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Trial registered on ANZCTR


Registration number
ACTRN12610000383066
Ethics application status
Approved
Date submitted
11/09/2008
Date registered
12/05/2010
Date last updated
21/10/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
A collaborative and international study of bronchiectasis in Indigenous children
Scientific title
Among Indigenous children with bronchiectasis, does weekly azithromycin (compared to weekly placebo) reduce rates of exacerbation?
Secondary ID [1] 713 0
Menzies School of Health Research project number R205A
Universal Trial Number (UTN)
Trial acronym
BIS (Bronchiectasis Interventional Study)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiectasis in Indigenous children 3672 0
Condition category
Condition code
Respiratory 3838 3838 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study drug (azithromycin) is in powder format and will be reconstituted with 9ml of sterile water to syrup for oral use. This makes up to 40mg/ml. Children will receive a weekly dose of oral azithromycin once per week at 30mg/kg for up to 2 years.
Intervention code [1] 3387 0
Treatment: Drugs
Comparator / control treatment
Placebo - powder for reconstitution to syrup for oral use. The study drug (placebo) is in powder format and will be reconstituted with 9ml of sterile water to syrup for oral use.

This makes up to 40mg/ml. Children will receive a weekly dose of medication once per week at 30mg/kg for up to 2 years.

The placebo medication will be prepared ensuring they are similar in appearance, taste, and smell and packaging to the active medication however will have no active ingredients, so that blinding during the study period is maintained.
Control group
Placebo

Outcomes
Primary outcome [1] 4736 0
Rate of pulmonary exacerbations of bronchiectasis by review of patient medical records.
Timepoint [1] 4736 0
Data will be collected every 3 months for up to 24 months from study entry. Data will be analysed at the interim analysis (at about 12 months from study commencement) and final analysis only (at about 24 months from study commencement).
Secondary outcome [1] 7998 0
Time to pulmonary exacerbation from review of patient medical records.
Timepoint [1] 7998 0
Data will be collected every 3 months for up to 24 months from study entry. Data will be analysed at the interim analysis and final analysis only.
Secondary outcome [2] 7999 0
Safety (antibiotic resistance, side effects). Antibiotic resistance in bacterial respiratory pathogens will be assessed by standard laboratory methods using internationally accepted cut points. Comparisons will be made of proportions of children found to be carrying azithromycin or penicillin resistance pneumococci or haemophilus influenzae during the treatment period.
The following adverse events will be monitored: chest pain, dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis, anemia and leukopenia, headache, hyperkinesia, dizziness, agitation, nervousness and insomnia, fever, face edema, fatigue, fungal infection, malaise and pain, rash and allergic reaction, cough increased pharyngitis, pleural effusion and rhinitis, eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash and conjunctivitis.
Any untoward medical occurrence that results in death or is life threatening, results in significant disability/incapacity pr requires inpatient hospitalisation or prolongation of existing hospitalisation will be monitored.
Assessment of adverse events will be done by monitoring of medical charts. In addition, staff from the relevant hospitals/community health centre will report all adverse events to the Chief investigator and/or Nursing Coordinator.
Timepoint [2] 7999 0
Data will collected every 3 months up to 24 months from study entry. Data will be analysed at the interim analysis and final analysis only.
Secondary outcome [3] 8000 0
Severity of pulmonary exacerbation episodes by review of patient medical records.
Timepoint [3] 8000 0
Data will collected every 3 months up to 24 months from study entry. Data will be analysed at the interim analysis and final analysis only.
Secondary outcome [4] 8001 0
Changes in High Resolution Computed Tomography (HRCT) and chest Xray scoring
Timepoint [4] 8001 0
Data will be analysed at the interim analysis and final analysis only..

Eligibility
Key inclusion criteria
Aboriginal, Pacific Islander or Maori children
Aged between 12 months to 8 years (less than 9 years old)
Current resident of study catchment community
At least one episode of pulmonary exacerbation in the last 12 months
No specific cause for bronchiectasis found despite appropriate investigation and hitorical review
Diagnosed with definite bronchiectasis (High resolution CT confirmed) OR a clinical diagnosis of Chronic Supporative Lung Disease after appropriate investigations have been completed (including Full Blood Count, Immunoglobulins and chest Xray)
Minimum age
12 Months
Maximum age
8 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Non Indigenous children. Incorrect age. Children who are on long term antibiotic use. Known cause of bronchiectasis such as cystic fibrosis, primary immnunodeficiency, Kartageners syndrome, primary ciliary dyskinesia, Marfans disease, severe burns, aspiration. Is currently undergoing treatment for cancer (having chemotherapy). Post transplant treatment (renal/cardiac and under immunosuppression treatment). Has diabetes. Has central or peripheral nervous system disorder. Has macrolide hypersensitivity. Non resident of study catchment area. Decision made by local doctor (or paediatrician) that "long-term antibiotics or long-term placebo" are not appropriate at this time.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Aboriginal children 12 months to 8 years old, seen by the study's paediatricians and diagnosed with probable or definite bronchiectasis are eligible. Informed consent is obtained from the child's parents. The enrolled child is randomly allocated to one of the two treatment regimes . Allocation concealment will be achieved by use of sequentially numbered sealed opaque envelopes. All treatment bottles are labelled identically as "Bronchiectasis Interventional Study Medicine". Patients, their families, care providers and investigators collecting data will be unaware of the treatment assigned to each child.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block design generated by computer will be used to generate the randomisation sequence (stratified by study site (New Zealand, Top End and Central Australia) & number if episodes of exacerbations in the last 12 months ('1 to 2 episodes' versus '3 episodes or more')). Children enrolled will be allocated the next treatment regimen on a list previously generated by an independent Queensland Institute of Medical Research (QIMR) statistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
None
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 1197 0
New Zealand
State/province [1] 1197 0
Auckland

Funding & Sponsors
Funding source category [1] 3848 0
Charities/Societies/Foundations
Name [1] 3848 0
Telstra Foundation
Address [1] 3848 0
Locked Bag 5680
Melbourne VIC 3001
Country [1] 3848 0
Australia
Funding source category [2] 3849 0
Government body
Name [2] 3849 0
National Health and Medical Research Council (NHMRC)
GPO Box 1421
Canberra ACT 2601
Address [2] 3849 0
Level 5, 20 Allara St, Canberra, ACT, 2601
Country [2] 3849 0
Australia
Funding source category [3] 3850 0
Charities/Societies/Foundations
Name [3] 3850 0
Asthma and Respiratory Foundation of New Zealand
Address [3] 3850 0
Level 1, Panama House, 22 Panama St, Wellington 6011
Country [3] 3850 0
New Zealand
Funding source category [4] 3851 0
Charities/Societies/Foundations
Name [4] 3851 0
Auckland Medical Research Foundation
Address [4] 3851 0
Suite 12/13 Lower Ground Floor
Building 15, Cornwall Complex
Greenlane Clinical Centre
Greenlane West
Auckland 1005
Country [4] 3851 0
New Zealand
Funding source category [5] 3853 0
Charities/Societies/Foundations
Name [5] 3853 0
Health Research Council of New Zealand
Address [5] 3853 0
Level 3, 110 Stanley St, Auckland, 1010
Country [5] 3853 0
New Zealand
Primary sponsor type
University
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina NT 0811
Country
Australia
Secondary sponsor category [1] 3460 0
None
Name [1] 3460 0
Address [1] 3460 0
Country [1] 3460 0
Other collaborator category [1] 406 0
Government body
Name [1] 406 0
Queensland Institute of Medical Research
Address [1] 406 0
300 Herston Rd, Herston Queensland, 4006
Country [1] 406 0
Australia
Other collaborator category [2] 407 0
Hospital
Name [2] 407 0
Starship Children's Hospital
Address [2] 407 0
Private Bag 92024
Grafton Auckland 1142
Country [2] 407 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5900 0
Central Australian Human Research Ethics Committee
Ethics committee address [1] 5900 0
PO Box 4066
Alice Springs NT 0871
Ethics committee country [1] 5900 0
Australia
Date submitted for ethics approval [1] 5900 0
Approval date [1] 5900 0
02/05/2008
Ethics approval number [1] 5900 0
Ethics committee name [2] 5901 0
Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [2] 5901 0
300 Herston Rd, Herston, Queensland, 4006
Ethics committee country [2] 5901 0
Australia
Date submitted for ethics approval [2] 5901 0
Approval date [2] 5901 0
11/05/2006
Ethics approval number [2] 5901 0
EC00278
Ethics committee name [3] 5902 0
Royal Children's Hospital and Health Service District Ethics Committee
Ethics committee address [3] 5902 0
Level 5, Woolworths Medical Building, Royal Children's Hospital, Herston Road, HERSTON QLD 4029
Ethics committee country [3] 5902 0
Australia
Date submitted for ethics approval [3] 5902 0
Approval date [3] 5902 0
15/11/2005
Ethics approval number [3] 5902 0
2005/083
Ethics committee name [4] 5904 0
Human Research Ethics Committee of Northern Territory Department of Health and Community Services and Menzies School of Health Research
Ethics committee address [4] 5904 0
PO Box 41096
Casuarina NT 0811
Ethics committee country [4] 5904 0
Australia
Date submitted for ethics approval [4] 5904 0
Approval date [4] 5904 0
16/04/2008
Ethics approval number [4] 5904 0
0777

Summary
Brief summary
Aboriginal children have repeated pneumonia episodes; some get better while others develop bronchiectasis (a chronic lung disease). The risk factors associated with progression to bronchiectasis, and the natural history of bronchiectasis in this population is little known. Given the similarities of these diseases among indigenous populations of affluent countries and to increase study size, a collaborative and international study of Indigenous children (Aboriginal and Torres Strait Islander, New Zealand Maori or Pacific Islander and Alaskan Native) has been initiated. We plan to follow up Aboriginal children aged 12 months to 8 years diagnosed with bronchiectasis or chronic moist cough. For those diagnosed with bronchiectasis, after fully informed consent is obtained from the parent(s), the child will be allocated by chance to one of the 2 treatment regimes: (1) Azithromycin nce/week or (2) placebo once/week. Children will receive the medication or the placebo for a period of 24 months. All these children will be clinically seen 2x/year by the study's paediatrician and 2x/year by the research nurse for the duration of the study.

The study size and study power calculations were based on our Central Australia data (Valery et al, Paed Inf Dis J, 2004) where Indigenous children diagnosed with bronchiectasis had on average 1 hospitalised episode of pulmonary exacerbation every 6 months (standard deviation=5.4), so the ‘placebo’ group is expected to have 4 episodes during a 24-months follow-up. Assuming we will follow these children for 24 months, if intervention is effective, assuming 50% reduction in the number of pulmonary exacerbation, the intervention group is expected to have 2 episodes vs. 3.4 episodes for the ‘placebo’ group (assuming we have 15% reduction in the placebo group as well due to better medical care due to the study) we have 95% power with 51 children in each group. Importantly, these estimates used hospitalised exacerbation rates as a conservative estimate of total exacerbation rates. In fact, if we determine the sample size required to estimate the difference between the rate parameters of two Poisson distributions over 24 months, 34 observations from each sample (68 child years at risk) are required to have a 90% chance of rejecting the null hypothesis when the true difference over 2 years equals 1.7 using a two-sided test (www.statlets.com/sample_size_rates.htm).

By documenting, for the first time, the epidemiology and natural history of children with chronic moist cough and bronchiectasis, the study will provide a much-needed rationale for their management. If we can scientifically show that this is true, that Azithromycin is effective in reducing the number of respiratory infections, this would be an achievable advance in the treatment "in the field" for these children.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 28920 0
A/Prof Peter Morris
Address 28920 0
Menzies School of Health Research PO Box 41096 Casuarina NT 0811
Country 28920 0
Australia
Phone 28920 0
+61 8 89228196
Fax 28920 0
Email 28920 0
peter.morris@menzies.edu.au
Contact person for public queries
Name 12077 0
A/Prof Dr Peter Morris
Address 12077 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 12077 0
Australia
Phone 12077 0
+61 8 89228196
Fax 12077 0
+61 8 89227876
Email 12077 0
Peter.Morris@menzies.edu.au
Contact person for scientific queries
Name 3005 0
Dr Dr Patricia Valery
Address 3005 0
Queensland Institute of Medical Research, 300 Herston Rd, Herston Queensland, 4029
Country 3005 0
Australia
Phone 3005 0
+61 7 3362 0244
Fax 3005 0
+61 7 3845 3502
Email 3005 0
Patricia.Valery@qimr.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary