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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
19/11/2018
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] 283270 0
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 290143 0
Health of Urban Aboriginal children 290144 0
Condition category
Condition code
Ear 290532 290532 0 0
Other ear disorders
Infection 290533 290533 0 0
Studies of infection and infectious agents
Public Health 290565 290565 0 0
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.
Intervention code [1] 287996 0
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] 290558 0
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] 290558 0
Day 7 (acceptable range Day 5-10).
Secondary outcome [1] 304785 0
Proportion of children with resolution of signs of AOM, through blinded Otolaryngologist assessment of video-pneumatic otoscopy (VO) images and tympanometry.
Timepoint [1] 304785 0
Day 0 and 7
Secondary outcome [2] 304786 0
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] 304786 0
Week 7
Secondary outcome [3] 304787 0
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] 304787 0
Days 3, 7 and 14 (acceptable range days 2-4, day 5-10 and day 11-17 respectively)
Secondary outcome [4] 304788 0
Parental/carer reported time to resolution of AOM symptoms assessed by carer report using AOM-SOS scale and AOM -Faces scale
Timepoint [4] 304788 0
Days 3, 7 and 14 (acceptable range days 2-4, day 5-10 and day 11-17 respectively)
Secondary outcome [5] 304789 0
Usage of analgesia for AOM symptom relief assessed by medical record review and parental/carer report
Timepoint [5] 304789 0
Any time during 7 week period
Secondary outcome [6] 304792 0
Parental/carer satisfaction with AOM treatment assessed by parental/carer report
Timepoint [6] 304792 0
2 weeks
Secondary outcome [7] 304796 0
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] 304796 0
7 weeks
Secondary outcome [8] 304851 0
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] 304851 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
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)
ACT,NSW,QLD

Funding & Sponsors
Funding source category [1] 288011 0
Government body
Name [1] 288011 0
NHMRC Project Grant #1046266
Address [1] 288011 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 288011 0
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] 286732 0
None
Name [1] 286732 0
Address [1] 286732 0
Country [1] 286732 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289935 0
Aboriginal Health & Medical Research Council Ethics Committee
Ethics committee address [1] 289935 0
PO Box 1565
Strawberry Hills NSW 2012
Ethics committee country [1] 289935 0
Australia
Date submitted for ethics approval [1] 289935 0
23/05/2013
Approval date [1] 289935 0
28/06/2013
Ethics approval number [1] 289935 0
EC00342
Ethics committee name [2] 289936 0
University of Western Sydney Human Research Ethics Committee
Ethics committee address [2] 289936 0
Office of Research Services
Kingswood Campus, Building K
Locked Bag 1797
Penrith NSW 2751
Ethics committee country [2] 289936 0
Australia
Date submitted for ethics approval [2] 289936 0
13/08/2013
Approval date [2] 289936 0
02/09/2013
Ethics approval number [2] 289936 0
EC00314
Ethics committee name [3] 289937 0
Metro South Health Service District Human Research Ethics Committee
Ethics committee address [3] 289937 0
Princess Alexandria Hospital
Centres for Health Research
Level 2, Building 35
Ipswich Road
Woolloongabba QLD 4102
Ethics committee country [3] 289937 0
Australia
Date submitted for ethics approval [3] 289937 0
11/06/2013
Approval date [3] 289937 0
06/08/2013
Ethics approval number [3] 289937 0
EC00167
Ethics committee name [4] 289938 0
Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [4] 289938 0
P0 Box 41096
Casuarina NT 0811
Ethics committee country [4] 289938 0
Australia
Date submitted for ethics approval [4] 289938 0
13/08/2013
Approval date [4] 289938 0
19/08/2013
Ethics approval number [4] 289938 0
EC00153
Ethics committee name [5] 289939 0
The University of Queensland Medical Research Ethics Committee
Ethics committee address [5] 289939 0
Research & Training Division
Cumbrae Stewart Building
The University of Queensland ST. LUCIA
QLD 4072
Ethics committee country [5] 289939 0
Australia
Date submitted for ethics approval [5] 289939 0
12/08/2013
Approval date [5] 289939 0
21/08/2013
Ethics approval number [5] 289939 0
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 [2] 1165 1165 0 0

Contacts
Principal investigator
Name 43150 0
Prof Jennifer Reath
Address 43150 0
Western Sydney University School Of Medicine Campbelltown Campus Building 30, Locked Bag 1797 Penrith, NSW, 2751
Country 43150 0
Australia
Phone 43150 0
61 02 4620 3725
Fax 43150 0
Email 43150 0
j.reath@westernsydney.edu.au
Contact person for public queries
Name 43151 0
Prof Jennifer Reath
Address 43151 0
Western Sydney University School of Medicine Campbelltown Campus
Building 30, Locked Bag 1797 Penrith, NSW, 2751
Country 43151 0
Australia
Phone 43151 0
61 02 4620 3725
Fax 43151 0
Email 43151 0
j.reath@westernsydney.edu.au
Contact person for scientific queries
Name 43152 0
Prof Jennifer Reath
Address 43152 0
Western Sydney University School of Medicine Campbelltown Campus
Building 30, Locked Bag 1797 Penrith, NSW, 2751
Country 43152 0
Australia
Phone 43152 0
61 02 4620 3725
Fax 43152 0
Email 43152 0
j.reath@westernsydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Data will be available but in de-identified format
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
Summary results
No Results