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Clinical Trial Results:
Oral steroids for the resolution of otitis media with effusion in children study (OSTRICH)

Summary
EudraCT number	2012-005123-32
Trial protocol	GB
Global end of trial date	27 Apr 2017

Results information
Results version number	v1(current)
This version publication date	29 Dec 2018
First version publication date	29 Dec 2018
Other versions
Summary report(s)	HTA report for OSTRICH

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SPON1030-11

ISRCTN number

ISRCTN49798431

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Cardiff University

Sponsor organisation address

McKensie House, Newport Road, Cardiff, United Kingdom, CF24 0DE

Public contact

Trial Manager, Cardiff University, 0044 029 20 687 609, OSTRICH@cardiff.ac.uk

Scientific contact

Trial Manager, Cardiff University, 0044 02920 687 609, OSTRICH@cardiff.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Apr 2017

Global end of trial reached?

Yes

Global end of trial date

27 Apr 2017

Was the trial ended prematurely?

Main objective of the trial

To determine the clinical and cost effectiveness of a 7 day course of oral prednisolone (steroid) on improving hearing in the short term in children with bilateral OME with confirmed hearing loss for at least 3 months.

Protection of trial subjects

The IDMC for the OSTRICH trial was build-up to safeguard the interests of the OSTRICH trial participants, potential participants, investigator and sponsor; to assess the safety and efficacy of the trial interventions, and to monitor the trial's overall conduct, and protect its validity and credibility. Six IDMC meetings were held (21/03/2013, 08/07/2014, 16/09/2014, 21/01/2015, 25/06/2015 and 08/03/2016 ). The IDMC received and reviewed the progress and accruing data of this trial and provided advice on the conduct of the trial to the Trial Steering Committee (TSC). Potential risk of clinical deterioration during the time between the patient's consultation with their ENT clinician and the end of the study treatment period was minimised as patients could follow their usual care pathway at 5 weeks post randomisation. There was a small risk of side effects (such as gastrointestinal disturbance or behavioural effects) from the trial medication, which were explained to participating parents/carer(s) and children (where appropriate). All adverse event were monitored and 24 hour emergercy unblinding was available. The Audiometry, Tympanometry and Otoscopy may cause minimal discomfort or intrusion in young children. However, these assessments are normally be conducted in usual care, and are conducted by trained ENT clinicians and Audiologists experienced in working with this age group, who would have been able to minimise any distress or discomfort the children may have experienced.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Scientific research

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 380

Worldwide total number of subjects

380

EEA total number of subjects

380

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

380

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Children were identified and followed up in ear, nose and throat (ENT) outpatient or Paediatric Audiology and Audiovestibular Medicine (AVM) clinics in Wales and England between 20th March 2014 and 5th April 2016. Sites were selected based on their recruitment potential and membership of clinical research networks.

Screening details

1. Eligible patients identified in secondary care centres. 2. Ear, Nose and Throat (ENT)/ /audiovestibular medicine (AVM) clinician checks eligibility and takes consent. 3. Pharmacy dispenses pre-randomised trial medication by selecting next sequentially ordered trial pack.

Period 1 title

Baseline (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Sequential pack numbers were randomly assigned to oral steroid or placebo (1:1) using computer generated random permuted block sizes stratified by site and child’s age group (2-5, 6-8 years old). Recruited children were allocated the next sequentially numbered trial pack at each site pharmacy. Children, parents/legal guardians, clinical staff and the trial team (including the statistician) were all blinded to treatment allocation.

Are arms mutually exclusive

Yes

Placebo

Arm description

Seven day course of placebo matched for packaging, colour, solubility, and consistency, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants in the placebo group received a 7-day course of oral soluble placebo. The placebo used in this trial was matched for consistency, colour and solubility, as well as visually and in its packaging.

Oral Steroid

Arm description

Seven day course of oral soluble Prednisolone, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Arm type

Active comparator

Investigational medicinal product name

Oral soluble prednisolone (oral steroid)

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants in the active treatment group received a 7-day course of oral soluble prednisolone.

Number of subjects in period 1	Placebo	Oral Steroid
Started	187	193
5 weeks post randomisation	180	183
6 months post randomisation	166	174
12 months post randomisation	162	170
Completed	162	170
Not completed	25	23
attended clinic but missing outcome data	10	2
Lost to follow-up	15	21

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Seven day course of placebo matched for packaging, colour, solubility, and consistency, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Reporting group title

Oral Steroid

Reporting group description

Seven day course of oral soluble Prednisolone, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Reporting group values	Placebo	Oral Steroid	Total
Number of subjects	187	193	380
Age categorical
Age of child at recruitment
Units: Subjects
2-5 years	133	131	264
6-8 years	54	62	116
Age continuous
Units: years
arithmetic mean (standard deviation)	5.08 ( 1.60 )	5.30 ( 1.60 )	-
Gender categorical
Units: Subjects
Female	85	84	169
Male	102	109	211

End points

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Reporting group title

Placebo

Reporting group description

Seven day course of placebo matched for packaging, colour, solubility, and consistency, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Reporting group title

Oral Steroid

Reporting group description

Seven day course of oral soluble Prednisolone, as a single daily dose of 20mg or 30mg for children aged 2-5 years or 6-8 years respectively.

Primary: 5 week follow-up

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End point title

5 week follow-up

End point description

End point type

Primary

End point timeframe

5 weeks

End point values	Placebo	Oral Steroid
Number of subjects analysed	180	183
Units: resolution of hearing
resolution of hearing	59	73
Hearing not resolved	121	110

Resolution of hearing

Comparison groups

Placebo v Oral Steroid

Number of subjects included in analysis

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.136

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

2.11

Adverse events

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Timeframe for reporting adverse events

Data on adverse events was collected daily during the 5 day course of trial medication and then weekly up to 5 weeks post randomisation.

Adverse event reporting additional description

All adverse events were recorded by parents in a symptom diary, with each symptom being rated from 0 to 6 by parents.

Assessment type

Non-systematic

Dictionary name

OSTRICH Diary

Dictionary version

1.9

Reporting group title

Adverse Events

Reporting group description

Serious adverse events	Adverse Events
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 380 (0.26%)
number of deaths (all causes)	0
number of deaths resulting from adverse events
Respiratory, thoracic and mediastinal disorders
Asthma attack
subjects affected / exposed	1 / 380 (0.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Adverse Events
Total subjects affected by non serious adverse events
subjects affected / exposed	47 / 380 (12.37%)
Gastrointestinal disorders
Digestion
Additional description: increased or low appetite, diarrhoea, constipation, nausea
subjects affected / exposed	16 / 380 (4.21%)
occurrences all number	16
Respiratory, thoracic and mediastinal disorders
Respiratory tract infection
Additional description: coughs, colds, headaches
subjects affected / exposed	22 / 380 (5.79%)
occurrences all number	22
Psychiatric disorders
Behaviour
Additional description: hyperactive, tired, frustration, sleep walking, change in behaviour
subjects affected / exposed	11 / 380 (2.89%)
occurrences all number	11

More information

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Were there any global substantial amendments to the protocol? Yes

11 Jul 2013

Substantial amendment - protocol version 2.0 · Amendment made to where follow up visits will be conducted: e.g. followed up in ENT or Audiology outpatient clinics and Figure 1 amended, · Additions made to inclusion criteria: First time in the OSTRICH trial, ability of parent/carer to understand and give informed consent, does not already have grommets (ventilation tubes), · Additions made to exclusion criteria: Ear infection, Kartagener’s or Primary Ciliary Dyskinesia, existing known sensory hearing loss, undergoing cancer treatment, on a waiting list for grommet surgery and anticipates having surgery within 5 weeks and unwilling to delay it, · Pharmacovigilance section amended to include section on expectedness, clarification on who is responsible for assessing causality and clarification of timeline for SUSARs e.g. ‘day zero is defined as the date the SAE form is initially received at SEWTU’. · Additional procedure added to 5 week follow-up: At the 5 week follow up appointment any unused trial medication will be collected and returned to pharmacy for disposal.

14 Nov 2013

Substantial amendment - protocol version 3.0 · Rewording made to inclusion/ exclusion criteria: the inclusion criterion ‘does not already have grommets (ventilation tubes)’ changed to the exclusion criterion of ‘child already has grommets (ventilation tubes)’, · Changes to study procedure: a designated member of the OSTRICH team (where possible) or the participant’s parent will collect the Trial pack from Pharmacy, · Unblinding telephone number added, · Amendment made to the different options that a parent can choose when withdrawing their child from the study, · Adverse events CRF completed at 5 week follow up as well as in parent diary to ensure all non-serious adverse reactions and events are recorded, · Changes to study procedure: Data linkage used to identify healthcare consultations during the 12 month follow up period in secondary care and primary care (where possible), · Timeframe windows for follow up added e.g. + 1 week for 5 week follow up, +/- 2 weeks for 6 and 12 month follow ups, · Pharmacovigilance section amended to include section on expectedness, clarification on who is responsible for assessing causality and clarification of timeline for SUSARs e.g. ‘day zero is defined as the date the SAE form is initially received at SEWTU’.

10 Apr 2014

Substantial amendment - protocol version 4.0 · Addition of sub-study on qualitative sub-study will explore parents’ understanding of the treatment options available to them and the views about the role of shared decision making in the context of managing glue ear, as well as their views on the use of oral steroids for glue ear. · Addition to ‘supply, packaging, storage and reconciliation of trial medication’ section, to say there is overage and extra tablets are to be returned at the 5 week follow up appointment.

12 Jun 2014

Substantial amendment Change to study documentation only Consent form and Information Sheet.

17 Jun 2014