| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Middle ear infection (children) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014020 |
| E.1.2 | Term | Ear pain |
| E.1.2 | System Organ Class | 10013993 - Ear and labyrinth disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065838 |
| E.1.2 | Term | Middle ear inflammation |
| E.1.2 | System Organ Class | 10013993 - Ear and labyrinth disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary research question:
1.1 Do active drops lead to a lower proportion of children consuming antibiotics by Day 8 (where Day 1 is the day of randomisation) compared with no drops (usual care)?
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| E.2.2 | Secondary objectives of the trial |
Key secondary outcome:
2.1. Do active drops provide superior pain relief in the first 24-36 hours compared to placebo drops?
Other secondary outcomes:
2.2. Do active drops lead to reduced oral analgesic consumption in the first 7 days after randomisation (where Day 1 is the day of randomisation) compared with placebo drops?
2.3. Do placebo drops provide superior pain relief in the first 24-36 hours after randomisation compared to ‘no drops’ (usual care)?
2.4. Do active drops provide superior pain relief during Day 1 (day of consultation) compared to placebo drops? (Measured at approximately 1 hour after administration of the drops and on the evening of Day 1)
2.5. Do active drops lead to a lower proportion of children consuming antibiotics by Day 8 post randomisation compared with placebo drops?
2.6. Do active drops alter the number of days before starting antibiotics in the first seven days after randomisation, compared with placebo drops and no drops (usual care)?
2.7. Do ac |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Due to a delay in the manufacture of the placebo, we will start the trial as a 2 arm pilot (active drops and usual care, vs usual care/no drops), for the first 3 months of the internal pilot period, and introduce the third arm when the placebo is ready.
Although there is no sub-study involving an interventional product or device, however there will be an observational cohort study recruiting children in parallel to the randomised controlled trial, and there will be a nested qualitative evaluation study within the randomised controlled trial. |
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| E.3 | Principal inclusion criteria |
Trial inclusion criteria (all criteria must be met):
1) Aged ≥ 12 months and <10 years
2) Presenting within 1 week of suspected AOM onset (other preceding respiratory tract infection symptoms may be longer)
3) Parent/legal guardian available to give consent
4) Parent-reported ear pain in 24 hours pre-enrolment (or parent-suspected ear pain if child is too young to report pain)
5) Clinician diagnosis of acute otitis media (although not an entry criterion, clinicians will be asked to report the presence of otoscopic evidence of acute tympanic membrane inflammation, operationalised as per our previous trial6 as: erythema with dullness or cloudiness; or bulging)
6) Child is immunocompetent
7) Clinician willing to use a NICE-recommended ‘no’ oral antibiotic prescribing strategy or a ‘delayed’ oral antibiotic prescribing strategy (as per NICE guidelines) for the AOM and other elements of the underlying acute respiratory tract infection. NICE recommends a ‘no’ or ‘delayed’ antibiotic prescribing strategy for most immune-competent children with acute otitis media.
8) Parent able to give ear drops.
9) Parent willing in principle to use ear drops before oral antibiotics and to wait before giving delayed antibiotics as per NICE guidelines.
10) Parent able to report the child’s ear pain.
11) Parent able and willing to complete daily Symptom and Recovery Questionnaire in the English language, and receive regular follow-up telephone calls, in the English language, today and every 2-3 days for up to 7 more days (or until child has been free of ear pain without medicines for two days running).
Observational study inclusion criteria (all criteria must be met):
1) Aged ≥12 months to <10 years
2) Presenting within 1 week of suspected AOM onset (other preceding respiratory tract infection symptoms may be longer)
3) Parent/legal guardian available to give immediate written or (if not present) telephone consent, and to provide written consent within 24 hours
4) Parent-reported ear pain in 24 hours pre-enrolment (or parent-suspected pain if child too young to report pain)
5) Clinician diagnosis of acute otitis media (although not an entry criterion, clinicians will be asked to report the presence of otoscopic evidence of acute tympanic membrane inflammation, operationalised as per our previous trial6 as: erythema with dullness or cloudiness; or bulging)
6) Child is immunocompetent.
7) Parent does not want to use trial ear drops (reason to be recorded).
8) Parent does not want to take part in the RCT (reason to be recorded).
9) Parent able to report the child’s ear pain.
10) Parent able and willing to complete daily Symptom and Recovery Questionnaire in the English language, and receive regular follow-up telephone calls, in the English language, today and every 2-3 days for up to 7 more days (or until child has been free of ear pain without medicines for two days running)
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|
| E.4 | Principal exclusion criteria |
Trial exclusion criteria (presence of any warrants exclusion):
1) Child requires immediate hospitalisation
2) Child requires same day oral antibiotic treatment for AOM or other elements of the underlying acute respiratory tract infection (assess these children for observational study eligibility). NICE recommends same day antibiotic treatment for:
2.1) Child younger than 2 years with bilateral acute otitis media
2.2) Otorrhoea (discharge from the ear)
2.3) Child systemically very unwell or showing signs of respiratory distress (e.g. tachypnoea, hypoxia or recession)
2.4) Child has symptoms and signs suggestive of serious illness and/or complications (particularly mastoiditis)
2.5) Child is at high risk of serious complications because of pre-existing comorbidity. NICE guidelines recommend the following children are excluded:
2.5.1) Child has significant heart, lung, renal, liver or neuromuscular disease (defined for the purposes of this study as requiring ongoing inpatient or outpatient care from specialist teams)
2.5.2) Child has immunosuppression (defined for the purposes of this study as a formal diagnosis of immunosuppression)
2.5.3) Child has cystic fibrosis
2.5.4) Child born prematurely (defined for the purposes of this study as born before 34 weeks and presenting within the first year of life)
NB: Children with other conditions who are at higher risk of AOM (e.g. Down’s Syndrome, cleft palate) may take part if the Responsible Clinician feels that they meet the inclusion criteria above)
3) Child requires same day oral antibiotics for another (non AOM) infection or topical antibiotic ear drops
4) Child is currently receiving (or has received in the past 7 days) oral or ear drop (to the AOM ear) antibiotic treatment
5) Suspected or confirmed tympanic membrane perforation (due to theoretical and unconfirmed risk of ototoxicity from active drops) or grommets still in situ
6) Known sensitivity to trial medicine (Auralgan) or to its ingredients (benzocaine, phenazone, glycerine, hydroxyquinoline sulphate) or similar substances (e.g. other ester-type anaesthetics such as procaine, tetracaine)
7) Known porphyria or haemoglobinopathy or glucose-6-phosphate dehydrogenase (G6PD) deficiency or methaemoglobinaemia
8) Known family history of G6PD deficiency (noting that G6DP deficiency is more common in African, Asian and Mediterranean populations)
9) Current use of sulphonamides or antimalarials or hyaluronidase or St John’s Wort
10) Child needs to continue taking other medicinal products containing benzocaine
11) Child has proven alternative source(s) of pain, other than and more severe than the ear symptoms with which they are presenting
12) Otoscopic appearances (as ascertained by clinician, where possible) consistent with observed fever, i.e. likely non-specific viral illness only (e.g. with just a slightly perfused or pink drum only)
13) Child has normal ear drum on examination
14) Child has otitis externa or other disorder of the outer ear or tympanic membrane, for which CEDAR ear drops should not be prescribed, in the AOM ear
15) Child has a hearing aid and parent feels hearing aid should remain in place in the AOM ear
16) Symptoms (i.e. hearing loss and longer duration of illness) more suggestive of a diagnosis of otitis media with effusion (glue ear)
17) Child has previously taken part in the CEDAR RCT
18) Child has taken part in any research involving medicines within the last 90 days, or any other AOM-related research within the last 30 days
Observational study exclusion criteria (presence of any warrants exclusion):
1) Child requires immediate hospitalisation
2) Child has proven alternative source(s) of pain, other than and more severe than the ear symptoms with which they are presenting
3) Otoscopic appearances (as ascertained by clinician, where possible) consistent with observed fever, i.e. likely non-specific viral illness only (e.g. with just a slightly perfused or pink drum only)
4) Child has normal ear drum on examination
5) Child has otitis externa or other disorder of the outer ear or tympanic membrane in the AOM ear
6) Child has a hearing aid and parent feels hearing aid should remain in place in the AOM ear
7) Symptoms (i.e. hearing loss and longer duration of illness) more suggestive of a diagnosis of otitis media with effusion (glue ear)
8) Child currently taking or has previously taken part in the CEDAR RCT
9) Child has taken part in any AOM-related research within the last 30 days
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Any antibiotic consumed by Day 8 (measured using daily Symptom and Recovery Questionnaire with telephone support calls during week 1), where Day 1 is the day of randomisation |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| We will ask parents to record any antibiotics given to the recruited child on each of the 8 days of the initial follow-up period (Days 1-8, where Day 1 is the day of study entry, and Day 8 is seven days post-randomisation). |
|
| E.5.2 | Secondary end point(s) |
| Ear pain over first 24-36 hours post randomisation using the parent completed, validated numerical rating scale successfully used in our previous trial (Symptom and Recovery Questionnaire with telephone support call in first three days). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| We will ask the parent to score the child's ear pain (using the 0-10 linear scale) on the evening of the day after they entered the trial (Day 2 of the parent and child's participation). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| (1) Placebo ear drops and usual care; (2) Usual care only (no ear drops). |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 120 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial will occur when the data analysis is complete. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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