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Trial registered on ANZCTR


Registration number
ACTRN12618000049279
Ethics application status
Approved
Date submitted
27/11/2017
Date registered
16/01/2018
Date last updated
5/08/2019
Date data sharing statement initially provided
5/08/2019
Date results information initially provided
5/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral prednisolone for acute middle ear infection in children
Scientific title
Oral prednisolone for acute otitis media in children: a pilot pragmatic, randomised, open-label, single-blind study to evaluate feasibility
Secondary ID [1] 293452 0
Nil known
Universal Trial Number (UTN)
U1111-1205-7619
Trial acronym
OPAL Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute otitis media in children 305630 0
Condition category
Condition code
Ear 304851 304851 0 0
Other ear disorders
Infection 304852 304852 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral prednisolone (tablet):
- The dose administered based on age range: once daily of 10 mg for children aged 6 months to < 2 years; 20 mg for children aged 2 years to < 6 years; and 30 mg for children aged 6 years to 12 years
- The duration of administration: 5 (five) days
- The mode of administration: oral tablet
Prednisolone tablets will be crushed by the pharmacist, then will be mixed with sweeteners, and packed in a daily-dose paper-wrap.
Children will be stratified based on disease severity to mild or severe acute otitis media (AOM).
Children with mild symptoms and signs of AOM (e.g. mild ear pain fever less than 39 degree Celcius, mild bulging of ear drum) will be randomly allocated to intervention group (will receive oral prednisolone plus 48-hour expectant observation) or control group (48-hour expectant observation alone).
Children with severe symptoms and signs of AOM (e.g. moderate to severe ear pain, fever 39 degree Celsius or more, moderate-to-severe bulging of the ear drum, AOM complications) will be randomly allocated to intervention group (will receive oral prednisolone plus antibiotics based on physicians' preferences) or control group (antibiotics alone).
Parents or the caregivers will give the study medication to their children at home, once daily, in the morning (before 9 am) after breakfast, with a glass of water, milk, or juice, or mix the study medication powder with a small amount of soft food such as jam and yoghurt. to make the taste more palatable for children.
Research team will send a daily text message to remind the parents/caregivers to give the study medicine daily for five days. We will also provide a symptom diary (consists of three mini booklets of diary that will record the symptoms at: (1) Day-1 to Day-3 (research team will collect the first booklet at Visit-1 or Day-3 after the randomisation/baseline visit); (2) Day-4 to Day-7 ( will be collected at Visit-2 or Day-7 after the randomisation); and (3) Day-8 to Day-14 (will be collected at Day-14 home visit.

We included a mechanistic sub-study using tympanometry as a sub-study or part of the main study. As we did not determine the sample size for the pilot study, the mechanistic study will involve all children in the pilot study (n=60), All children will undergo tympanometry examination in each follow-up visit (Visit-0/Day-0; Visit-1/Day-3; Visit-2/Day-7; Visit-3/Day-30; Visit-4/Day-90), regardless to groups they are allocated to.
At each visit, after a consultation and ENT examination conducted by a physician, the subject will undergo a tympanometry examination . The audiologists will identify the condition of ear canal (e.g. ear wax) and estimate the size of the ear cuffs. Then the audiologist will insert appropriate-size ear cuffs into the probe tip and ask for the assistance of an attending nurse or the parents to hold the subject's head. She/he then will slowly insert the probe tip into the ear canal, until the graph appears on the screen. After the graph indicates the sufficient results (e.g. no air leak, no block), then she/he will conduct a similar procedure in the other side of the ears and print the results of both ears. The audiologist will write a subject registration number and date of examination on the printed paper, make a copy of the printed paper, record the tympanometry results of both ears (i.e. tympanogram curve types. ear canal volumes, compliance/static acoustic admittance, middle ear pressure), and attach the copied result of tympanometry examination on the 'Outcomes form'. The physicians then will analyse and interpret the tympanometry results. This procedure may require 10 to 30 minutes, depends on the subject's cooperation and the condition of the ear canals.
Intervention code [1] 299696 0
Treatment: Drugs
Comparator / control treatment
Control treatment is without prednisolone. However, the study subject will receive a standard treatment based on their stratified group.
For example, those in mild group will have 48-hour expectant observation alone and those in severe group will receive antibiotic treatment.
A 48-hour expectation is a close-observation conducted by parents or care-givers for any worsening symptoms, no improvement, or complications during the first 48 hours. At the baseline visit, we advise the parents to bring their children back to the hospitals if their children experiencing these symptoms/complications or to contact a 24-hour call center where parents can consult these to the chief investigator.
Children in the severe group will receive antibiotic treatment. Due to the pragmatic nature of this study, physicians may prescribe any antibiotics, including the type, dose, duration, and mode of administration, based on their clinical preferences. This will be recorded on the case report form. However, in order to help them decide, we will provide the list of antibiotics recommended by the 2013 American Academy of Pediatrics.


Control group
Active

Outcomes
Primary outcome [1] 304054 0
Recruitment rates. It is defined as recruitment rates that will be assessed monthly
Timepoint [1] 304054 0
We will assess this outcome at each month for the overall 6-month recruitment duration of the pilot study.
Primary outcome [2] 304055 0
The success of the study procedures. We will assess this outcome by identifying the process and obstacles during the following procedures: (1) obtaining informed consents from the patients and their parents; (2) the recruitment using prespecified eligibility criteria and the use of otoscope to confirm AOM if feasible; (3) the stratification and randomisation, including accessing the randomisation number and dispensing the study medication; and (4) the identification of AOM symptoms and signs by clinical history taking and examination using otoscope and tympanometry.
Timepoint [2] 304055 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).
Primary outcome [3] 304056 0
Ability to measure planned outcomes in the main study. We will identify the ability and challenges in measuring planned outcomes in the main study, as follows: (1) the proportion of children with pain reduced by at least the minimum clinically important reduction, at Day-3 after randomisation; (2) the severity of pain and other AOM-relevant symptoms at various time points using visual analogue scale (VAS) and acute otitis media severity of symptoms scale (AOM-SOS); (3) duration to AOM resolution; (4) adverse effects; (5) complication of AOM (e.g. perforation of tympanic membrane, mastoiditis); (6) AOM recurrence, defined as a new episode of AOM at one to three months after randomisation; and (7) the change of middle ear effusion at various time points, including the duration and its correlation with ear pain and other symptoms (i.e. ear tugging, irritability, crying, lack of sleep, lack of appetite, less of playfulness, fever). We will use a questionnaire as a feedback form for physicians, audiologists, nurses, pharmacists, and the parents. The questionnaire consists of questions regarding the experience and challenges they encounter when measuring the outcomes (e.g. recruiting the children, conducting otoscopic and tympanometry examination, completing the case report forms, completing the symptom diary, preparing and dispensing the study medication), We will read the questions along with several options for answers from the feedback form and tick the answers accordingly. If their answers are not available on the form or they have other opinions, then we will write their answers on the 'others' column.
In assessing the symptoms of AOM, we will use validated scales, such as VAS and AOM-SOS. We have translated the English version of AOM-SOS into the Indonesian version through forward and backward translation process. We have designed the other questions in the 'Outcome form' (e.g. questions of the complication of AOM, side effects, the management for the side effects) and the questionnaire in the 'Feedback form' specifically for this study.
Timepoint [3] 304056 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).
Secondary outcome [1] 340806 0
Compliance to study visits and study medication. The compliance to study visits and study medication is defined as a proportion of children who regularly take the study medication according to the prespecified dose and duration (assessed using the symptom diary and the number of any left-over drug) and who come to follow-up visits per protocol. Participants will be followed closely by clinicians and research staff. Children will return for a visit at Day-3 after randomisation (Visit-1), ensuring collection of the primary outcome.
Timepoint [1] 340806 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).
Secondary outcome [2] 340808 0
The mechanistic sub-study using tympanometry:
Primary outcome - The change of middle ear effusion. We will measure MEE using static acoustic admittance, defined as “the amount of energy absorbed by the tympanic membrane and middle ear, measured in mmho or mL”.
This sub-study will include all children in the pilot study (n=60), as we did not determine a sample size for the pilot study. The sample size of the mechanistic sub-study was determined based on the main primary outcome, which is the mean value of static acoustic admittance or acoustic compliance in the tympanogram. In a previous study of children with middle ear effusion (MEE) who underwent tympanometry assessment and had a history of chronic or recurrent middle ear disease, the response within each subject group was normally distributed with standard deviation 0.3. If the true difference in the experimental and control means is 0.3 units, we will need to study 22 experimental subjects and 22 control subjects to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.9. The Type I error probability associated with this test of this null hypothesis is 0.05. With a 20% allowance for dropouts, the total sample size becomes 56 or we will include 60 children for this pilot study.
Timepoint [2] 340808 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).
Secondary outcome [3] 340809 0
The mechanistic sub-study using tympanometry:
Secondary outcome - The duration of middle ear effusion.
The duration of middle ear effusion is defined as a duration of middle ear effusion represented by the normalisation of the value of static acoustic admittance.
This sub-study will include all children in the pilot study (n=60).
Timepoint [3] 340809 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).
Secondary outcome [4] 340810 0
The mechanistic sub-study using tympanometry:
Secondary outcome - The correlation between ear pain and other symptoms (i.e. ear tugging, irritability, crying, lack of sleep, lack of appetite, less of playfulness, fever) with the changes of middle ear effusion at various time points. At each time point, we will assess the correlation between the value of static acoustic admittance with the severity of ear pain (assessed using VAS) and other non-specific AOM symptoms (assessed using AOM-SOS).
This sub-study will include all children in the pilot study (n=60).
Timepoint [4] 340810 0
At the baseline visit (Visit-0), Day-3 (Visit-1), Day-7 (Visit-2), Day-30 (Visit-3), and Day-90 (Visit-4).

Eligibility
Key inclusion criteria
Children with acute otitis media, defined as a current onset within 48 to 72 hours of ear-related symptoms (e.g. ear pain, ear tugging/rubbing or irritability for non-verbal young children) and/or signs of acute inflammation (e.g. erythema ear drum) and middle ear effusion (e.g. bulding ear drum, air-fluid level, purulent appearance of ear drum) if feasible to assess using otoscope,
Minimum age
6 Months
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Children with major and severe medical conditions (e.g. heart failure, kidney failure)
2. Immunocompromised children (e.g. HIV, children receiving cancer treatment)
3. Children with congenital malformations and/or syndromes (e.g. cleft palate, Down’s syndrome)
4. Children with high risk of risk of strongyloidiasis infection
5. Children with ear ventilation tube(s)
6. Children who had exposed to persons with varicella (chicken pox) or active Zoster infection in the past 3 weeks without any prior varicella immunisation or infection
7. Children who have taken systemic (i.e. oral, injection) or topical steroids in the preceding four weeks
8. Children who have taken antibiotics in the preceding two weeks
9. Children who are hypersensitive to prednisolone or prednisone, or other corticosteroids.

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)
The appointed nurses will access the randomisation website to obtain information regarding the intervention allocation and 3-digit subject randomisation ID. This randomisation website was developed by Centre for Research in Evidence-Based Practice (CREBP) Bond University, Queensland, Australia. Based on this information, children will be randomly allocated to either prednisolone plus expectant observation or expectant observation alone in the mild group and either prednisolone plus antibiotic or antibiotic alone in the severe group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Before the randomisation, children will be stratified based on the disease severity to either mild or severe acute otitis media group, For the sequence generation, a permuted block randomisation sequence will be computer-generated.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Pragmatic
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
For the recruitment rate, we report the outcome as the proportion of children in percentage (%). For the success of the study procedures and the ability to measure planned outcomes in main study, we will report the outcomes as the proportion of clinicians in percentage (%) based on the grading scale of their feedback reporting on prespecified outcome measure tools. For the compliance to study and study drug, we will report the outcomes as the proportion of children in percentage (%) who attend the follow-up visits and complete the cycle of study drug.
To assess the verification of sample size calculation for main study, we will report this outcome as the proportion of children in each stratum (mild and severe AOM group) and those with pain at Day-3 after randomisation in the control group.
For the mechanistic sub-study, we will report continuous variables (i.e. the change in MEE at various time points (mean in days standard deviation), the duration of MEE) as a mean difference (MD) with 95% confidence intervals (CI) also the difference between two groups. We also will report the correlation between ear pain and other symptoms with the changes in MEE at various time points.

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 outside Australia
Country [1] 9395 0
Indonesia
State/province [1] 9395 0
DKI Jakarta (i.e. Central Jakarta, East Jakarta) and West Java (i.e. Bekasi)

Funding & Sponsors
Funding source category [1] 298078 0
University
Name [1] 298078 0
The Australian Government Research Training Program Scholarship
Address [1] 298078 0
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226, Queensland Australia
Country [1] 298078 0
Australia
Funding source category [2] 300549 0
Government body
Name [2] 300549 0
the Australian National Health and Medical Research Council (NHMRC) [#1044904]
Address [2] 300549 0
16 Marcus Clarke St
Canberra ACT 2601
Country [2] 300549 0
Australia
Funding source category [3] 300550 0
Government body
Name [3] 300550 0
Advance Queensland, Australia (Women’s Academic Fund Maternity funding WAF-7026811-298)
Address [3] 300550 0
Department of Tourism, Major Events, Small Business and the Commonwealth Games
PO Box 15168
CITY EAST QLD 4002
Country [3] 300550 0
Australia
Primary sponsor type
Individual
Name
Respati Wulansari Ranakusuma
Address
Centre for Research in Evidence-Based Practice
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226, Queensland
Australia
Country
Australia
Secondary sponsor category [1] 297160 0
University
Name [1] 297160 0
Centre for Research in Evidence-Based Practice, Bond University
Address [1] 297160 0
Centre for Research in Evidence-Based Practice
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226, Queensland
Australia
Country [1] 297160 0
Australia
Secondary sponsor category [2] 297226 0
Hospital
Name [2] 297226 0
Clinical Epidemiology and Evidence-Based Medicine Unit, Dr Cipto Mangunkusumo Hospital and Faculty of Medicine Universitas Indonesia
Address [2] 297226 0
Building H, Level 2 Dr Cipto Mangunkusumo Hospital
Diponegoro 71
Jakarta 10430
Country [2] 297226 0
Indonesia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299100 0
The Ethics Committee of the Faculty of Medicine University of Indonesia
Ethics committee address [1] 299100 0
Salemba Raya 6
Jakarta 10430
Ethics committee country [1] 299100 0
Indonesia
Date submitted for ethics approval [1] 299100 0
07/08/2017
Approval date [1] 299100 0
23/10/2017
Ethics approval number [1] 299100 0
852/UN2.F1/ETIK/2017 (For amendment No 1088/UN2.F1/ETIK/X/2017
Ethics committee name [2] 299106 0
Bond University’s Human Research Ethics Committee (BUHREC)
Ethics committee address [2] 299106 0
Bond University
14 University Drive
Robina 4226
Queensland
Ethics committee country [2] 299106 0
Australia
Date submitted for ethics approval [2] 299106 0
02/11/2017
Approval date [2] 299106 0
09/01/2018
Ethics approval number [2] 299106 0
0000016208

Summary
Brief summary
Antibiotic resistance, a major health global threat, is mostly driven by antibiotic prescribing. Antibiotics are commonly prescribed in primary care for acute respiratory infections, including acute otitis media (AOM). AOM is an inflammation of the middle ear commonly found in children. Expectant observation with pain management is commonly recommended for children with mild AOM (e.g. mild ear pain, fever < 39°C) who can be reliably followed-up. Those with severe symptoms, bilateral AOM in young age children, or perforated ear drums are more likely to benefit from antibiotics. The option of using antibiotics must be balanced against common adverse effects (e.g. vomiting, diarrhoea, or rash). In Australian general practice, 89% of new AOM cases are managed with antibiotics. In Indonesia, similarly, our survey study demonstrated about 88% of physicians would prescribe antibiotics for children with mild AOM. Indonesian practice guidelines on the criteria for antibiotic use for AOM are vague..
Alternative treatments have been proposed for treating AOM, including herbal preparations, decongestants, and corticosteroids. However, the evidence for these are too weak to be recommended in clinical practice. The anti-inflammatory effect of corticosteroids suggests it could be a viable treatment alternative for AOM. Moreover, corticosteroids are effective additions to treatment for other, more serious acute respiratory infections, including pneumonia and bacterial meningitis. However, there is insufficient evidence of efficacy and harms for AOM: a systematic review of randomised controlled trials (RCTs) of corticosteroids for AOM (two small studies; very low to low quality) indicated it might be useful clinically, but the small sample size and wide confidence intervals around the observed results leave too much uncertainty. An additional RCT showed a reduction of the duration of ear discharge in children with AOM and ventilation tubes.
Accordingly, we plan to conduct an adequately powered clinical trial to address the uncertainties around the effectiveness of corticosteroids for AOM in children. Initially, we need to conduct this pilot study with an associated mechanistic sub-study using tympanometry. The pilot study will test the feasibility of characteristics of our main study design and all the study procedures, as well as other operational strategies in our proposed main study. As one of our outcomes is to assess the ability to measure planned outcomes of the proposed main study, we will also obtain the outcomes and report these narratively. The mechanistic sub-study will explore the potential mechanism of action of corticosteroids in the resolution of middle ear effusion in AOM.
Trial website
Trial related presentations / publications
Public notes
Attachments [2] 2224 2224 0 0
/AnzctrAttachments/374057-Explanatory Statement and consent.pdf (Participant information/consent)
Attachments [3] 2225 2225 0 0
/AnzctrAttachments/374057-Complete CRFs.pdf (Supplementary information)
Attachments [4] 2241 2241 0 0
/AnzctrAttachments/374057-FMUI Bond Approvals.pdf (Ethics approval)

Contacts
Principal investigator
Name 79286 0
Dr Respati Wulansari Ranakusuma
Address 79286 0
Centre for Research in Evidence-Based Practice
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226
Queensland
Country 79286 0
Australia
Phone 79286 0
+61755951588
Fax 79286 0
Email 79286 0
rranakus@bond.edu.au
Contact person for public queries
Name 79287 0
Dr Respati Wulansari Ranakusuma
Address 79287 0
Centre for Research in Evidence-Based Practice
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226
Queensland
Country 79287 0
Australia
Phone 79287 0
+61755951588
Fax 79287 0
Email 79287 0
OPAL.study@bond.edu.au
Contact person for scientific queries
Name 79288 0
Dr Respati Wulansari Ranakusuma
Address 79288 0
Centre for Research in Evidence-Based Practice
Faculty of Health Sciences and Medicine Bond University
14 University Drive, Robina 4226
Queensland
Country 79288 0
Australia
Phone 79288 0
+61755951588
Fax 79288 0
Email 79288 0
OPAL.study@bond.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
Confidential issues
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 3596 0
Study protocol
Citation [1] 3596 0
Ranakusuma RW, McCullough AR, Safitri ED, Pitoyo Y, Widyaningsih W, Del Mar CB, et al. Oral prednisolone for acute otitis media in children: protocol of a pilot randomised, open-label, controlled study (OPAL Study)
Email [1] 3596 0
Other [1] 3596 0
Attachment [1] 3596 0
Type [2] 3597 0
Informed consent form
Citation [2] 3597 0
Ranakusuma RW, McCullough AR, Safitri ED, Pitoyo Y, Widyaningsih W, Del Mar CB, et al. Oral prednisolone for acute otitis media in children: protocol of a pilot randomised, open-label, controlled study (OPAL Study)
Email [2] 3597 0
Other [2] 3597 0
Attachment [2] 3597 0
Type [3] 3598 0
Ethical approval
Citation [3] 3598 0
Link [3] 3598 0
Email [3] 3598 0
Other [3] 3598 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary