Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001847202
Ethics application status
Approved
Date submitted
3/07/2018
Date registered
14/11/2018
Date last updated
14/11/2018
Date data sharing statement initially provided
14/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effect of a common antibiotic (amoxicillin with clavulanate) on the microbiome of tonsil tissue in children with recurrent tonsillitis
Scientific title
The effect of Amoxicillin and Clavulanic acid on the microbiome of tonsillar tissue in patients with recurrent tonsillitis: A randomised control trial
Secondary ID [1] 293290 0
None
Universal Trial Number (UTN)
U1111-1194-5081
Trial acronym
TAACS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tonsillitis 308643 0
Condition category
Condition code
Infection 307588 307588 0 0
Studies of infection and infectious agents
Oral and Gastrointestinal 309108 309108 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This randomised, investigator-blinded, prospective study will be conducted at Gillies and Starship Hospitals in Auckland, New Zealand. The study will only take place one the appropriate ethics and institutional approvals have been obtained. All patients will give written informed consent wherever possible, or their legal guardian will provide assent before entering the study.

The primary objectives of the study are to compare the microbiome of palatine tonsil tissue in two groups of patients with recurrent tonsillitis. One group of 30 patients will be prescribed a 7-day course of Amoxicillin and Clavulanic acid immediately prior to surgery. The other group of 30 patients will receive no antibiotic. The dose of Amoxicillin and Clavulanic acid (Augmentin) will be prescribed according to Medsafe, New Zealand guidelines as follows:

Children 3-9 months: 1.25mL of AUGMENTIN Syrup 125 three times a day.
Children 9 months - 2 years: 2.5mL of AUGMENTIN Syrup 125 three times a day.
Children 2-6 years: 5mL of AUGMENTIN Syrup 125 three times a day.
Children 7-12 years: 5mL of AUGMENTIN Syrup 250 three times daily.
Adults and Children 40kg and over: 1 AUGMENTIN 500 Tablet twice daily.

Prior to tissue being excised by the surgeon, a surface swab will be taken from the right and left palatine tonsils.16s sequencing will be performed on tonsil swab specimens to determine the microbiome. This information will be supplemented with live/dead bacterial staining from the surface of these tissues as one of the limitations of 16s is that we are unable to determine which bacteria are alive or dead. Without live/dead staining we would not be able to determine which bacteria had been killed by the antibiotic.

A computerised randomisation schedule will be used to assign eligible patients to the antibiotic/no antibiotic group. Study medications will be provided by an independent individual (not a study investigator) of the hospital pharmacy, whereas results from microbiome analysis will be evaluated by the study investigators. An independent investigator (research nurse) will contact the patients on the day prior to surgery to ensure compliance with medication. Should the patient have not been compliant with medication then he/she will be excluded from the study. Compliance will be monitored by the use of dose cards on which patients record each dose of the study medication taken. Information regarding adverse events will be obtained by the research nurse upon conversation with the patient prior to surgery. Patients will be advised to stop taking the medication should they notice any adverse effects. They will be provided with the contact details of the research nurse and coordinating investigator. They will be encouraged to contact either party should they have any concerns. All adverse events will be recorded on a medical-event form. The investigator will classify events as serious or non-serious according to the guidelines of the International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use and will judge whether the event is related or unrelated to the study medication.
Intervention code [1] 301718 0
Treatment: Drugs
Comparator / control treatment
The primary objectives of the study are to compare the microbiome of palatine tonsil tissue in two groups of patients with recurrent tonsillitis. The control group of 30 patients will receive no antibiotic.
Control group
Active

Outcomes
Primary outcome [1] 306562 0
The primary endpoint of this study is the difference in the tonsillar microbiome of patients with recurrent tonsillitis who have been treated with a course of Amoxicillin and Clavulanic acid versus those who have not. A combination of bacterial 16S rRNA gene-targeted amplicon sequencing and histological techniques will be used to determine the bacterial composition and spatial distribution of bacterial microcolonies in the collected samples. Droplet digital PCR will also be performed to measure the bacterial load in each sample.
Timepoint [1] 306562 0
Immediately following surgery, the crypts of the right and left tonsils will be swabbed and the outcome assessed.
Secondary outcome [1] 348888 0
The secondary endpoint of this study is the difference in proportions of live/dead bacteria in tonsillar specimens of patients with recurrent tonsillitis who have been treated with a course of Amoxicillin and Clavulanic acid versus those who have not. Live/dead bacterial staining will be performed on tonsillar tissue swabs immediately following surgery.
Timepoint [1] 348888 0
Immediately following surgery, the crypts of the right and left tonsils will be swabbed and the outcome assessed.

Eligibility
Key inclusion criteria
Age 0-16 years.

History of recurrent tonsillitis.

Waitlisted to undergo tonsillectomy for recurrent tonsillitis.

Must have had previous course of Amoxicillin and Clavulanic acid without adverse effects.
Minimum age
0 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with genetic syndromes, metabolic disorders, neurologic diseases or congenital malformations will be excluded.

Patients with an anatomical abnormality of the upper aerodigestive tract.

Patients who have had antibiotics within the 6 weeks prior to surgery.

Previous adenoidectomy, tonsillectomy, or grommet insertion.

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Diversity indices (including Shannon–Wiener index and Inverse-Simpson index) and rarefaction curves will be calculated for all samples from OTU tables using QIIME, and then values will be formally compared using Student’s t-test and the Kruskal-Wallis test. The Adonis function in Calypso will be used to analyze the impact of sampling site on the multi-species community structure of adenoid samples. An ANOVA test will be performed to compare the 20 most abundant genera by sample site in the tonsils using Calypso. Pairwise comparisons of site-specific differences in relative abundance will be calculated using the Kruskal-Wallis test followed by Dunn's test of multiple comparisons with Bonferroni adjustment. Non-metric multidimensional scaling (nMDS) plots will be constructed using R software (version 3.3.0) based on weighted and unweighted UniFrac distance matrices.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
1/11/2017
Date of last participant enrolment
Anticipated
31/12/2018
Actual
Date of last data collection
Anticipated
31/12/2018
Actual
Sample size
Target
60
Accrual to date
50
Final
Recruitment outside Australia
Country [1] 10605 0
New Zealand
State/province [1] 10605 0
Auckland

Funding & Sponsors
Funding source category [1] 297914 0
Charities/Societies/Foundations
Name [1] 297914 0
Garnett Passe and Rodney Williams Memorial Foundation
Country [1] 297914 0
Australia
Primary sponsor type
University
Name
The University of Auckland
Address
Auckland Clinical School, Level 12, Auckland City Hospital Support Building, 2 Park Road, Grafton, Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 296974 0
None
Name [1] 296974 0
Address [1] 296974 0
Country [1] 296974 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298964 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 298964 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 298964 0
New Zealand
Date submitted for ethics approval [1] 298964 0
20/04/2017
Approval date [1] 298964 0
12/05/2017
Ethics approval number [1] 298964 0
17/NTB/76

Summary
Brief summary
Understanding the complexities of the tonsillar associated microbiome, and especially the manner in which they are affected by commonly prescribed antibiotics is vital for how we treat these conditions going forward. In this randomised control trial, we aim to investigate whether or not Amoxicillin and Clavulanic acid alters the microbiome of patients with tonsillar hyperplasia from recurrent tonsillitis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78814 0
Dr James Johnston
Address 78814 0
Auckland Clinical School, Level 12, Auckland City Hospital Support Building, 2 Park Road, Grafton, Auckland 1023
Country 78814 0
New Zealand
Phone 78814 0
+64211716814
Fax 78814 0
Email 78814 0
[email protected]
Contact person for public queries
Name 78815 0
Dr James Johnston
Address 78815 0
Auckland Clinical School, Level 12, Auckland City Hospital Support Building, 2 Park Road, Grafton, Auckland 1023
Country 78815 0
New Zealand
Phone 78815 0
+64211716814
Fax 78815 0
Email 78815 0
[email protected]
Contact person for scientific queries
Name 78816 0
Dr James Johnston
Address 78816 0
Auckland Clinical School, Level 12, Auckland City Hospital Support Building, 2 Park Road, Grafton, Auckland 1023
Country 78816 0
New Zealand
Phone 78816 0
+64211716814
Fax 78816 0
Email 78816 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
We will not provide individual participant data unless an appropriate ethical amendment has been obtained.


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
EmbaseThe Effect of Amoxicillin with Clavulanate on the Microbiota of Tonsillar Tissue in Disease: a Randomized Control Trial.2022https://dx.doi.org/10.1128/spectrum.01239-22
N.B. These documents automatically identified may not have been verified by the study sponsor.