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Trial registered on ANZCTR


Registration number
ACTRN12619000564156
Ethics application status
Approved
Date submitted
23/03/2019
Date registered
10/04/2019
Date last updated
7/08/2019
Date data sharing statement initially provided
10/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
REPEAT: Reducing Exacerbations in people with primary ciliary dyskinesia (PCD) using Erdosteine and Azithromycin Therapy
Scientific title
Improving outcomes of children and young adults with primary ciliary dyskinesia: a multi-centre, double-blind, double-dummy, 2x2 partial factorial, randomised controlled trial using azithromycin and erdosteine
Secondary ID [1] 297794 0
Nil known
Universal Trial Number (UTN)
Trial acronym
REPEAT Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
primary ciliary dyskinesia 312140 0
Condition category
Condition code
Respiratory 310694 310694 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 310708 310708 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Azithromycin: Oral 10mg/kg/dose (max 500 mg/dose), 3x weekly for 12 months. Supplied as powder for suspension
Erdosteine: Oral twice daily doses for 12 months [15-19 kg 5mls/dose; 20-30 kg 7.5ml/dose; >30 kg 10ml/dose or one capsule]. For children weighing 30 kgs or less, this will be supplied as powder for suspension. For those >30 kgs, powder for suspension will be used in those unable to take capsules.

Adherence will be monitored by return of bottles
Intervention code [1] 314032 0
Treatment: Drugs
Comparator / control treatment
Respective matching placebos. For azithromycin (equivalent volume of oral suspension). For erdosteine (equivalent volume of oral suspension or matching placebo capsule). In both, inert, matched excipients are used
Control group
Placebo

Outcomes
Primary outcome [1] 319548 0
Respiratory exacerbation rate. An acute respiratory episode is defined by an acute respiratory event that: (a) is treated with antibiotics and (b) an increase in sputum volume or purulence, for 3 or more days of change in cough (at least 20% increase in cough score or type [dry to wet/productive]) or physician confirmed acute change in respiratory rate, work of breathing or chest signs.
These will be collected by participant reports and medical records.
Timepoint [1] 319548 0
12 months
Secondary outcome [1] 368630 0
PCD-Quality of Life (QoL) scores
Timepoint [1] 368630 0
12 months
Secondary outcome [2] 368631 0
Time to next acute exacerbation. Defined from time of trial medications to next acute respiratory exacerbation, measured in days. Respiratory exacerbation rate. An acute respiratory episode is defined by an acute respiratory event that: (a) is treated with antibiotics and (b) an increase in sputum volume or purulence for 3 or more days of change in cough (at least 20% increase in cough score or type [dry to wet/productive]) or physician confirmed acute change in respiratory rate, work of breathing or chest signs.
These will be collected by participant reports and medical records.
Timepoint [2] 368631 0
Within next 12 months
Secondary outcome [3] 368632 0
Time to next respiratory-related hospitalization. These will be collected by participant reports and medical records.
Timepoint [3] 368632 0
Within next 12 months
Secondary outcome [4] 368633 0
Spirometry values (FEV1, FEV1 % predicted, FEV1/FVC ratio)
Timepoint [4] 368633 0
12 months
Secondary outcome [5] 368634 0
Adverse events, including non-pulmonary infections requiring antibiotics (e.g. vomiting, nausea, use of additional antibiotics for non-respiratory conditions) during the duration of the intervention i.e. for 12 months post randomisation. These will be collected by participant reports and medical records.
Timepoint [5] 368634 0
12 months
Secondary outcome [6] 368635 0
Presence of macrolide-resistant respiratory pathogens in the upper airways. Measured by sensitivity of bacterial pathogens (cultured from nasal swabs) to macrolides
Timepoint [6] 368635 0
15 months
Secondary outcome [7] 368636 0
Whole exome sequencing (WES) data i.e. mutation of genes
Timepoint [7] 368636 0
Not applicable. This is not a time sensitive time point. Specimen will be collected at any time point during the trial period.
Secondary outcome [8] 368637 0
Incremental cost-effectiveness ratio. Cost estimation will involve the cost of azithromycin and erdosteine, medical retrieval, patient/escort travel and other indirect cost, by using actual expenditure and contractual data and costing for hospitalisation by using average cost estimates (from Australian data)
Timepoint [8] 368637 0
12 months
Secondary outcome [9] 368871 0
Acute exacerbation rate using definition-2 i.e. an acute respiratory episode that has at least 3 of the below criteria: (a) increased cough
(b) change in sputum volume and/or colour
(c) increased shortness of breath perceived by parent or patient
(d) decision to start or change antibiotic treatment because of perceived pulmonary symptoms
(e) malaise, tiredness, fatigue or lethargy
(f) New or increased haemoptysis
(g) temperature greater than 38 degrees C
ERJ Open Research 2019 5: 00147-2018; DOI: 10.1183/23120541.00147-2018
Timepoint [9] 368871 0
12 months

Eligibility
Key inclusion criteria
1. Children or young adults (aged 2-40.01 years)
2. Known PCD (defined by genetics or through electron microscopy) or chronic wet/productive cough and a PICADAR score of at least 5 with nasal nitric oxide measurement (nNO) less than 77 nL/min [or equivalent cut-offs] on 2 occasions (when nNO levels can be measured i.e. aged over 5 years);
3. At least two exacerbations in the last 18 months; AND
4. Plan to remain at one of the study sites for at least 15 months
Minimum age
2 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Cystic fibrosis
2. On regular azithromycin (within the last 8 weeks) but if a participant is too unstable off azithromycin (defined by the participant’s primary specialist), the participant may be enrolled and will just be allocated to the erdosteine/placebo component (1:1 allocation)
3. Past (last 6 months) or current infection with non-tuberculous mycobacteria
4. Contraindication for macrolide or erdosteine use (e.g. liver dysfunction, hypersensitivity, renal failure, deficiency of the cystathionine-synthetase enzyme, phenylketonuria, active peptic ulcer)
5. Pregnant, pregnancy planned (in next 12 months) or nursing mothers
6. Abnormal ECG (QTc over 460 msec) or history of cardiac arrhythmia
7. Previously randomised
8. Hospitalised in the last 4 weeks for respiratory instability

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)
Individual participants will be allocated (using minimisation method) to one of four study groups according to a computer-generated number to be obtained by a single phone call to the NHMRC Clinical Trial Centre (CTC). This will achieve balance between (i) treatment groups for site (Brisbane, Melbourne, Sydney, Darwin, Perth), (ii) age groups (16 years and under, over 16 years) and (iii) PCD confirmation (definite/probable). A random component will be used. The allocated number will be provided to the local pharmacy who will dispense the trial medications to the participant
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be undertaken as part of the minimisation method described above, by the NHMRC Clinical Trial Centre (CTC).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Double dummy trial. Partial factorial as participants may be randomised only to the azithromycin/placebo intervention. Individual participants will be allocated (using minimisation method) to one of four study groups according to a computer-generated number to be obtained by a single phone call to the NHMRC Clinical Trial Centre (CTC). A random component will be used. For randomising, the first question asked by CTC will be whether the participant will be in both components (azithromycin and erdosteine) of the study. A participant involved in only the azithromycin component will then be allocated to either azithromycin or placebo(A) using the same minimisation method. Also, some children may receive the azithromycin/placebo component before receiving the erdosteine/placebo component
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data will be analysed as 2 separate studies consisting of comparing (i) azithro vs. placebo(A) and (ii) erdosteine vs. placebo(E).

For primary outcome: Acute exacerbation rate in those allocated (1:1) to the azithro group [those allocated to azithro+placebo(E) or azithro+erdosteine)] will be compared to its control group [those allocated to placebo(A)+placebo(E) or erdosteine+placebo(E)]. The erdosteine group [those allocated erdosteine+placebo(A) or erdosteine+azithro) or erdosteine alone] will be compared to the controls [those allocated to placebo(A)+placebo(E) or azithro+placebo(E) or placebo(E) alone].

We will use two regression models (i.e. one for each intervention). For each, we will use a negative binomial regression model (as recommended including treatment group and number of months in the study included as an offset) to determine between-group differences (with 95%CI). We will document (but do not expect) any interaction between the interventions (azithro+erdosteine) by tabulating the data as recommended.

The change (12 months minus baseline) in (i) respective domain scores of the QoL, (ii) spirometry values [% predicted values of FEV1 and FVC] between treatment arms will be analysed using ANCOVA and presented as the mean difference (95%CI). A Kaplan-Meier curve will be constructed for each group (intervention vs respective controls) for time to the first acute exacerbation and respiratory-related hospitalisation, and we will perform a log-rank test and report a hazard ratio (using Cox regression model).

Recruitment
Recruitment status
Not yet recruiting
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)
NSW,NT,QLD,WA,VIC
Recruitment hospital [1] 13473 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 13474 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [3] 13475 0
Concord Repatriation Hospital - Concord
Recruitment hospital [4] 13476 0
Perth Children's Hospital - Nedlands
Recruitment hospital [5] 13477 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 26088 0
4101 - South Brisbane
Recruitment postcode(s) [2] 26089 0
0810 - Tiwi
Recruitment postcode(s) [3] 26090 0
2139 - Concord
Recruitment postcode(s) [4] 26091 0
6009 - Nedlands
Recruitment postcode(s) [5] 26092 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 302317 0
Government body
Name [1] 302317 0
National Health and Medical Research Council - MRFF
Address [1] 302317 0
National Health and Medical Research Council
GPO Box 1421
Canberra
ACT 2601
Country [1] 302317 0
Australia
Funding source category [2] 302318 0
Charities/Societies/Foundations
Name [2] 302318 0
Children's Hospital Foundation (Queensland)
Address [2] 302318 0
PO Box 8009 Woolloongabba, QLD 4102
Country [2] 302318 0
Australia
Primary sponsor type
University
Name
Menzies School of Health Research
Address
PO Box 41096, Casuarina NT 0811, Australia
John Mathews Building (Bldg 58) |
Royal Darwin Hospital Campus, Rocklands Drive, Casuarina NT 0810
Country
Australia
Secondary sponsor category [1] 302207 0
University
Name [1] 302207 0
Queensland University of Techonology
Address [1] 302207 0
CCHR
Graham Street,
South Brisbane
Qld 4101
Country [1] 302207 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302990 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 302990 0
Level 7
CCHR
Graham Street
South Brisbane
Qld 4101
Ethics committee country [1] 302990 0
Australia
Date submitted for ethics approval [1] 302990 0
30/04/2019
Approval date [1] 302990 0
06/06/2019
Ethics approval number [1] 302990 0
HREC/19/QCHQ/53457
Ethics committee name [2] 302991 0
Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [2] 302991 0
PO Box 41096
Casuarina
NT 0811
Ethics committee country [2] 302991 0
Australia
Date submitted for ethics approval [2] 302991 0
15/05/2019
Approval date [2] 302991 0
Ethics approval number [2] 302991 0

Summary
Brief summary
Primary ciliary dyskinesia (PCD), is a rare, incurable, progressive, serious disorder with a large unmet need in both the diagnosis & treatment. We will test the benefits of a currently used (but unapproved for long term use in PCD) antibiotic (azithromycin) and a novel mucolytic (erdosteine). We plan a parallel, multicentre, double-blinded, double-dummy RCT. Our primary question is: Among children/young adults with PCD, does azithromycin or erdosteine reduce acute respiratory exacerbations during 12-mo of treatment? Study sites are Sydney, Brisbane, Melbourne, Darwin, Perth.

Our secondary aims are to:
2. Determine the effects of 12-months of the azithromycin or erdosteine on PCD-quality of life (QoL), its cost effectiveness and impact on bacterial type and antibiotic resistance
3. Assess whether whole exome sequencing (WES) can identify known and unknown gene mutations in PCD, and whether knowing this improves the patient's journey
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92094 0
Prof Anne Chang
Address 92094 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 92094 0
Australia
Phone 92094 0
+61 7 30681111
Fax 92094 0
Email 92094 0
anne.chang@menzies.edu.au
Contact person for public queries
Name 92095 0
Mrs Anne Cook
Address 92095 0
Cough, Asthma & Airways Research Group
Queensland University of Technology
Centre for Children's Health Research
62 Raymond Tce
South Brisbane QLD 4101

Country 92095 0
Australia
Phone 92095 0
+61 7 3069 7283
Fax 92095 0
Email 92095 0
anne.cook@qut.edu.au
Contact person for scientific queries
Name 92096 0
Prof Anne Chang
Address 92096 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 92096 0
Australia
Phone 92096 0
+61 7 30681111
Fax 92096 0
Email 92096 0
anne.chang@menzies.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is in accordance to Menzies' policy relating to Indigenous Health Research
What supporting documents are/will be available?
No other documents available
Summary results
No Results