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Trial registered on ANZCTR


Registration number
ACTRN12623000504617
Ethics application status
Approved
Date submitted
2/05/2023
Date registered
17/05/2023
Date last updated
17/05/2023
Date data sharing statement initially provided
17/05/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Dissolving the glue in glue ear: Assessment of the efficacy of the use of Dornase alfa as an adjunct therapy to ventilation tube insertion.
Scientific title
Dissolving the glue in glue ear: Assessment of the efficacy of the use of Dornase alfa as an adjunct therapy to ventilation tube insertion.
Secondary ID [1] 309470 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is a pilot study to ACTRN12619001306101.

Health condition
Health condition(s) or problem(s) studied:
otitis media 329733 0
Condition category
Condition code
Ear 326631 326631 0 0
Other ear disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Children will act as their own internal control. Ears will be individually randomised for each child to receive a single application of 1 ml of Dornase alfa (Pulmozyme®, Genentech) immediately prior to ventilation tube insertion or 1 ml placebo (sterile saline). Intervention will be administered by the ear nose throat specialist performing the ventilation tube insertion surgery. Administration to the correct ear is recorded by the attending researcher and drug containers are returned to the clinical trials phramacy following the surgery to ensure adherance. Following ventilation tube insertion, Ciloxan® (topical ciprofloxacin) drops will be administered bilaterally as per normal procedure (5 drops twice daily for 5 days).
Intervention code [1] 325895 0
Treatment: Drugs
Intervention code [2] 325896 0
Prevention
Comparator / control treatment
Children will act as their own internal control. For the ears randomised to receive placebo, 1 ml placebo (sterile saline) will be administered to the ear immediately prior to ventilation tube insertion. Intervention will be administered by the ear nose throat specialist performing the ventilation tube insertion surgery. Administration to the correct ear is recorded by the attending researcher and drug containers are returned to the clinical trials phramacy following the surgery to ensure adherance. Following ventilation tube insertion, Ciloxan® (topical ciprofloxacin) drops will be administered bilaterally as per normal procedure (5 drops twice daily for 5 days).
Control group
Placebo

Outcomes
Primary outcome [1] 334624 0
Efficacy of a single application of Dornase alfa at time of ventilation tube insertion as assessed by need for repeat surgery due to the recurrence of chronic otitis media with effusion (cOME). cOME is determined using tympanometry and video otoscopy and defined as having an effusion present at 2 consecutive visits at least 3 months apart.
Timepoint [1] 334624 0
At time of repeat ventilation tube insertion or at 2 years post intervention
Secondary outcome [1] 421446 0
Efficacy of a single application of Dornase alfa at the time of ventilation tube insertion as assessed by occurrence of otorrhoea as determined by parental report, medical records and/or video otoscopy at scheduled visits.
Timepoint [1] 421446 0
Any time until 2 years post intervention or until time of repeat ventilation tube insertion
Secondary outcome [2] 421447 0
Efficacy of a single application of Dornase alfa at the time of ventilation tube insertion as assessed by occurrence of blocked ventilation tubes using tympanometry and video otoscopy.
Timepoint [2] 421447 0
Any time until 2 years post intervention or until time of repeat ventilation tube insertion
Secondary outcome [3] 421448 0
Efficacy of a single application of Dornase alfa at the time of ventilation tube insertion as assessed by recurrence of otitis media indicated by parental report of acute otitis media episodes or consecutive type B tympanograms over 3 months
Timepoint [3] 421448 0
Any time until 2 years post intervention or until time of repeat ventilation tube insertion
Secondary outcome [4] 421449 0
Safety of a single direct application of Dornase alfa into the middle ear at time of first ventilation tube insertion as assessed by any change in hearing levels when measured by audiometry.
Timepoint [4] 421449 0
Audiometry conducted 2-4 weeks post intervention
Secondary outcome [5] 421450 0
Safety of a single direct application of Dornase alfa into the middle ear at time of first ventilation tube insertion as assessed by no change in body temperature as measured using an axillary thermometer.
Timepoint [5] 421450 0
Temperature collected daily for 5 days post-intervention
Secondary outcome [6] 421451 0
Tolerability of a single direct application of Dornase alfa into the middle ear at time of first ventilation tube insertion as assessed by any change in pain in the intervention ear according to parental scoring using a numerical scale developed for this trial.
Timepoint [6] 421451 0
Pain scores collected per ear and daily for 5 days post-intervention

Eligibility
Key inclusion criteria
1. 6 months-5years of age.
2. Undergoing surgery for ventilation tube insertion for recurrent Acute Otitis Media (rAOM) and/or otitis media with effusion (OME).
3. Have a bilateral effusion for 3 months or longer.
Minimum age
6 Months
Maximum age
5 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Sensorineural hearing loss
2. Suspected or diagnosed immunodeficiency.
3. Cystic fibrosis.
4. Craniofacial disorder.
5. Immotile cilia syndrome.
6. Other suspected or diagnosed genetic syndromes.
7. Have experienced an allergic reaction to protein of Chinese Hamster Ovary origin.

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)
Double-blind identical appearance of study drug and placebo
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomised number
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
Intervention assignment
Other
Other design features
Ears individually randomised in each child
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Differences between ears treated with the Dornase alfa and those treated with the placebo (ear pain, ear discharge) will be determined using McNemar tests. Differences in audiological outputs between the 2 ears will be determined using Wilcoxin signed-rank tests. P<0.05 will be considered statistically significant. Infection rates post ventilation tube insertion (VTI) between treatment and non-treatment ears will be compared by assessing differences in binomial proportion. Time to recurrence of infection, ventilation tube blockage and extrusion, and until disease recurrence, will be assessed using Kaplan Meier survival curve analyses with Log Rank tests comparing the Dornase alfa and placebo treated ears.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
24/05/2012
Date of last participant enrolment
Anticipated
Actual
8/04/2014
Date of last data collection
Anticipated
Actual
6/04/2016
Sample size
Target
60
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 24654 0
Subiaco Private Hospital - Subiaco
Recruitment hospital [2] 24655 0
Colin Street Day Surgery - West Perth
Recruitment postcode(s) [1] 40264 0
6008 - Subiaco
Recruitment postcode(s) [2] 40265 0
6005 - West Perth

Funding & Sponsors
Funding source category [1] 313666 0
Government body
Name [1] 313666 0
Government of Western Australia Department of Health
Country [1] 313666 0
Australia
Primary sponsor type
Other
Name
Telethon Kids Institute
Address
15 Hospital Av
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 315598 0
University
Name [1] 315598 0
University of Western Australia
Address [1] 315598 0
School of Medicine
35 Stirling Hwy
Crawley
WA 6008
Country [1] 315598 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312831 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 312831 0
15 Hospital Av
Nedlands
WA 6009
Ethics committee country [1] 312831 0
Australia
Date submitted for ethics approval [1] 312831 0
02/05/2011
Approval date [1] 312831 0
27/09/2011
Ethics approval number [1] 312831 0
831EP

Summary
Brief summary
Bacteria in biofilm contributes to the persistence and recurrence of infection within the middle ear. Our preliminary data shows that as well as biofilm being present on the surface of the middle ear mucosa, bacterial biofilms are also present within extensive DNA scaffolding in the viscous middle ear effusion (MEE). We have demonstrated otopathogenic bacteria both in biofilm microcolonies and singularly throughout DNA strands within 92% of MEEs tested. The DNA appears to be mainly neutrophil derived and is largely produced via an active immune mechanism known as neutrophil extracellular traps (NETs). The extensive DNA stranding and the involvement of biofilm microcolonies is similar to what is observed in broncho-alveolar lavage fluids from children with cystic fibrosis (CF). This DNA increases the viscosity of the sputum in the lung and it is within this viscous fluid that bacterial biofilm aggregates exist. Sputum viscosity is targeted in CF through the use of a recombinant human deoxyribonuclease I (Dornase alfa or Pulmozyme®). Dornase alfa acts to selectively cleave DNA which reduces fluid viscosity and allows bacterial clearance from the lung. We propose that administration of Dornase alfa to the middle ear at time of VTI may help to reduce the viscosity of the MEE and thereby permit clearance of the bacteria that are the cause of recurring ear infections. Our preliminary in vitro studies have demonstrated that Dornase alfa successfully dissociates the DNA scaffolding in MEE from children with OM.

Dornase alfa is used extensively in the treatment of CF in adults and in children and has been proven both safe and efficacious in humans when administered by inhalation via a nebuliser. These patients are often administered with 2.5ml of a 1mg/ml solution of the enzyme twice daily. Furthermore, Dornase alfa has been tested in a chinchilla model, testing for toxicity to cochlear outer hair cells and any changes in the auditory brain response following application to the round window. These studies determined that Dornase alfa is non-ototoxic when administered into the middle ear of chinchillas. This group has subsequently gone on to conduct a clinical trial investigating the use of Dornase alfa to unblock clogged ventilation tubes (VTs) in children (ClinicalTrials.gov identifier: NCT00419380).

The aim of this study is to evaluate whether Dornase alfa treatment at the time of ventilation tube insertion (VTI) will break down the DNA scaffold and the associated biofilms in the MEE improving bacterial clearance from the middle ear. We believe this will reduce the recurrence of infection and reduce the number of repeat VTIs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126074 0
Prof Peter Richmond
Address 126074 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009
Country 126074 0
Australia
Phone 126074 0
+61 864565604
Fax 126074 0
Email 126074 0
[email protected]
Contact person for public queries
Name 126075 0
Tamara Hunter
Address 126075 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009
Country 126075 0
Australia
Phone 126075 0
+61 863191644
Fax 126075 0
Email 126075 0
[email protected]
Contact person for scientific queries
Name 126076 0
Ruth Thornton
Address 126076 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009
Country 126076 0
Australia
Phone 126076 0
+61 8 6319 1000
Fax 126076 0
Email 126076 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Consent not obtained for this


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
EmbaseSafety, tolerability, and effect of a single aural dose of Dornase alfa at the time of ventilation tube surgery for otitis media: A Phase 1b double randomized control trial.2024https://dx.doi.org/10.1016/j.ijporl.2023.111832
N.B. These documents automatically identified may not have been verified by the study sponsor.