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Trial registered on ANZCTR

Registration number

ACTRN12615000132549

Ethics application status

Approved

Date submitted

16/01/2015

Date registered

12/02/2015

Date last updated

13/05/2019

Date data sharing statement initially provided

13/05/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Researching Intervention in Chronic Cough in Kids Study

Scientific title

A randomised controlled trial to evaluate the efficacy of an evidence based cough algorithm compared to standard care in reducing cough duration in children aged < 15 years who develop chronic cough (> 4 weeks) following acute respiratory infection.

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

U1111-1166-0388

Trial acronym

RICCi Kids Study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cough

Acute respiratory infection

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The intervention is an evidence-based cough management algorithm that has been evaluated in children referred to a paediatric respiratory physician with prolonged cough (Chang et al, Pediatrics 2012). Children with cough are reviewed by a paediatrician and enter specific pathways depending on cough type and whether it is a specific or non-specific cough. Relevant investigations are performed (eg haemotology, biochemistry, pertussis serology, chest xray, spirometry) and management is dependent on initial diagnoses. Management may include watchful waiting, trials of inhaled corticosteroids or antibiotics, and brief interventions such as smoking education. Children are reviewed again 2 weeks following the initial review. Ongoing management is dependent on the diagnosis.

Intervention code [1]

Treatment: Other

Comparator / control treatment

The control arm will undergo standard care. This predominantly involves advising the parent/guardian to seek the advice of their general practitioner if they are concerned about the cough. At the community level, children will consult a GP up to 5 times before obtaining a referral to a paediatrician. This may take up to 4 months before specialist review occurs.

Control group

Active

Outcomes

Primary outcome [1]

Resolution of cough in days assessed via validated parent completed daily cough diary cards and weekly telephone/email/home visiting contact with families

Timepoint [1]

Assessed daily from date of enrolment and date of randomisation for 8 weeks in total (4 weeks post randomisation).

Secondary outcome [1]

Direct (eg cost of medication) and indirect costs of illness (eg parental time off work) assessed by daily burden of illness diaries and weekly telephone/email/home visiting contact with families. Cost of illness is a composite outcome.

Timepoint [1]

Day 56 post enrolment

Secondary outcome [2]

Nasal carriage of respiratory viruses and bacteria. Anterior nasal swabs will be collected using the Virocult specimen collection system. Swabs will be tested at the Queensland Paediatric Infectious Diseases Laboratory for 5 bacteria and 18 viruses by quantitative polymerase chain reaction methods.

Timepoint [2]

Day 0, 14, 28, 42 and 56

Eligibility

Key inclusion criteria

1. Is aged 0 - < 15 years
2. Presents to participating primary health care centre with cough as a symptom
3. Parent/guardian provides written informed consent
4.. If the child is a young person aged 12 - < 15 years, written assent from that person must be obtained

Minimum age

0 Years

Maximum age

14 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Known, doctor diagnosed, chronic lung disease (excluding asthma)

2. Known immunosuppressive condition or on long term immunosuppressant therapy (oral or inhaled steroids in the past 30 days are allowed.

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)

Children presenting to the participating primary health care services with an illness with parent reported cough as a symptom will be identified by a dedicated study research officer through discussion with the clinic staff. The research officer will then approach the child’s parents/guardians to determine willingness to participate in the study. Written informed consent will be obtained following provision and explanation of a plain language statement that explains the study in detail. Pictorial information statements may be used for those with limited literacy skills if required. Written assent will be obtained from children aged equal to or greater than 12 years.

At day-29 (+3), after confirmation of the presence of chronic cough, eligible children will be allocated (1:1) to either active intervention or standard care. Randomisation will be stratified by site (n=3) and cough duration at day 28 (less than 6 weeks and equal to or greater than 6 weeks) with permuted block sizes. Stratifying by cough duration will control for children who had a cough history of greater than 14 days at time of cohort enrolment.

Randomisation codes will be computer generated by an independent biostatistician and concealed in opaque envelopes. At the time of randomisation, staff will contact the study coordinator with the child’s stratum details and the next consecutive envelope in that stratum will be selected and opened to allocate the child to a study arm according to the allocation code.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The randomised sequence generation will be conducted by an independent biostatistician using Stata (StataCorp, Texas).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

The RCT is nested within 3 prospective cohort studies of acute respiratory illness with cough as a symptom in urban and rural children

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Demographic, clinical, economic, risk factor and microbiological data will be tabulated for the study population overall, by centre and by randomisation group and expressed as proportions and/or means of the selected characteristics by study centre, and presence/absence of chronic cough at day 56 with the corresponding 95% confidence intervals (CI). Differences between groups will be assessed using t-tests for comparisons of means and chi-square test for comparisons of proportions, conditional on test assumptions for each being satisfied. Non-normally distributed data will be analysed with appropriate non-parametric tests.

Primary objective
Intention to treat analyses will be employed. The proportion of children with cough resolution at Day 56 (4 weeks post randomisation) will be compared between the intervention and control group and absolute risk differences will be calculated. Multinomial logistic regression will be undertaken to account for stratification variables and any baseline variables considered to be unequally distributed between groups. Robust standard errors will be employed to account for clustering by siblings and bootstrapping methods used to examine potential biases in estimates.

Secondary analysis of primary outcome
A per-protocol analysis will be performed as a secondary analysis. Per protocol analyses will exclude children who met elimination criteria, those with unknown cough status at day 56 and those randomised to the intervention group who did not receive the intervention. Logistic regression will be employed as described in the primary analysis above.

Economic objectives
Costing of the intervention will be done according to established methods including detailed subanalyses of data that account for epidemiological, social, cultural, risk factor and microbiological variables. Cost effectiveness analysis (CEA) will be modelled with a focus on the health sector but incorporating broader societal issues using data from the trial as described above and augmented by the evidence from the literature, especially systematic reviews. CEA will involve: identification of resources using the intervention pathway (activities, probabilities and unit costs); measurement of resource use/outcomes; and valuation of costs using unit costs published in the literature. The time horizon will be specified and current practice (standard care) will be the comparator; and future costs and benefits will be discounted to present values. Central to this analysis will be the modelling of uncertainty surrounding data quality and gaps, and extension of time horizon using sensitivity analyses. The key outcomes will be incremental cost-effectiveness, and cost-savings to the health system due to the interventions.

Other objectives:
Multivariable modelling will be employed to: a) evaluate the microbiological predictors of chronic cough following an ARI as determined at days 14, 28, 42 and 56 post enrolment; b) evaluate the epidemiological, clinical, socio-economic and cultural predictors of chronic cough following an ARI at day 28 post ARI; c) evaluate the epidemiological, clinical, socio-economic and cultural predictors of success or failure of the intervention at day 56; and, d) to compare these predictors between the three study populations. Crude and adjusted relative risks and their 95% CIs will be presented, with differences considered statistically significant at p <0.05.

The 3 cohort studies within which the RCT is nested are anticipated to enrol approximately 700 children based on our current and previous work. On the basis of that work, we expect approximately 30% of children to have persistent cough at day 28. For the primary endpoint of cough resolution at day 56, we anticipate a 54% reduction in the proportion of children (54.3% in early arm compared to 29.5% in delayed-arm) with persistent cough at day 56. Hence, 89 children per group with complete evaluable data at day 56 will provide 90% power (a=0.05), to detect this 54% reduction for our primary aim. Assuming a 20% loss to follow-up, we will therefore randomise a minimum of 107 children per group at day 28 across all 3 sites (214 in total randomised within the cohort of approximately 700 children)

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

6/04/2015

Actual

7/07/2015

Date of last participant enrolment

Anticipated

31/10/2018

Actual

31/10/2018

Date of last data collection

Anticipated

28/12/2018

Actual

28/12/2018

Sample size

Target

700

Accrual to date

Final

509

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Toowoomba Hospital - Toowoomba

Recruitment hospital [2]

Lady Cilento Children's Hospital - South Brisbane

Recruitment hospital [3]

Caboolture Hospital - Caboolture

Recruitment postcode(s) [1]

4510 - Caboolture

Recruitment postcode(s) [2]

4352 - Toowoomba

Recruitment postcode(s) [3]

4370 - Warwick

Recruitment postcode(s) [4]

4101 - South Brisbane

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

Queensland University of Technology

Address

Cnr Musk and Victoria Park Rd
Kelvin Grove QLD 4059

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Queensland University of Technology University Research Ethics Committee

Ethics committee address [1]

88 Musk Ave
Kelvin Grove
Queensland 4059

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

19/01/2015

Approval date [1]

05/03/2015

Ethics approval number [1]

Summary

Brief summary

ARI in  children is a leading cause of hospitalisation and preventable death and repeat episodes in infancy are associated with an increased risk of chronic lung disease. Cough in children, commonly triggered by a viral ARI is a substantial cause of morbidity and associated health and societal economic costs. Chronic wet cough in children implies increased airway secretions and lower airway infection. This novel proposal aims to determine whether a validated evidence-based cough algorithm initiated at the development of chronic cough, defined as >4 weeks duration, following an ARI improves clinical outcomes in Indigenous children compared to standard care.

Trial website

None to date

Trial related presentations / publications

None to date

Public notes

Contacts

Principal investigator

Name

Dr Kerry-Ann O'Grady

Address

Centre for Children's Health Research
L7, 62 Graham Street
South Brisbane, QLD 4010

Country

Australia

Phone

+61 439 933 777

Fax

[email protected]

Contact person for public queries

Name

Kerry-Ann O'Grady

Address

Centre for Children's Health Research
L7, 62 Graham Street
South Brisbane, QLD 4010

Country

Australia

Phone

+61 439 933 777

Fax

[email protected]

Contact person for scientific queries

Name

Kerry-Ann O'Grady

Address

Centre for Children's Health Research
L7, 62 Graham Street
South Brisbane, QLD 4010

Country

Australia

Phone

+ 61 439 933 777

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

All data other than personal identifying information will be available on request

When will data be available (start and end dates)?

From when the primary papers addressing primary and secondary objectives have been published in a peer-review journal

Available to whom?

Researchers with specific interest and expertise in ARI and cough in children

Available for what types of analyses?

Descriptive and analytical

How or where can data be obtained?

Persons seeking access to the data will be required to put a request in writing to the Chief Investigator detailing the proposed use of the data. Data will be made available electronically on confirmation of the appropriate ethics clearances.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
2059	Study protocol					367776-(Uploaded-13-05-2019-09-45-55)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Effectiveness of a cough management algorithm at the transitional phase from acute to chronic cough in Australian children aged <15 years: Protocol for a randomised controlled trial.	2017	https://dx.doi.org/10.1136/bmjopen-2016-013796
Embase	Effectiveness of a chronic cough management algorithm at the transitional stage from acute to chronic cough in children: a multicenter, nested, single-blind, randomised controlled trial.	2019	https://dx.doi.org/10.1016/S2352-4642%2819%2930327-X

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically