Oral prednisolone for acute otitis media in children: protocol of a pilot randomised, open-label, controlled study (OPAL study)

Background Acute otitis media (AOM) is an acute inflammation of the middle ear commonly found in children, for which antibiotics are frequently prescribed. However, antibiotics are beneficial for only one third of AOM cases, and then, with only modest benefit. Since antibiotic use leads to risk of side effects and resistance, effective alternative treatments are required. Corticosteroids are a candidate because of their anti-inflammatory effects, although evidence of their efficacy and harms is insufficient. Accordingly, we plan a large, rigorous clinical trial to test this. Initially, we will test pre-specified methods and procedures (including the overall process, resources, management, and scientific components) in a pilot study of corticosteroids for AOM, which will inform a future, definitive trial. Methods This is a pilot pragmatic, randomised, open-label, single-blind, controlled study of corticosteroids as either monotherapy or an addition to antibiotics in 60 children aged 6 months to 12 years with AOM in two cities (Jakarta and Bekasi) in Indonesia. We will randomise eligible children to prednisolone or control. We will also stratify by disease severity and randomise those with mild AOM to expectant observation plus prednisolone or observation alone and those with severe AOM to prednisolone plus antibiotic or antibiotic alone. Our outcomes are to determine (1) recruitment rates, (2) the success of the study procedures, (3) the ability to measure planned outcomes of the proposed main study, (4) the compliance to study visits and study medication, and (5) verification of the sample size calculation for the main study. We will also assess middle ear effusion using tympanometry as part of a mechanistic sub-study. Discussion This study will test all procedures in preparation for the main study, including several potential obstacles and challenges from the perspective of participating physicians, nurses, pharmacists, and the parents of eligible children. This information will be useful for developing strategies to overcome practical and procedural issues. This study may also provide information about the effects of corticosteroids on middle ear effusion in AOM. Trial registration Study registry number: ACTRN12618000049279. Name of registry: the Australian New Zealand Clinical Trials Registry (ANZCTR). Date of registration: 16 January 2018. Electronic supplementary material The online version of this article (10.1186/s40814-018-0337-x) contains supplementary material, which is available to authorized users.


Objectives of the study Primary objectives
To assess the overall process and procedures of a large main study, including (1) the recruitment criteria; (2) the process of stratification and randomisation; (3) clinical outcomes measures using validated and customized tools.
To identify any practical and operational issues that potentially occur in the large main study.
To verify a sample size calculation for the large main study.

Secondary objectives
To identify and explain the mechanism of corticosteroids in improving middle ear effusion and other clinical symptoms of AOM in a mechanistic sub-study using tympanometry.
Oral prednisolone for acute otitis media in children (OPAL) study 9 A Pilot study and a mechanistic sub-study P Children aged 6 month to 12 years with acute otitis media (AOM) [N=60].

FORM01. Study recruitment log book
The research summary The overall procedures in the study, including the follow-up visit Potential side effects Compensation Voluntary participation CRF01. Information sheet and consent form children (6 months -12 years) with AOM, defined as a current onset within 48 hours of ear-related symptoms (e.g. ear pain, ear tugging/rubbing or irritability) and if possible to assess, otoscopic findings of acute inflammation (e.g. erythema) and middle ear effusion (e.g. bulging, air-fluid level)

Inclusion criteria
Children with or who: 1. major and severe medical conditions (e.g. heart/kidney failure) 2. immunocompromised children (e.g. HIV, in cancer treatment) 3. congenital malformations and/or syndromes (e.g. cleft palate) 4. high risk of strongyloidiasis infection 5. ear ventilation tube(s) 6. had exposed to persons with varicella or active Zoster infection in the past 3 weeks without any prior varicella immunization/ infection 7. have taken oral or topical steroids in the preceding four weeks 8. have taken antibiotics in the preceding two weeks 9. are hypersensitive to prednisolone other corticosteroids. Obtaining the consent to the study In obtaining and documenting IC, the investigator should comply with the applicable regulatory requirement(s), GCP and to the ethical principles that have their origin in the Declaration of Helsinki.
The subject or the subject's legally acceptable representative should be informed in a timely manner if new relevant information becomes available. The communication of this information should be documented.
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
None of the oral and written information concerning the trial, including the written IC form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator / institution for negligence.
The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide IC, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.

The anticipated prorated payment and anticipated expenses (if any)
Voluntary participation and the subject may refuse to participate or withdraw from the trial, at any time The auditor(s) or IRB/IEC will be granted direct access to the subject's medical records for verification of clinical trial procedures The records identifying the subject will be kept confidential the subject or the subject's legally representative will be informed if relevant information becomes available The person(s) to contact for further information regarding the trial , including trial-related injury events The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated.
The expected duration of the trial, including the approximate number of subjects involved in the trial.