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Trial registered on ANZCTR


Registration number
ACTRN12625000362493
Ethics application status
Approved
Date submitted
3/04/2025
Date registered
24/04/2025
Date last updated
24/04/2025
Date data sharing statement initially provided
24/04/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Using biological markers in saliva to diagnose and monitor treatment for gum disease around dental implants
Scientific title
Extracellular vesicles and titanium ions for peri-implantitis diagnosis and treatment monitoring
Secondary ID [1] 314077 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peri-implant disease 336839 0
Peri-implantitis 337064 0
Condition category
Condition code
Oral and Gastrointestinal 333320 333320 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
Conditions observed –
Participants will be allocated into three groups based on clinical diagnosis parameters, per the World Workshop Classification (Berglundh et al. 2018):
• Group 1 (Peri-implant health) healthy controls: No signs of suppuration or bleeding on probing, absence of clinical signs of inflammation, absence of bone loss beyond crestal bone level changes resulting from initial bone remodelling
• Group 2 (Peri-implant mucositis): Presence of bleeding and/or suppuration on probing, absence of bone loss beyond crestal bone level changes resulting from initial bone remodelling
• Group 3 (Peri-implantitis): Presence of bleeding and/or suppuration in combination with PPD >=6 mm and a radiographic bone loss >=3 mm apical of the most coronal portion of the intraosseous part of the implant

Frequency and duration of observation –
• Group 1 (Peri-implant health): Baseline visit (T0)
• Group 2 (Peri-implant mucositis): Baseline visit (T0), phone follow-up at 1 week
• Group 3 (Peri-implantitis): Baseline visit (T0), phone follow-up at 1 week plus in-person follow-up visits at: 3 months post-treatment (T1), 6 months post-treatment (T2), 9 months (treatment only as part of standard of care), 12 months post-treatment (T3)

Data collected –
• Clinical examinations, sample collection, and treatments will be performed by registered periodontists or periodontal postgraduate students under supervision of a registered periodontist. All clinical providers will be calibrated.
• Examination, sample collection and interventions will take place at Brisbane City Periodontics & Implants (BCPI) private practice clinics and Herston Oral Health Centre, The University of Queensland
• All clinical measurements, biological samples will be collected at all timepoints (T0, T1, T2 and T3). PROMS will be collected at 1 week and 3 months (T1). Radiographic measurements will be made at T0, T2 and T3.
Clinical measurements will include full mouth plaque score (FMPS), full mouth bleeding score (FMBS), probing pocket depth (PPD), clinical attachment level (CAL), recession, suppuration.
Saliva collection: Participants are to refrain from eating/drinking for greater than or equal to 1 hour prior to collection and are to rinse with approximately 15mL water to remove food debris. Collection of unstimulated whole saliva by spitting and samples to be placed in 50ml falcon tube.
Peri-implant crevicular fluid (PICF) collection: Sites dried and isolated to avoid saliva contamination. PerioPaper strips (Oraflow Inc) placed into the peri-implant sulcus/pockets for 30 seconds. Four sites per implant (Mesial, Distal, Buccal, Lingual/Palatal) collected. For peri-implant diseased patients: up to 6 paper strips per implant. Control GCF from a healthy tooth or PICF from a healthy implant (if applicable) will be collected. Samples pooled and eluted into 300µL of PBS.
Plaque collection: Subgingival plaque collected using periodontal probe/scaler for 10-20 seconds per tooth surface and transferred to sterile microcentrifuge tube containing 100µL PBS.

Treatment (standard routine non-surgical treatment for all peri-implant patients) -
Pre-enrolment treatment phase -
• Patients with >=5 sites with PD greater than or equal to 5mm will receive periodontal therapy per the EFP S3 level clinical practice guideline (Sanz et al. 2020) and be reviewed after 6 weeks and at 3 months
• Patients must achieve the therapeutic endpoint (Feres et al. 2020) and display adequate oral hygiene (FMPS less than or equal to 25%, FMBS less than or equal to 25%) before enrollment in the study
Implant treatment phase -
Consistent with the standard of care, implant treatment is to be provided for all patients according to EFP S3 guidelines (Herrera et al. 2023). For group 3 (peri-implantitis/diseased group) treatment will be provided at baseline and at each follow-up visit (T1, T2, 9 months, T3). If Peri-implant stability* is achieved at follow-up examinations oral hygiene instruction & PMPR will be provided instead of submarginal instrumentation. Rescue surgical treatment is to be provided if persistent suppuration and/or progressive bone loss is detected at T2 (6 months). Surgical peri-implantitis therapy will be offered at the end of the study (T3), if peri-implant stability is not achieved,

*Peri-implant stability or patient responder is defined as residual probing depths <=5 mm with no BOP at more than one point and no suppuration (Herrera et al. 2023)

Sample Storage - All samples (PICF, GCF, saliva and plaque) will be stored at -80 degrees C until the commencement of experiments at the Research Lab, Level 6, Oral Health Centre, University of Queensland. Sample processing, extraction and analysis will be conducted according to established protocols.
Sample Analysis - Host-derived extracellular vesicles (EVs) will be isolated from saliva and PICF samples using immunoaffinity methods, while bacterial EVs (BEVs) will be isolated from the remaining supernatant using size-exclusion chromatography. Host EVs will undergo cytokine profiling to analyze inflammatory content, while BEVs will be subjected to microbiome profiling through 16S rRNA sequencing to identify associated bacterial populations. Titanium ions released from dental implants will be analyzed using inductive coupled plasma atomic emission spectrometry (ICP-AES). Inflammatory cytokines will be measured using a multiplex assay capable of simultaneously detecting multiple inflammation-related proteins to track changes following treatment.
Intervention code [1] 330648 0
Diagnosis / Prognosis
Comparator / control treatment
Individuals in the peri-implant health group (Group 1) will serve as healthy controls, as they are already in a healthy condition and do not require additional treatment.
Control group
Active

Outcomes
Primary outcome [1] 340896 0
Host and microbial EVs
Timepoint [1] 340896 0
Host and non-host EVs numbers in peri-implant health, mucositis and peri-implantitis patients following non-surgical treatment over time (up to 12months).
Primary outcome [2] 340905 0
Titanium Ions
Timepoint [2] 340905 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [1] 445398 0
Peri-implant stability
Timepoint [1] 445398 0
Group 3 = 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [2] 445399 0
Inflammatory cytokines
Timepoint [2] 445399 0
Cytokine numbers in peri-implant health, mucositis and peri-implantitis patients following non-surgical treatment over time (up to 12months).
Secondary outcome [3] 445400 0
Probing pocket depths
Timepoint [3] 445400 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [4] 445401 0
Bleeding on probing
Timepoint [4] 445401 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [5] 445402 0
Radiographic bone level changes
Timepoint [5] 445402 0
Group 3 = Baseline, 6-, 12-months post peri-implantitis treatment.
Secondary outcome [6] 445403 0
Number of moderate (4-5mm) pockets
Timepoint [6] 445403 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [7] 445404 0
Number of deep pockets (>5mm)
Timepoint [7] 445404 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [8] 445406 0
Suppuration on probing
Timepoint [8] 445406 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [9] 445409 0
Full mouth plaque score (FMPS)
Timepoint [9] 445409 0
Group 1 and Group 2 = Baseline, Group 3 = Baseline, 3-, 6-, 12-months post peri-implantitis treatment
Secondary outcome [10] 446165 0
Patient reported outcome measures (PROMS) - Overall satisfaction
Timepoint [10] 446165 0
Recorded at 1 week for Group 2 (phone survey) and Group 3 at 1 week (phone survey), 3- months post peri-implantitis treatment.
Secondary outcome [11] 446275 0
Patient reported outcome measures (PROMS) - Pain
Timepoint [11] 446275 0
Recorded at 1 week for Group 2 (phone survey) and Group 3 at 1 week (phone survey), 3- months post peri-implantitis treatment.
Secondary outcome [12] 446714 0
Adverse events
Timepoint [12] 446714 0
Recorded at 1 week for Group 2 (phone survey) and Group 3 at 1 week (phone survey), 3-, 6- and 12-months post peri-implantitis treatment.

Eligibility
Key inclusion criteria
• Patients 18 years of age or older
• All eligible patients with implants will be enrolled based on clinical diagnostic parameters
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Current smokers
• Uncontrolled diabetes (HbA1c >= 6.5)
• Pregnancy, cardiovascular disease, active infectious disease
• Immunosuppressive, anti-inflammatory drugs, or antibiotic therapy three months prior to the investigation
• Peri-implantitis treatment within the last 6 months
• Implant mobility or residual bone of <=2mm around the implant
• Patient unable to achieve a defined end-point following periodontal treatment (Feres et al. 2020) or adequate oral hygiene (FMPS <=25%, FMBS <=25%)

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
Power calculation -
Summary statistics on EV levels for similar patient groups were obtained from Chaparro et al. (2020). Based on this information a sample size was calculated to detect a significant F-test for group effect (i.e. at least one of the group means is different from the others). To detect this effect with 80% power and a significance level of 0.05, a total of 93 participants are required, with 31 participants in each group. The sample size was calculated using Stata version 17, under the one-way analysis of variance approach. This sample size is deemed sufficient to address the study's primary research question, while also considering ethical and feasibility constraints. To account for potential dropouts, the recruitment target for group 3 was increased to 34 participants.

Statistical methods to be employed -
• 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 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 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 (plaque control, age, sex, ethnicity).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/05/2025
Actual
Date of last participant enrolment
Anticipated
13/05/2026
Actual
Date of last data collection
Anticipated
13/05/2027
Actual
Sample size
Target
96
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD

Funding & Sponsors
Funding source category [1] 318585 0
Other
Name [1] 318585 0
International Team for Implantology
Country [1] 318585 0
Switzerland
Funding source category [2] 318587 0
University
Name [2] 318587 0
School of Dentistry - University of Queensland
Country [2] 318587 0
Australia
Primary sponsor type
University
Name
School of Dentistry - University of Queensland
Address
Country
Australia
Secondary sponsor category [1] 320983 0
None
Name [1] 320983 0
Address [1] 320983 0
Country [1] 320983 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317183 0
The University of Queensland Human Research Ethics Committee A
Ethics committee address [1] 317183 0
Ethics committee country [1] 317183 0
Australia
Date submitted for ethics approval [1] 317183 0
24/03/2021
Approval date [1] 317183 0
13/04/2021
Ethics approval number [1] 317183 0
2018001225
Ethics committee name [2] 317185 0
Metro North Health Human Research Ethics Committee B
Ethics committee address [2] 317185 0
Ethics committee country [2] 317185 0
Australia
Date submitted for ethics approval [2] 317185 0
15/07/2020
Approval date [2] 317185 0
17/03/2021
Ethics approval number [2] 317185 0
54584

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

Contacts
Principal investigator
Name 140274 0
Dr Pingping Han
Address 140274 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 140274 0
Australia
Phone 140274 0
+61 7 336 58172
Fax 140274 0
Email 140274 0
[email protected]
Contact person for public queries
Name 140275 0
Dr Pingping Han
Address 140275 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 140275 0
Australia
Phone 140275 0
+61 7 336 58172
Fax 140275 0
Email 140275 0
[email protected]
Contact person for scientific queries
Name 140276 0
Prof Saso Ivanovski
Address 140276 0
The University of Queensland, School of Dentistry, 288 Herston Road, Herston, 4006, QLD
Country 140276 0
Australia
Phone 140276 0
+61 7 336 58064
Fax 140276 0
Email 140276 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


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.