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Trial registered on ANZCTR

Registration number

ACTRN12613001068752

Ethics application status

Approved

Date submitted

24/09/2013

Date registered

24/09/2013

Date last updated

24/03/2022

Date data sharing statement initially provided

19/11/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Watchful waiting for urban Aboriginal and Torres Strait Islander Children with Acute Otitis Media (middle ear infection)

Scientific title

A multi-centre open label randomised non-inferiority study to compare the efficacy of antibiotics versus watchful waiting for Acute Otitis Media without perforation in low-risk urban Aboriginal and Torres Strait Islander children

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1148-2676

Trial acronym

WATCH

Linked study record

Health condition

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

Acute Otitis Media

Health of Urban Aboriginal children

Condition category

Condition code

Ear

Other ear disorders

Infection

Studies of infection and infectious agents

Public Health

Epidemiology

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Watchful waiting: no immediate provision of antibiotic therapy at the time of enrollment. A General Practitioner (GP) can start antibiotics at any subsequent visit if they choose.
This intervention will take place over a total study period of 7 weeks.
We will not adopt strategies to improve adherence to either allocated treatment. We will however assess self-reported adherence at Day 3 and Day 7 and Day 14.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Antibiotic group: immediate prescription of antibiotic therapy (choice at the discretion of the GP based on current guidelines).
This intervention will take place over a total study period of 7 weeks.

Control group

Active

Outcomes

Primary outcome [1]

Proportion of children with clinical resolution of AOM, defined as all of the following: no pain, no fever >38oC, no bulging eardrum and no complications of otitis media (no perforation or mastoiditis) assessed by:

1. GP or Nurse Practitioner clinical examination on Day 7*
2. Where 1 is not available, GP/Nurse Practitioner assessment of parental report and review of video pneumatic otoscopy, and no fever >38oC

Timepoint [1]

Day 7 (acceptable range Day 5-10).

Secondary outcome [1]

Proportion of children with resolution of signs of AOM, through blinded Otolaryngologist assessment of video-pneumatic otoscopy (VO) images and tympanometry.

Timepoint [1]

Day 0 and 7

Secondary outcome [2]

Proportion of children with middle ear effusion, perforation and chronic suppurative otitis media (CSOM), as assessed by an independent blinded observer reviewing VO and tympanometry data

Timepoint [2]

Week 7

Secondary outcome [3]

iii) Proportion of children with new antibiotic prescriptions for an ear infection (where ‘new’ is any antibiotic prescription provided after Day 0 up to Day 14*) assessed by review of medical record and by Parent/Carer report

Timepoint [3]

Days 3, 7 and 14 (acceptable range days 2-4, day 5-10 and day 11-17 respectively)

Secondary outcome [4]

Parental/carer reported time to resolution of AOM symptoms assessed by carer report using AOM-SOS scale and AOM -Faces scale

Timepoint [4]

Days 3, 7 and 14 (acceptable range days 2-4, day 5-10 and day 11-17 respectively)

Secondary outcome [5]

Usage of analgesia for AOM symptom relief assessed by medical record review and parental/carer report

Timepoint [5]

Any time during 7 week period

Secondary outcome [6]

Parental/carer satisfaction with AOM treatment assessed by parental/carer report

Timepoint [6]

2 weeks

Secondary outcome [7]

The relative cost effectiveness of watchful waiting and immediate antibiotic treatment will be measured by the incremental cost-effectiveness ratio (ICER). The ICER is defined as: ICER = (C2-C1)/Q2-Q1)
where Ci and Qi denote costs and Quality Adjusted Life Years (QALYs) associated with the treatment received in trial arm i, and i is 1 for antibiotic treatment and 2 for watchful waiting.

Timepoint [7]

7 weeks

Secondary outcome [8]

The attitudes and experiences of the study participants and the health care providers to both immediate antibiotic prescription or watchful waiting, and the research process and its findings will be assessed throughout the study. This will comprise a qualitative research study component and an integrated process evaluation and will utilise a range of data sources, including site specific implementation plans, semi-structured interviews with parents/carers, research officers, site Reference Groups, and clinical staff of the participating sites.

Timepoint [8]

Monthly, 3-6 months, 9 months, End of Study

Eligibility

Key inclusion criteria

1. Aboriginal and/or Torres Strait Islander child (as defined by the health service they are attending)
2. Aged 18 months to 16 years (inclusive)
3. First enrolment into the study
4. Current acute otitis media without perforation diagnosed by a medical practitioner due to fluid in the middle ear on tympanometry (Type B tympanogram) and at least one of the following:
bulging of the eardrum on otoscopy,
ear pain

Minimum age

18 Months

Maximum age

16 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

The child has been on any antibiotic in the previous 4 days
At high risk of chronic suppurative otitis media (CSOM), as defined by residing in geographic area known to have prevalence of CSOM >4%
A grommet in situ, or current or past history of tympanic membrane perforation
A condition which increases the risk of complications (e.g.,
immunosuppression, genetic or chromosomal abnormality, cleft palate or mid-face abnormalities such as seen in Down Syndrome)
Systemic features necessitating antibiotic treatment (e.g.,
septicaemia, meningitis, pneumonia, or urinary tract infection)

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 will be recruited into the study at each of the 6 sites when diagnosed by a GP or Nurse Practitioner as having AOM without perforation. GPs and clinic staff in the participating sites will be informed about the trial and there will be AMS ROs in each of the participating sites to assist with recruitment. An Associate Investigator (AI) at each site (to be appointed) will assist the AMS RO as required.
The AMS RO or AI will call the NHMRC CTC IVRS to determine allocation of an eligible patient after consent to the study. The AMS RO and AI, and WSU will not be blind to allocation.

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

Children will be randomised to watchful waiting or immediate antibiotic therapy using the NHMRC Clinical Trial Centre (CTC) Interactive Voice Response System (IVRS). IVRS is a 24 hours per day, 7 days per week automated system which enables an immediate allocation to predetermined groups, subsequently confirmed by fax/email.

http://www.ctc.usyd.edu.au/our-research/biostatistics/randomisation.aspx#costs

Randomisation will be stratified using permuted blocks, using the following two characteristics:
1. participating site
2. Child age (18 months to 6 years versus 7 to 16 years)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

The primary outcome measure is clinical resolution on Day 7 as defined above. We will compare the proportions of children meeting the definition of clinical resolution using intention to treat analysis but as it is a non-inferiority design we will also perform a per protocol analysis for increased validity of findings.

Per protocol Analysis:
In non-inferiority trials using an intention to treat analysis could create a bias towards finding non-inferiority (if patients in the inferior arm switch to the superior arm but are analysed according to the original arm). Therefore, we will also perform a per-protocol analysis to account for non-adherence and change in treatment to describe any short-term benefits and harms associated with antibiotic use. The per protocol population will consist of all randomised patients who have complied with the treatment allocated, were not lost to follow-up, and who have no major protocol deviations.

For protocol deviations where participant data are available, these will be analysed and the impact of their inclusion assessed and reported.

Available data analysis:
All participants with Day 7 data will be included in the analysis.

Sensitivity Analysis:
We will determine the impact of each of the following alternative assumptions:

i) missing = clinical failure
ii) missing = clinical success
iii) missing = extrapolation from Day 3 phone call
iv) missing = best case for watchful waiting
v) missing = worst case for watchful waiting

Non inferiority will be evaluated by testing if the lower bound of the 95% confidence interval (CI) for difference in resolution rates excludes a 10% difference (non-inferiority margin). Non-inferiority of watchful waiting over antibiotic treatment will be accepted if the lower bound of the 95% CI around the estimated difference in the primary endpoint rates lies above 10%.
Data analysis will include analysis using Fisher’s exact and Chi-square tests for categorical outcomes, and parametric and non-parametric tests for continuous measures, as required. The difference in the primary endpoint between the two groups will be expressed as a risk difference. Where appropriate, odds ratios (ORs) will be calculated and will include both unadjusted (crude) and adjusted ORs. Adjusted ORs will be obtained using multivariable logistic regression, adjusting for baseline covariates.

Subgroup analyses:
We will also perform secondary analyses by
i) treatment received,
ii) participating site, and
iii) by age (18 months to 6 years versus 7 to 16 years)

Data analysis – secondary outcome 1
Outcomes will be assessed using logistic regression adjusting for baseline covariates, and stratification factors. Relative risks and 95% confidence intervals will be estimated and reported.

Differences between interventions over time will be tested using mixed effects (multilevel) models as it adjusts for the repeated measures per person. Here observations are clustered within individuals, who are clustered within sites.

Time to resolution of AOM symptoms (outcome iv) will be modelled using a multilevel Cox (proportional hazards) regression analysis and graphically displayed using Kaplan-Meier curves.

Data analysis – secondary outcome 2
The secondary outcome 2 is a single number, the incremental cost-effectiveness ratio (ICER) that depends on the costs and QALYs corresponding to the two arms of the trial. There are two methodological issues that need to be addressed in the computation of the ICER: missing data and sensitivity analysis.

Given the structure of the current protocol we do not expect a considerable amount of missing data, but we need to be prepared to deal with it. Data may be missing for a variety of reasons, and we will be monitoring the structure of the missing data as the data are collected in case we detect any systematic pattern that could possibly be corrected.

Our preferred strategy to deal with missing data is to use imputation, rather than deleting observations. We plan to use the multiple imputation algorithm Amelia II, that was developed by J. Honaker, G. King and M. Blackwell. Amelia II has an easy-to-use implementation in the publicly available statistical software R, and it can be found as part of the software package “Amelia”, which can be freely downloaded at http://gking.harvard.edu/amelia.

Sensitivity analysis is particularly important in this case, since QALYs estimate that are specific to the Aboriginal and Torres Strait Islander population are not available, and therefore our estimates, based on the general population, will carry significant uncertainty.

In order to perform sensitivity analysis we will first identify the main components of costs and QALYs, and perform an initial one way sensitivity analysis on each component. The outcome of this first step will be a tornado diagram that will identify the main sources of variation in the ICER estimate. We will then proceed to perform two multi-way, Monte Carlo simulations: in one we will vary all the parameters at once, and in the other we will only vary the QALYs parameters. In this way we will get an understanding of how much the uncertainty on QALYs contributes to the overall results.

In both cases the key output is set of conditions under which the ICER remains in an acceptable range. Stated differently, our goal is to make a statement of the following form: “if these parameters remain within these ranges then the ICER remains in this range”, in order to provide the conditions under which watchful waiting can be considered cost-effective.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

3/03/2014

Actual

1/09/2014

Date of last participant enrolment

Anticipated

31/03/2026

Actual

Date of last data collection

Anticipated

30/06/2026

Actual

Sample size

Target

495

Accrual to date

252

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Recruitment hospital [1]

Inala Indigenous Health Service – Southern Queensland Centre of Excellence - Inala

Recruitment hospital [2]

Kalwun Health Service - Miami Clinic - Miami

Recruitment hospital [3]

Tharawal Aboriginal Medical Service - Airds

Recruitment hospital [4]

Townsville Aboriginal and Islander Health Service - Garbutt

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC Project Grant #1046266

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

University

Name [2]

Ainsworth Medical Research Innovation Fund Via Western Sydney University

Address [2]

Western Sydney University
Locked Bag 1797
Penrith NSW 2751

Country [2]

Australia

Primary sponsor type

University

Name

Western Sydney University

Address

Western Sydney University
School of Medicine,
Locked Bag 1797
Penrith NSW 2751

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Aboriginal Health & Medical Research Council Ethics Committee

Ethics committee address [1]

PO Box 1565
Strawberry Hills NSW 2012

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

23/05/2013

Approval date [1]

28/06/2013

Ethics approval number [1]

EC00342

Ethics committee name [2]

University of Western Sydney Human Research Ethics Committee

Ethics committee address [2]

Office of Research Services
Kingswood Campus, Building K
Locked Bag 1797
Penrith NSW 2751

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

13/08/2013

Approval date [2]

02/09/2013

Ethics approval number [2]

EC00314

Ethics committee name [3]

Metro South Health Service District Human Research Ethics Committee

Ethics committee address [3]

Princess Alexandria Hospital
Centres for Health Research
Level 2, Building 35
Ipswich Road
Woolloongabba QLD 4102

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

11/06/2013

Approval date [3]

06/08/2013

Ethics approval number [3]

EC00167

Ethics committee name [4]

Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research

Ethics committee address [4]

P0 Box 41096
Casuarina NT 0811

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

13/08/2013

Approval date [4]

19/08/2013

Ethics approval number [4]

EC00153

Ethics committee name [5]

The University of Queensland Medical Research Ethics Committee

Ethics committee address [5]

Research & Training Division 
Cumbrae Stewart Building 
The University of Queensland ST. LUCIA 
QLD 4072

Ethics committee country [5]

Australia

Date submitted for ethics approval [5]

12/08/2013

Approval date [5]

21/08/2013

Ethics approval number [5]

EC00179

Summary

Brief summary

Complications of ear disease, including hearing impairment and chronically infected ears, particularly chronic
suppurative otitis media, can affect education, social circumstances and quality of life. Aboriginal and Torres
Strait Islander children are known to have higher rates of otitis media than other children and to be more
likely to develop complications. However, almost all of the research into prevalence, risk factors and
treatment has been done in remote settings, despite the majority of Aboriginal and Torres Strait Islander
peoples living in urban areas.

In developed countries, immediate antibiotic treatment confers only a modestly decreased duration of pain
and fever. Given the public health risks of antibiotic resistance, a “watchful waiting” approach to treatment is
recommended for children at low risk of complications of AOM. Similarly, a recent change in national
guidelines for treatment of AOM in Aboriginal and Torres Strait Islander children has recommended a shift
from giving immediate antibiotic therapy for all such children, to using a “watchful waiting” approach in urban
children presumed to be at low risk of complications.

We will work with five Aboriginal Community Controlled Health Services and one Indigenous health service.
With these services we will recruit approximately 500 children in order to provide randomised controlled trial
(RCT) evidence to determine if watchful waiting is at least as effective as immediate antibiotic treatment for
urban Aboriginal and Torres Strait Islander children with AOM. In addition, we will examine the cost
effectiveness of the two treatment approaches from health services, societal and individual patient
perspectives. We will also undertake qualitative research including process evaluation to document the
implementation of the trial in each site, and the views and attitudes of the health care providers and study
participants to the study and to the conduct of an RCT in Aboriginal and Torres Strait Islander communities.

This is the first trial of antibiotics versus watchful waiting in urban Aboriginal and/or Torres Strait Islander
children who present to a primary health care service with AOM.
This research addresses two NHMRC priorities: Aboriginal health; and hearing. Our investigator team

includes two Aboriginal researchers and staff from three Aboriginal health services who have contributed to
this proposal from its early stages. Our research team is well placed to ensure translation of the research
findings into policy and practice.

Trial website

http://www.westernsydney.edu.au/medicine/som/research/general_practice/general_practice_research/watch_trial

Trial related presentations / publications

A multi-centre open-label randomised non-inferiority trial comparing watchful waiting to antibiotic treatment for acute otitis media without perforation in low-risk urban Aboriginal and Torres Strait Islander children (the WATCH Trial): study protocol for a randomised controlled trial. Abbott et al. Trials (2016) 17:119

Public notes

Attachments [1]

/AnzctrAttachments/365023-Abbott Penelop-2016-A multi-centre open-label.pdf (Publication)

Attachments [2]

/AnzctrAttachments/365023-WATCH Trial_Koori Mail.pdf (Other)

Contacts

Principal investigator

Name

Prof Jennifer Reath

Address

Western Sydney University School Of Medicine Campbelltown Campus Building 30, Locked Bag 1797 Penrith, NSW, 2751

Country

Australia

Phone

61 02 4620 3725

Fax

[email protected]

Contact person for public queries

Name

Jennifer Reath

Address

Western Sydney University School of Medicine Campbelltown Campus
Building 30, Locked Bag 1797 Penrith, NSW, 2751

Country

Australia

Phone

61 02 4620 3725

Fax

[email protected]

Contact person for scientific queries

Name

Jennifer Reath

Address

Western Sydney University School of Medicine Campbelltown Campus
Building 30, Locked Bag 1797 Penrith, NSW, 2751

Country

Australia

Phone

61 02 4620 3725

Fax

[email protected]

Data sharing statement

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

No/undecided IPD sharing reason/comment

Data will be available but in de-identified format

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
5923	Informed consent form					365023-(Uploaded-26-11-2019-14-14-57)-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	Randomised clinical trial research within Aboriginal and Torres Strait Islander primary health services: A qualitative study.	2021	https://dx.doi.org/10.1136/bmjopen-2021-050839
Embase	Acute otitis media symptoms and symptom scales in research with Aboriginal and Torres Strait Islander children.	2023	https://dx.doi.org/10.1371/journal.pone.0280926

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

Trial Review

Documents added manually

Documents added automatically