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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]

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

Condition category

Condition code

Ear

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]

Treatment: Drugs

Intervention code [2]

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]

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]

At time of repeat ventilation tube insertion or at 2 years post intervention

Secondary outcome [1]

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]

Any time until 2 years post intervention or until time of repeat ventilation tube insertion

Secondary outcome [2]

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]

Any time until 2 years post intervention or until time of repeat ventilation tube insertion

Secondary outcome [3]

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]

Any time until 2 years post intervention or until time of repeat ventilation tube insertion

Secondary outcome [4]

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]

Audiometry conducted 2-4 weeks post intervention

Secondary outcome [5]

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]

Temperature collected daily for 5 days post-intervention

Secondary outcome [6]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Subiaco Private Hospital - Subiaco

Recruitment hospital [2]

Colin Street Day Surgery - West Perth

Recruitment postcode(s) [1]

6008 - Subiaco

Recruitment postcode(s) [2]

6005 - West Perth

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Government of Western Australia Department of Health

Address [1]

189 Royal St
East Perth
WA 6004

Country [1]

Australia

Primary sponsor type

Other

Name

Telethon Kids Institute

Address

15 Hospital Av
Nedlands
WA 6009

Country

Australia

Secondary sponsor category [1]

University

Name [1]

University of Western Australia

Address [1]

School of Medicine
35 Stirling Hwy
Crawley
WA 6008

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Child and Adolescent Health Service Human Research Ethics Committee

Ethics committee address [1]

15 Hospital Av
Nedlands
WA 6009

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

02/05/2011

Approval date [1]

27/09/2011

Ethics approval number [1]

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

Prof Peter Richmond

Address

Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009

Country

Australia

Phone

+61 864565604

Fax

[email protected]

Contact person for public queries

Name

Tamara Hunter

Address

Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009

Country

Australia

Phone

+61 863191644

Fax

[email protected]

Contact person for scientific queries

Name

Ruth Thornton

Address

Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009

Country

Australia

Phone

+61 8 6319 1000

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Source	Title	Year of Publication	DOI
Embase	Safety, 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.	2024	https://dx.doi.org/10.1016/j.ijporl.2023.111832

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added automatically