximum Eligible Age

6 Months

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Telethon Kids Institute

OTHER

Sponsor Role collaborator

The University of Queensland

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Peter D Sly, MMBS MD DSc

Role: STUDY_CHAIR

The University of Queensland

Stephen M Stick, MBBChir PhD

Role: STUDY_CHAIR

Telethon Kids Institute

Locations

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Sydney Children's Hospital

Sydney, New South Wales, Australia

Site Status

Westmead Children's Hospital

Sydney, New South Wales, Australia

Site Status

Queensland Children's Hospital

Brisbane, Queensland, Australia

Site Status

Mater Children's Hospital

Brisbane, Queensland, Australia

Site Status

Royal Children's Hospital

Brisbane, Queensland, Australia

Site Status

Women's and Children's Hospital

Adelaide, South Australia, Australia

Site Status

Monash Medical Centre

Melbourne, Victoria, Australia

Site Status

Royal Children's Hospital

Melbourne, Victoria, Australia

Site Status

Perth Children's Hospital

Perth, Western Australia, Australia

Site Status

Starship Hospital

Auckland, , New Zealand

Site Status

Countries

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Australia New Zealand

References

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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.

Reference Type BACKGROUND
PMID: 19010992 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19372250 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19616787 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35662406 (View on PubMed)

Related Links

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http://arestcf.org

The Australia Respiratory Early Surveillance Team for Cystic Fibrosis

http://ichr.uwa.edu.au

Telethon Institute for Child Health Research

Other Identifiers

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STICK10K0

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AZI001

Identifier Type: -

Identifier Source: org_study_id

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