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Trial registered on ANZCTR


Registration number
ACTRN12619000560190
Ethics application status
Approved
Date submitted
6/04/2019
Date registered
10/04/2019
Date last updated
2/12/2019
Date data sharing statement initially provided
10/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Benefits of systemically administered adjunctive azithromycin with non-surgical periodontal therapy in treating advanced gum disease.
Scientific title
Systemic administration of azithromycin as an adjunct to non-surgical periodontal therapy in generalized stage III and IV, grade C periodontitis- a randomized controlled trial.
Secondary ID [1] 294310 0
'None'
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stage III and IV, grade C periodontitis
307017 0
Condition category
Condition code
Oral and Gastrointestinal 306117 306117 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
Systemic administration of azithromycin will be the intervention in the proposed clinical trial
Test group: Non-surgical periodontal therapy + systemic azithromycin
-the dose administered, 500mg
- the duration of administration, once daily for 3 days
- the mode of administration, oral capsules
Control group:
Non-surgical periodontal therapy plus placebo capsules
Both the test and control groups will be treated with non-surgical periodontal therapy(periodontal debridement) at the Oral Health Centre, Herston, Brisbane City Periodontics and Implants, Brisbane, Mount Gravatt and Specialist Dental Centre, Penrith by calibrated periodontists. Non-surgical periodontal therapy will be completed within three days.
Test group will start azithromycin oral capsules on the first day of non-surgical periodontal therapy.
Control group will receive placebo capsules on the first day of non-surgical periodontal therapy. Another two doses of azithromycin and placebo capsules will be taken on the next subsequent days (day 2 and day 3).
Text message reminders/phone call reminders will be made to the participants to monitor adherence to the intervention.
Intervention code [1] 300612 0
Treatment: Drugs
Comparator / control treatment
Non-surgical periodontal therapy with similar looking placebo capsules will be the control treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 305138 0
The mean change in overall periodontal inflamed surface area (PISA) scores in patients with stage III and IV, grade C periodontitis. PISA score is a composite score calculated using clinical attachment level, gingival recession and bleeding on probing measured using a periodontal probe.
Timepoint [1] 305138 0
Assessed at baseline and 12 months after treatment.
Secondary outcome [1] 345740 0
The mean change in the periodontal inflamed surface area scores at pockets equal to or greater than 6 mm.
Timepoint [1] 345740 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months.
Secondary outcome [2] 345741 0
The mean change in overall clinical attachment level measured using a periodontal probe in patients with stage III and IV, grade C periodontitis.
Timepoint [2] 345741 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months.
Secondary outcome [3] 348814 0
The mean change in overall probing pocket depth measured using a periodontal probe in patients with stage III and IV, grade C periodontitis.
Timepoint [3] 348814 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months.
Secondary outcome [4] 351158 0
Changes in the levels of proinflammatory cytokines [ IL-1ß, IL-6, IL-8, IL-10, IL-17, Tumor Necrosis Factor-a (TNF-a) and prostaglandin E2(PGE2) ], using gingival crevicular fluid and saliva assay of stage III and IV, grade C periodontitis. This is a composite secondary outcome measuring changes in the levels of proinflammatory cytokines.

Timepoint [4] 351158 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [5] 351159 0
Changes in the levels of matrix metalloproteinases [ MMP-8, MMP-3, and MMP-13,] as well as Tissue Inhibitors of MetalloProteinases-1 (TIMP-1) by gingival crevicular fluid and saliva assay among patients with stage III and IV, grade C periodontitis. This is a composite secondary outcome measuring the changes in the levels of matrix metalloproteinases.

Timepoint [5] 351159 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [6] 368584 0
Changes in the levels of bone biomarkers (pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), receptor activator of nuclear factor-B-ligand (RANK-L), osteoprotegerin (OPG) and osteopontin) by saliva and gingival crevicular fluid assay of patients with stage III and IV periodontitis. This is a composite secondary outcome measuring the changes in the levels of bone biomarkers.

Timepoint [6] 368584 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [7] 368585 0
To assess the antibiotic resistance among subgingival plaque bacteria treated with and without systemic azithromycin as an adjunct to non-surgical periodontal therapy in stage III and IV, grade C periodontitis

Timepoint [7] 368585 0
Assessed at baseline and 12 months after treatment.
Secondary outcome [8] 368586 0
Analysis of the number of sites with probing periodontal pocket depth equal to or more than 6mm
Timepoint [8] 368586 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [9] 368587 0
Analysis of the number of sites with periodontal pockets wherein a change of equal to or more than 2 mm was noted, measured clinically using a periodontal probe.
Timepoint [9] 368587 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [10] 369128 0
Analysis of tooth mobility assessed clinically in stage III and IV, grade C periodontitis,
Timepoint [10] 369128 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [11] 369129 0
Analysis of the composite outcome of patient-reported outcomes and adverse effects by participant self-reported information. Examples of adverse effects related to medications include diarrhoea, stomach upset and nausea and examples of adverse effects related to periodontal treatment include pain/discomfort in the gums and shrinkage of the gums.
Timepoint [11] 369129 0
Assessed following treatment, 3 months and 6 months.
Secondary outcome [12] 369147 0
The mean change in clinical attachment level in periodontal pockets equal to or greater than 6 mm.
Timepoint [12] 369147 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [13] 369148 0
The mean change in probing pocket depth in pockets equal to or greater than 6 mm
Timepoint [13] 369148 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [14] 369171 0
Analysis of the periodontal sites with furcation involvement assessed clinically in patients with stage III and IV, grade C periodontitis
Timepoint [14] 369171 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [15] 369172 0
Analysis of the periodontal sites with infrabony defects assessed radiographically in stage III and IV, grade C periodontitis.
Timepoint [15] 369172 0
Assessed at baseline and 12 months after treatment.
Secondary outcome [16] 369173 0
Analysis of the overall clinical prognosis of the patient assessed using Troy and Ivanovski 2017 prognosis model.
McGowan T, McGowan K, Ivanovski S. A Novel Evidence-Based Periodontal Prognosis Model. J Evid Based Dent Pract. 2017 Dec;17(4):350-360.
Timepoint [16] 369173 0
Assessed at baseline, 3 months and 12 months
Secondary outcome [17] 369205 0
To evaluate the microbiological changes in the subgingival plaque of patients with stage III and stage IV, grade C periodontitis treated with and without systemic azithromycin as an adjunct to non-surgical periodontal therapy.
Timepoint [17] 369205 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [18] 369206 0
To evaluate the levels of azithromycin in the gingival crevicular fluid of patients.
Timepoint [18] 369206 0
Assessed at randomization at baseline, 3 months and 12 months after treatment.

Eligibility
Key inclusion criteria
a) diagnosis of stage III and IV periodontitis, defined by at least 30% of the sites with probing depth or clinical attachment level (CAL) equal to or greater than 4 mm with bleeding on probing (BOP). Additionally the presence of pocket depth equal to or greater than 6 mm with bleeding on probing on at least 6 sites on a minimum of 3 teeth.
Grade C periodontitis is further defined by presence of ONE of the following features:
• equal to greater than 2 mm of CAL loss over 5 years,
• % bone loss/age > 1.0,
• destruction exceeds expectation given biofilm deposits, specific clinical patterns suggestive of periods of rapid progression and early onset disease (e.g., molar/incisor pattern),
• smokers equal to greater than 10 cigarettes/day,
• HbA1c equal to or greater than 7.0% in patients with diabetes mellitus
b. age 25 to 75 years;
c. At least 16 natural teeth.
Minimum age
25 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. use of antimicrobials within 3 months preceding the start of the study;
b. history of sensitivity to azithromycin or macrolides
d. prolonged QT interval or history of cardiac arrhythmia or history of myocardial infarction
e. periodontal debridement in the past 6 months
f. pregnant women


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 randomization by computers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated random number list will be used for the purposes of randomization.
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Exit criteria for patients: A deterioration of probing depth of equal to greater than 2 mm with bleeding on probing at any site, will be considered an exit criterion for the study. A person non-involved in the study will break the code (received from compounding pharmacy) regarding medication concealment and check whether patients were on azithromycin or placebo. If patients were on azithromycin, alternative treatment options will be offered(eg. periodontal surgery). If patients were on placebo, these patients will be given azithromycin and will form a subset of the study (although excluded).
Possible adverse effects seen in patients due to the administration of azithromycin will be recorded. Patient experiences regarding provided dental treatment will be collected from patients.
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
With at least 25 subjects per arm, we will be able to detect an effect size of reduction of periodontal inflamed surface area (PISA) of 297 mm2 at 80% power and a two-sided alpha level of 0.05. PISA score is an integrated score that measures the inflammatory burden on the periodontium calculated from clinical attachment loss, pocket depth and bleeding on probing. It is proposed to enroll 56 (28 controls and 28 test group) patients to compensate for drop out.
Collected data will be assessed using SPSS 25.0 version (IBM Corporation, Armonk, New York, U.S.A.) statistical software. To evaluate the statistical significance of the mean difference between the two groups (control and intervention groups) at various time points analysis of variance (ANOVA) will be used. To assess the difference in means between the control and intervention groups analysis of covariance (ANCOVA) model will be used to adjust the baseline parameters, wherein the treatment groups will be the factors and baseline PISA scores will be the covariates. A repeated measure ANOVA will be used to perform a group comparison across the different time points (baseline, three, six, nine and twelve months) by treatment groups. The level of statistical significance will be set at p< 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment postcode(s) [1] 22046 0
4006 - Herston
Recruitment postcode(s) [2] 26075 0
2750 - Penrith
Recruitment postcode(s) [3] 26076 0
4000 - Brisbane
Recruitment postcode(s) [4] 26077 0
4122 - Mount Gravatt

Funding & Sponsors
Funding source category [1] 298945 0
University
Name [1] 298945 0
School of Dentistry, University of Queensland
Address [1] 298945 0
School of Dentistry,
University of Queensland
Herston, Qld
4006
Country [1] 298945 0
Australia
Primary sponsor type
University
Name
School of Dentistry, University of Queensland
Address
School of Dentistry,
University of Queensland
Herston, Qld
4006
Country
Australia
Secondary sponsor category [1] 300558 0
None
Name [1] 300558 0
Address [1] 300558 0
Country [1] 300558 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299882 0
The Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 299882 0
The Prince Charles Hospital
Research office
Building 14
Rode Road
CHERMSIDE QLD 4032
Ethics committee country [1] 299882 0
Australia
Date submitted for ethics approval [1] 299882 0
03/05/2018
Approval date [1] 299882 0
20/06/2018
Ethics approval number [1] 299882 0
TPCH HREC Project ID 40730

Summary
Brief summary
Periodontitis, especially stage III and IV, grade C periodontitis carries significant chances of tooth loss. Adjunctive systemic antimicrobials may provide additional benefits in these patients, however, the evidence is unclear. If the adjunctive antimicrobial has additional anti-inflammatory properties it may help in the modulation of the host response. Azithromycin is one such antimicrobial with additional host-modulating properties. Although the anti-microbial properties of azithromycin have been studied extensively, there are few studies on its host-modulating properties in periodontitis. It is hypothesized that adjunctive administration of azithromycin will result in decreased periodontal inflamed surface area scores, gain in clinical attachment level, reduced pocket depth, decreased levels of pro-inflammatory cytokines in the gingival crevicular fluid & saliva and decrease in the number of pathogenic bacteria in the periodontal pockets.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81854 0
Prof Prof Saso Ivanovski
Address 81854 0
Prof Saso Ivanovski
Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81854 0
Australia
Phone 81854 0
+61733658064
Fax 81854 0
Email 81854 0
s.ivanovski@uq.edu.au
Contact person for public queries
Name 81855 0
Prof Prof Saso Ivanovski
Address 81855 0
Prof Saso Ivanovski
Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81855 0
Australia
Phone 81855 0
+61733658064
Fax 81855 0
Email 81855 0
s.ivanovski@uq.edu.au
Contact person for scientific queries
Name 81856 0
Prof Prof Saso Ivanovski
Address 81856 0
Prof Saso Ivanovski
Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81856 0
Australia
Phone 81856 0
+61733658064
Fax 81856 0
Email 81856 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?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 1805 0
Ethical approval
Citation [1] 1805 0
Link [1] 1805 0
Email [1] 1805 0
Other [1] 1805 0
Type [2] 1806 0
Study protocol
Citation [2] 1806 0
Link [2] 1806 0
Email [2] 1806 0
Other [2] 1806 0
Type [3] 1807 0
Informed consent form
Citation [3] 1807 0
Link [3] 1807 0
Email [3] 1807 0
Other [3] 1807 0
Type [4] 1808 0
Informed consent form
Citation [4] 1808 0
Link [4] 1808 0
Email [4] 1808 0
Other [4] 1808 0
Participant information sheet
Summary results
No Results