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Trial registered on ANZCTR


Registration number
ACTRN12619001306101
Ethics application status
Approved
Date submitted
2/08/2019
Date registered
25/09/2019
Date last updated
10/11/2021
Date data sharing statement initially provided
25/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
ATOMIC Ears: A Phase IIB randomised controlled trial to assess safety, tolerability and acceptability of a 5-day Dornase alfa treatment as an adjunct therapy to ventilation tube insertion for otitis media in children
Scientific title
ATOMIC Ears: A Phase IIB randomised controlled trial to assess safety, tolerability and acceptability of a 5-day Dornase alfa treatment as an adjunct therapy to ventilation tube insertion for otitis media in children
Secondary ID [1] 298895 0
None
Universal Trial Number (UTN)
Trial acronym
ATOMIC Ears
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent acute otitis media 313870 0
Chronic otitis media with effusion ("glue ear") 313871 0
Condition category
Condition code
Ear 312283 312283 0 0
Other ear disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised 1:1 to Dornase alfa or placebo (normal saline). Administration will be blinded.
1. Pulmozyme® solution containing 1.0 mg/mL recombinant human deoxyribonuclease I (Dornase alfa). The first dose of Dornase alfa will be administered intra-operatively. The participant’s Ear Nose and Throat (ENT) surgeon will administer 0.5mL of Dornase alfa into the participant’s ear/s intra-operatively following ventilation tube (VT) insertion. This may be unilateral if only a single VT is inserted or bilateral if a VT is inserted in both ears. Post-operatively the participant’s parent/legal guardian will administer an additional 10 doses of Dornase alfa. The dosing regimen will be 5 drops twice daily (intra-auricular) for all participants, commencing on the first evening post-Ventilation tube insertion (day 0) until the final dose is administered during the morning of the fifth post-operative day (day 5). A minimum period of 4 hours must be observed between the intra-operative dose of Dornase alfa and the first post-operative dose.
The intra-operative dose administered by the participant's ENT surgeon will be documented in the participant's hospital medication record and also documented by the study staff on a centrally maintained master log.
To monitor compliance with parental administration of Dornase alfa the clinical trials pharmacist will record the weight of the filled ear dropper bottle when it is dispensed and again when it is returned to pharmacy post-visit 2 (day 14). Parents/legal guardians will also be asked to complete a “study medication administration card” each time they administer the Dornase alfa, which will include the time of each dose. If a dose is missed or is not administered as per the administration instructions (5 drops) this will also be noted by the parent/ legal guardian on the “study medication administration card”.

2. All participants allocated to the Dornase alfa group will also receive Ciloxan (Ciprofloxacin) 0.3% ear drops, as per standard medical practice post-ventilation tube insertion. Parents will be advised to wait at least 10 minutes between administering the Dornase alfa (first) and the ciprofloxacin ear drops (second). Parents/legal guardians will also be asked to complete the “study medication administration card” each time they administer the ciprofloxacin ear drops.

Intervention code [1] 315173 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomised 1:1 to Dornase alfa or placebo. Administration will be blinded.
The placebo is normal saline (0.9% saline). All participants allocated to the placebo group will also receive Ciloxan (Ciprofloxacin) 0.3% ear drops, as per standard medical practice post-ventilation tube insertion. Parents will be advised to wait at least 10 minutes between administering the placebo (first) and the ciprofloxacin ear drops (second). Parents/legal guardians will also be asked to complete the “study medication administration card” each time they administer the ciprofloxacin ear drops.

Control group
Placebo

Outcomes
Primary outcome [1] 320922 0
To determine the safety and tolerability of a twice daily 5 day course of Dornase alfa treatment into the middle ear post-ventilation tube insertion in children with chronic otitis media with effusion (cOME) and recurrent acute otitis media (rAOM).

This will be assessed by:
1. Proportion of children experiencing local or systemic symptoms within 10 days of commencing Dornase treatment into the middle ear post-ventilation tube insertion (VTI) surgery. Local symptoms (including ear pain and otorrhoea) and systemic symptoms (including fever greater or equal to 38 degrees Celsius, dizziness, cough, nasal discharge and sore throat) will be sought for and recorded by the parent/guardian in the solicited adverse events sections of the 10-day diary card, which will be issued at visit 1 (day of VTI insertion).
2. Proportion of children experiencing a serious adverse event (related or unrelated) within 30 days of commencing Dornase alfa treatment into the middle ear post-VTI surgery. Serious adverse events are defined as an event that meets at least one of the following criteria: is fatal, life-threatening, requires in-patient hospitalisation or prolongation of an existing hospitalisation, results in persistent or significant disability/incapacity, congenital anomaly/birth defect and/or is medically significant according to the investigator's judgement. Serious adverse events occurring within the first 10 days post-VTI will be recorded by the parent/legal guardian on the 10-day diary card and after this time point on the study supplied Memory Aid. Parents/legal guardians are advised to contact study staff at any time that their child experiences a serious medical event.
3. Proportion of children experiencing a related serious adverse event within 24 months of commencing Dornase alfa treatment into the middle ear post-VTI surgery. Serious adverse events occurring with the first 10 days of the study may be recorded by the parent/legal guardian on the 10-day diary card and after this time point on the study supplied Memory Aid. Parents/legal guardians are advised to contact study staff at any time that their child experiences a serious medical event.
4. Regular audiometry to determine the proportion of children experiencing hearing loss (greater than or equal to 20dB) at any threshold in either ear.
Timepoint [1] 320922 0
1. Within 10 days of commencing Dornase treatment into the middle ear post-ventilation tube insertion (VTI) surgery.
2. Within 30 days of commencing Dornase alfa treatment into the middle ear post-VTI surgery.
3. Within 24 months of commencing Dornase alfa treatment into the middle ear post-VTI surgery.
4. Within 24 months after commencing Dornase alfa treatment into the middle ear post-VTI surgery. Audiometry will be specifically performed at 14 days, 6 months, 12 months and 24 months post-VTI insertion or at any time that there is a clinical concern.
Secondary outcome [1] 373353 0
To determine the acceptability of a 5 day course of Dornase alfa treatment into the middle ear post-ventilation tube insertion in children with chronic otitis media with effusion (cOME) and recurrent acute otitis media (rAOM).

This will be assessed via parental report documented on the study medication administration card.
Timepoint [1] 373353 0
10 days after commencing Dornase alfa treatment into the middle ear post-ventilation tube insertion surgery.
Secondary outcome [2] 373354 0
Incidence of otorrhoea following a 5 day course of Dornase alfa treatment into the middle ear at 12 months post-ventilation tube insertion.

This will be assessed reported using the study-specific 10 -day diary card, the study, study-specific Memory Aid and direct report to study staff via scheduled reminder contacts (SMS/email/phone call).
Timepoint [2] 373354 0
Parents will be actively contacted (text message or email) by the study staff regarding the onset of otorrhoea, initially at two weekly intervals from the day of surgery up until visit 4 (6 months post-surgery) and then monthly until visit 6 (12 months post-surgery). Details of the event will be captured in the study-specific 10 day diary card (if occurring during the first 10 days of the study) or after this time point in the study-specific Memory Aid.
Secondary outcome [3] 373355 0
Time taken until tube extrusion after using Dornase alfa treatment post-ventilation tube insertion surgery.

Time until tube extrusion will be reported using the study-specific memory aid and via direct report to study staff. This will also be assessed during regular clinical assessments, including video otoscopy and tympanometry performed at 14 days, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months post-VTI.
Timepoint [3] 373355 0
Parents may actively report tube extrusion at any time that this is identified outside of the study (i.e. by their Ear, Nose and Throat surgeon during routine care or other health care provider) from the day of surgery to 24 months post-ventilation tube insertion surgery. In addition this will be actively assessed during the study visits conducted at 14 days, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months post-VTI.
Secondary outcome [4] 373356 0
Incidence of tube blockage or extrusion following a 5 day course of Dornase alfa treatment into the middle ear at 12 months post-ventilation tube insertion.

This will be assessed using the study-specific memory aid and via regular clinical assessments, including video otoscopy and tympanometry performed at 14 days, 3 months, 6 months, 9 months and 12 months post-VTI.
Timepoint [4] 373356 0
Parents may actively report tube blockage or extrusion at any time that this is identified outside of the study (i.e. by their Ear, Nose and Throat surgeon during routine care or other health care provider) from the day of surgery to 12 months post-ventilation tube insertion surgery. In addition this will be actively assessed during the study visits conducted at 14 days, 3 months, 6 months, 9 months, 12 months post-VTI.

Eligibility
Key inclusion criteria
1. Aged 6 months to less than 5years of age.
2. Undergoing surgery for ventilation tube insertion for recurrent acute otitis media or chronic otitis media with effusion, either unilateral or bilateral, which will be performed by a collaborating ear, nose and throat (ENT) surgeon.
N.B. participants undergoing concurrent adenoidectomy and/or tonsillectomy are permitted to participate.
4. Has either a current medically confirmed unilateral or bilateral middle ear effusion that has been present for 3 months or longer and/or had 3 episodes of medically confirmed acute otitis media in the previous 6 months or 4 or more episodes in the previous 12 months.
5. Considered to be generally healthy as established by medical history before entering the study, excluding medical conditions listed in inclusion criterion 3.
N.B. The participant must also not meet exclusion criterion 8.
6. Parent/legal guardian has given written informed consent and is willing and able to comply with the scheduled visits and study procedures. This includes access to a telephone for surveillance contacts.
7. Is available for the entire study period.
Minimum age
6 Months
Maximum age
4 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Has a diagnosed sensorineural hearing loss, cystic fibrosis, a craniofacial disorder or immotile cilia syndrome.
2. Has a confirmed or suspected immunosuppressive or immunodeficient condition.
3. Has a suspected or diagnosed genetic syndrome or chromosomal disorder.
4. Has experienced an allergic reaction to protein of Chinese Hamster Ovary origin.
5. Has experienced an allergic reaction or has a contra-indication to ciprofloxacin.
6. Does not have access to a refrigerator to store the 5 day course of study medication that will be administered to the participant at home by the parent/legal guardian.
7. Has received any investigational or non-registered drugs, vaccines or devices within 6 months of study visit 1 (day of surgery) or planned administration during the entire study period.
8. Any other significant acute or chronic medical condition that in the opinion of the investigator may interfere with the interpretation of study results or place the participant at increased risk if they participate in the study.

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)
Randomisation will be conducted by the delegated clinical trials pharmacists at the Perth Children’s Hospital using an electronic randomisation program. The pharmacists will be unblinded, while all other study staff will remain blinded throughout the study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomised table created by computer software. Randomisation will be stratified according to concurrent adenoidectomy to permit assessment of outcomes between the two different groups (ventilation tube insertion with and without concurrent adenoidectomy).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Sample size: Power calculations were performed on the frequency of the most relevant and common side effects seen in the previous Dornase alfa tria conducted by our research teaml for children following ventilation tube insertion. We hypothesised that parents would consider using an efficacious treatment that was associated with a small increase in side effects but not one where the increase was more than 25% in symptom frequency. With a sample size of 60 children in each group (120 in total) we will have approximately 80% power or more, based on a two-sided test with a equals 0.05, to determine an increase in symptom frequency for the Dornase alfa group of at least 25%: Ear pain from 60% to 86% (from 36 children to 51 children, 88% power), ventilation tube otorrhoea from 30% to 55% (from 18 children to 33 children, 80% power), fever from 8.6% to 34% (from 5 children to 20 children, 93% power), cough from 40% to 65% (from 24 children to 39 children, 79% power), sore throat from 47% to 72% (from 28 children to 43 children, 80% power) and dizziness from 19% to 46% (from 11 children to 26 children, 85% power). For the clinically relevant secondary combined outcomes of blocked or extruded ventilation tubes at 12 months based on the 78% prevalence in the saline treated group in our pilot study, we would have 80% power to detect a decrease to 54% and 90% power to detect a decrease to 51% in the Dornase alfa group.

Statistical analysis: Differences in side effects including ear pain, fever, cough, sore throat and dizziness, will be assessed between each group following unblinding. Complications including if the tubes become blocked or if the child develops otorrhoea (discharge from the middle ear) will also be assessed. Group comparisons (treatment versus placebo) will be conducted using multiple regression adjusting for relevant covariates (age, sex, daycare attendance) which may not be fully balanced between the randomised groups. For proportion outcomes (side-effect symptom occurrence, Serious Adverse Event occurrence etc) binary logistic regression will be used, for count outcomes (episodes of otorrhoea, blocked tubes etc) Poisson regression with time-at-risk as an offset will be used, and for the time-to-event outcome (Ventilation tube extrusion), Cox proportional hazards regression will be used. Exploratory outcomes will be assessed using descriptive statistics for hypothesis generation and planning sample sizes for future interventional and mechanistic trials.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/11/2019
Actual
28/08/2020
Date of last participant enrolment
Anticipated
1/10/2022
Actual
Date of last data collection
Anticipated
1/10/2023
Actual
Sample size
Target
120
Accrual to date
32
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 14376 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [2] 14377 0
Subiaco Private Hospital - Subiaco
Recruitment hospital [3] 14378 0
South Perth Hospital - South Perth
Recruitment hospital [4] 14379 0
Perth Children's Hospital - Nedlands
Recruitment hospital [5] 14929 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 27378 0
6008 - Subiaco
Recruitment postcode(s) [2] 27379 0
6151 - South Perth
Recruitment postcode(s) [3] 27380 0
6009 - Nedlands
Recruitment postcode(s) [4] 28201 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 303438 0
University
Name [1] 303438 0
University of Western Australia
Country [1] 303438 0
Australia
Primary sponsor type
Other
Name
Telethon Kids Insitute
Address
Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, NEDLANDS WA 6009
Country
Australia
Secondary sponsor category [1] 303492 0
None
Name [1] 303492 0
Address [1] 303492 0
Country [1] 303492 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303972 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 303972 0
Ethics committee country [1] 303972 0
Australia
Date submitted for ethics approval [1] 303972 0
16/04/2019
Approval date [1] 303972 0
10/07/2019
Ethics approval number [1] 303972 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95414 0
Dr Ruth Thornton
Address 95414 0
Telethon Kids Institute, Perth Children's Hospital, 15 Hospital Avenue, NEDLANDS WA 6009
Country 95414 0
Australia
Phone 95414 0
+61 8 6319 1850
Fax 95414 0
Email 95414 0
ruth.thornton@uwa.edu.au
Contact person for public queries
Name 95415 0
Beth Arrowsmith
Address 95415 0
Telethon Kids Institute, Perth Children's Hospital, 15 Hospital Avenue, NEDLANDS WA 6009
Country 95415 0
Australia
Phone 95415 0
+61 8 6319 1473
Fax 95415 0
Email 95415 0
Beth.Arrowsmith@telethonkids.org.au
Contact person for scientific queries
Name 95416 0
Ruth Thornton
Address 95416 0
Telethon Kids Institute, Perth Children's Hospital, 15 Hospital Avenue, NEDLANDS WA 6009
Country 95416 0
Australia
Phone 95416 0
+61 8 6319 1850
Fax 95416 0
Email 95416 0
ruth.thornton@uwa.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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTargeting host-microbial interactions to develop otitis media therapies.2021https://dx.doi.org/10.1071/MA21019
EmbaseBiofilms and intracellular infection in otitis media.2023https://dx.doi.org/10.1071/MA23025
N.B. These documents automatically identified may not have been verified by the study sponsor.