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Trial registered on ANZCTR


Registration number
ACTRN12624001367538
Ethics application status
Approved
Date submitted
4/10/2024
Date registered
15/11/2024
Date last updated
15/11/2024
Date data sharing statement initially provided
15/11/2024
Type of registration
Retrospectively registered

Titles & IDs
Public title
Biofluid derived extracellular vesicles in periodontitis and peri-implantitis
Scientific title
Biofluid derived extracellular vesicles in periodontitis and peri-implantitis
Secondary ID [1] 311460 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
periodontal disease 332760 0
peri-implant disease 332761 0
Condition category
Condition code
Oral and Gastrointestinal 329484 329484 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
o Baseline and initial treatment visit (0-month; 1 hour duration)
o Pre-operative periodontal charting recorded by registered periodontists (Ivanovaki, Lee, and other relevant staff) or DClinDent postgraduate registrars, with a periodontal UNC probe. All examiners will be calibrated.
o This will allocate participants into the group categories: Group #1: periodontal health, gingivitis and periodontitis (with and without systemic diseases); Group #2: peri-implant health, peri-implant mucositis and peri-implantitis (with and without systemic diseases)
o Saliva, gingival crevicular fluid (GCF) and plaque samples will be collected from all Group #1 patients; saliva, Peri-Implant Crevicular Fluid (PICF) and dental plaque will be collected from all Group #2 patients
- For saliva collection: participants will be asked to refrain from eating and drinking for at least one hour prior to saliva sample collection. At the appointment, participants will rinse their mouths with ~10 mL of water to remove the food debris. Unstimulated whole saliva through spitting (5mL ideally; minimum 1-1.5ml) will be collected.
- GCF and PICF will be collected prior to commencing treatment to avoid contamination via blood. This will be conducted using our established protocol (Han et al, 2023, PMID: 35771077) where paper strips (Oraflow) will be inserted into the deepest site of each quadrant (to reduce saliva contamination) and pooled.
- For healthy patients: 4 paper strips will be collected each from 4 healthy sites (free of inflammation and BOP) from the same tooth and pooled.
- For gingivitis patients: 6 paper strips will be collected from 6 inflamed sites (or 2 sites from the same tooth)
- For periodontitis/peri-implant diseased patients: up to 6 paper strips will be collected each from 1 deepest site and 1 healthy site
o Plaque, GCF/PICF and saliva samples will be placed in sterile glycerol (final concentrations: 15-30%), or stored immediately at -80 degrees at the Research Lab, Level 6, Oral Health Centre, until elution and extraction. Samples containing glycerol may be subjected to in vitro culturing for biofilm development prior to the extraction of bacterial EVs from the cultured media. EVs will be isolated, characterised and omics (proteome, methylome, microbiome, lipidome and metabolome or relevant omes), with saliva, GCF/PICF and plaque samples used as controls.

Patients in the periodontitis group will be allocated the next available appointment for standard care, receiving supragingival and subgingival non-surgical debridement using hand scalers and ultrasonic instruments over 2 appointments (60-90 mins duration per appointment).

Follow-up reviews (3-, 6- and 12-mo post-periodontal or post-peri-implant treatment; 1-1.5 hours duration)
o Periodontitis or peri-implantitis patients will be recalled 3 mo following debridement to re-assess periodontal parameters and recollect saliva and GCF (from the same sites as baseline appointment). Patients with peri-implant diseases (peri-implant mucositis and peri-implantitis) will undergo non-surgical periodontal implant therapy, as per EFP S3 level clinical practice guideline (PMID: 37271498), which includes supra- and sub-marginal mechanical instrumentation using titanium and/or stainless steel area-specific curettes, and ultrasonic/ sonic instruments. The use of air-polishing devices with glycine powder will be limited to supra-marginal instrumentation (subject to the presentation and access in a given case).
o They will then receive the standard protocol of care, including oral hygiene instruction (OHI), non-surgical re-instrumentation of persistent sites and supragingival maintenance of remaining sites.
o Patients will then be recalled at the 6 and 12 mo time points (since initial therapy)
o Peri-implant disease patients may be undergoing peri-implant surgery treatment if patients are not responding to non-surgical peri-implant treatment.
o Patient compliance with treatment reviews will be recorded using a clinic attendance checklist.

The diagnosis of extracellular vesicles (EVs) in patients with periodontitis and peri-implantitis will be compared to investigate the distinct mechanisms of disease pathogenesis related to EVs.
Intervention code [1] 327911 0
Diagnosis / Prognosis
Intervention code [2] 327912 0
Early Detection / Screening
Comparator / control treatment
Individuals in the periodontally healthy and peri-implant health groups will serve as healthy controls, as they are already in a healthy condition and do not require additional treatment. All these patients do not have systematic diseases.
Periodontally healthy patients are healthy patients who do not have any periodontal disease but were treated by dentists at the same clinic (for dental conditions other than a periodontal disease).

Unstimulated saliva and plaque samples (from molars) will be collected from these healthy controls
GCF samples from periodontally healthy patients: up to 6 paper strips will be collected each from up to 6 healthy sites (free of inflammation and BOP) from the same tooth and pooled,
PICF from peri-implant health patients: 4 paper strips will be collected each from up to 4 healthy sites per implant (free of inflammation and BOP) from the same tooth and pooled,
Control group
Active

Outcomes
Primary outcome [1] 337363 0
Levels of EVs particle numbers in all collected samples
Timepoint [1] 337363 0
Baseline, 3-, 6-, 12-month post routine periodontal and peri-implant treatment
Secondary outcome [1] 431586 0
Change in probing pocket depth (PPD)
Timepoint [1] 431586 0
Baseline, 3-, 6-, 12-month post routine periodontal and peri-implant treatment
Secondary outcome [2] 431587 0
Change in bleeding on probing (BOP)
Timepoint [2] 431587 0
Baseline, 3-, 6-, 12-month post routine periodontal and peri-implant treatment
Secondary outcome [3] 440841 0
combined omics of EV microbiome and proteome profiles
Timepoint [3] 440841 0
Baseline, 3-, 6-, 12-month post routine periodontal and peri-implant treatment

Eligibility
Key inclusion criteria
Patients 18 years of age or older.

For the periodontal health group (n=30):
BOP<=10% and PPD<=3mm

For the gingivitis group* (n=20):
>=20% BOP and PPD<=3mm

For the periodontitis group* (n=40):
Stage III-IV periodontitis patients will have interdental CAL=5mm, PPD=6mm, and significant radiographic bone loss.

*Based on Chapple et al 2018

All eligible patients requiring implants will be enrolled based on clinical diagnosis parameters per the latest guidelines (PMID: 29926955): a) Peri-implant health (n=20): absence of PPD>=5 mm, no signs of BOP, inflammation, peri-implant bone loss and suppuration; b) peri-implant mucositis (n=20): swelling, presence of BOP and/or suppuration, absence of bone loss beyond crestal bone level changes resulting from initial bone remodelling; c) Peri-implantitis (n=20): all signs of peri-implant mucositis in combination of PPD>=6 mm and a radiograph of hic bone loss =>3 mm apical of the most coronal portion of the intraosseous part of the implant.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Current smokers
Uncontrolled diabetes (HbA1c>=6.5)*
Long-term use of immunosuppressive or anti-inflammatory drugs, periodontal treatment or antibiotics therapy six months prior to investigation
pregnancy, cardiovascular disease, smokers, active infectious disease
*Based on American Diabetes Association 2018

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Convenience sample
Timing
Both
Statistical methods / analysis
• For descriptive analysis of categorical data, absolute and relative frequencies will be calculated. The numerical data will be first assessed for approximate normality. Chi-square tests and one-way ANOVA will be used for inferential analysis comparing the demographic data and outcome characteristics at baseline. Data will be displayed in a table form.

• To take into account correlations within subjects, random-intercept linear regression models will be applied to evaluate EVs or EV content changes over time in periodontal study groups (healthy, gingivitis, periodontitis) and peri-implant study groups (peri-implant health, peri-implant mucositis and peri-implantitis). This will be displayed in the form of a line graph showing trends over time.

• The significance of differences (expression level of EVs and EV content) between periodontal study groups (healthy, gingivitis, periodontitis) and peri-implant study groups (peri-implant health, peri-implant mucositis and peri-implantitis) at each time-point will be assessed using one-way ANOVA and Kruskal-Walls tests.

• The significance of differences within pairs of groups over certain time points will be assessed using paired Friedman test followed by post-tests.

• Confidence interval 95% with p value < 0.05.

• Multi-variate analyses using will be conducted to adjust for confounders (smoking, plaque control, age, sex, ethnicity) and subanalysis of different staging of periodontitis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
1/09/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/10/2030
Actual
Sample size
Target
150
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD

Funding & Sponsors
Funding source category [1] 315741 0
University
Name [1] 315741 0
School of Dentistry - University of Queensland
Country [1] 315741 0
Australia
Primary sponsor type
University
Name
School of Dentistry - University of Queensland
Address
Country
Australia
Secondary sponsor category [1] 317935 0
None
Name [1] 317935 0
Address [1] 317935 0
Country [1] 317935 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314604 0
Metro North Health Human Research Ethics Committee B
Ethics committee address [1] 314604 0
Ethics committee country [1] 314604 0
Australia
Date submitted for ethics approval [1] 314604 0
15/07/2020
Approval date [1] 314604 0
17/03/2021
Ethics approval number [1] 314604 0
54584
Ethics committee name [2] 314665 0
The University of Queensland Human Research Ethics Committee A
Ethics committee address [2] 314665 0
Ethics committee country [2] 314665 0
Australia
Date submitted for ethics approval [2] 314665 0
24/03/2021
Approval date [2] 314665 0
13/04/2021
Ethics approval number [2] 314665 0
2018001225

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

Contacts
Principal investigator
Name 132150 0
Dr Pingping Han
Address 132150 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 132150 0
Australia
Phone 132150 0
+61 7 336 58172
Fax 132150 0
Email 132150 0
p.han@uq.edu.au
Contact person for public queries
Name 132151 0
Pingping Han
Address 132151 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 132151 0
Australia
Phone 132151 0
+61 7 336 58172
Fax 132151 0
Email 132151 0
p.han@uq.edu.au
Contact person for scientific queries
Name 132152 0
Prof Saso Ivanovski
Address 132152 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 132152 0
Australia
Phone 132152 0
+61 7 336 58064
Fax 132152 0
Email 132152 0
s.ivanovski@uq.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
No additional documents have been identified.