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Trial registered on ANZCTR


Registration number
ACTRN12619000597190
Ethics application status
Approved
Date submitted
6/04/2019
Date registered
17/04/2019
Date last updated
17/04/2019
Date data sharing statement initially provided
17/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Benefits of systemically administered adjunctive azithromycin in periodontitis patients non-responsive to initial non-surgical periodontal therapy.
Scientific title
The clinical benefit of using azithromycin in non-surgical periodontal therapy in periodontitis patients where initial treatment has not been successful- a randomized controlled trial
Secondary ID [1] 294238 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Periodontitis patients' non-responsive to initial periodontal therapy 306913 0
Condition category
Condition code
Oral and Gastrointestinal 306007 306007 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
the dose administered - 500mg
the duration of administration - once daily for 3 days
the mode of administration - oral capsules
Both the intervention and control groups will be treated with periodontal debridement at Brisbane City Periodontics and Implants, Brisbane, Mount Gravatt and Oral Health Centre, Herston by calibrated periodontists.
Test group will receive azithromycin 500 mg capsules along with periodontal debridement on first day (day 1). The remaining two capsules will be taken on the subsequent days (day 2 and 3).
Control group will receive identical placebo capsules with periodontal debridement.
Text message/phone call reminders will be placed to the study participants to monitor adherence to the intervention.

Intervention code [1] 300532 0
Treatment: Drugs
Comparator / control treatment
Repeat scaling and periodontal debridement with placebo capsules will be the control treatment. Placebo capsules contain avicel, which is microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 305043 0
The primary outcome will be the changes in clinical attachment level (CAL) in residual periodontal pockets equal to or greater than 6 mm at the end of one year in patients non-responsive to initial periodontal therapy. Clinical attachment level will be measured by the periodontist using a periodontal probe.
Timepoint [1] 305043 0
Assessed at baseline and 12 months after treatment
Secondary outcome [1] 343979 0
Changes in the overall mean clinical attachment level in patients non-responsive to initial periodontal therapy. Clinical attachment level will be measured by the periodontist using a periodontal probe.
Timepoint [1] 343979 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [2] 348808 0
Changes in the probing depth at sites with residual periodontal pockets equal to or more than 6 mm in patients non-responsive to initial periodontal therapy. Probing pocket depth will be measured by a periodontist using a periodontal probe.
Timepoint [2] 348808 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [3] 367522 0
Changes in the overall mean probing depth in patients non-responsive to initial periodontal therapy. Probing pocket depth will be measured by a periodontist using a periodontal probe.
Timepoint [3] 367522 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [4] 367725 0
Changes in the scores of Periodontal Inflamed Surface Area at residual pockets equal to or more than 6 mm in patients non-responsive to initial periodontal therapy. Periodontal inflamed surface area score is a composite score calculated using clinical attachment level, gingival recession and bleeding on probing. Clinical attachment level, gingival recession and bleeding on probing are measured by periodontist using a periodontal probe. This is a composite secondary outcome.

Timepoint [4] 367725 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [5] 367726 0
Changes in the overall scores of Periodontal Inflamed Surface Area score (calculated using clinical attachment levels, gingival recession and bleeding on probing) in patients non-responsive to initial periodontal therapy. Periodontal inflamed surface area score is a composite score calculated using clinical attachment levels, gingival recession and bleeding on probing. Clinical attachment level, gingival recession and bleeding on probing is measured using a periodontal probe.
Timepoint [5] 367726 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [6] 367727 0
Changes in the levels of pro-inflammatory cytokines, [IL (Interleukin)-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-alpha) and other cytokines] from residual periodontal pockets equal to or greater than 6 mm. Gingival crevicular fluid (GCF) and saliva of periodontitis patients non-responsive to initial periodontal therapy will be analyzed using ELISA. This is a composite secondary outcome measuring the pro-inflammatory cytokines.
Timepoint [6] 367727 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [7] 367729 0
Changes in the sub-gingival plaque bacteria from residual periodontal pockets equal to or greater than 6 mm in periodontitis patients non-responsive to initial periodontal therapy measured using quantitative Polymerase Chain Reaction (qPCR).
Timepoint [7] 367729 0
Assessed at baseline, 3 months and 12 months after treatment.
Secondary outcome [8] 368349 0
Changes in the levels of antimicrobial resistance to azithromycin among periodontal bacteria. This will be assessed by antimicrobial susceptibility test using E test strips containing a concentration gradient of azithromycin
Timepoint [8] 368349 0
Assessed at baseline and 12 months after treatment.
Secondary outcome [9] 368499 0
Analysis of the number of sites with probing depth equal to or more than 6 mm assessed by a periodontist using a periodontal probe.
Timepoint [9] 368499 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [10] 368500 0
Analysis of the number of sites wherein a change of pocket depth equal to more than 2 mm was noted. This will be measured by a periodontist using a periodontal probe.
Timepoint [10] 368500 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment.
Secondary outcome [11] 369126 0
Analysis of tooth mobility assessed by a periodontist using the blunt end of two dental instruments
Timepoint [11] 369126 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months after treatment
Secondary outcome [12] 369127 0
Analysis of the adverse effects related to medications and periodontal treatment by the participant self-reported information. Commonly seen adverse events related to azithromycin include diarrhoea, stomach upset and nausea. Commonly seen adverse events related to periodontal treatment include the sensitivity of the teeth and shrinkage of the gums.
Timepoint [12] 369127 0
assessed after treatment, 3 months and 6 months
Secondary outcome [13] 369189 0
Analysis of the number of sites with furcation involvement assessed by a periodontist using a periodontal probe.
Timepoint [13] 369189 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months.
Secondary outcome [14] 369190 0
Analysis of the periodontal prognosis of the patient assessed by the periodontist according to the Troy and Ivanovski prognosis model 2017.
Reference: 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 [14] 369190 0
Assessed at baseline, 3 months, 6 months, 9 months and 12 months
Secondary outcome [15] 369191 0
Analysis of the number of sites with infrabony defects assessed radiographically by a periodontist.
Timepoint [15] 369191 0
Assessed at baseline and 12 months
Secondary outcome [16] 369193 0
Assessment of the pain/discomfort (patient reported outcome) associated with periodontal treatment by a study-specific questionnaire.
Timepoint [16] 369193 0
Assessed following treatment, 3 months and 6 months
Secondary outcome [17] 369209 0
Assessment of whether the gums felt healthier (patient reported outcome) following periodontal treatment using a study-specific questionnaire
Timepoint [17] 369209 0
Assessed following treatment, 3 months and 6 months
Secondary outcome [18] 369210 0
Assessment of whether expectations regarding periodontal treatment (patient reported outcome) were fulfilled among patients using a study-specific questionnaire
Timepoint [18] 369210 0
Assessed following treatment, 3 months and 6 months.

Eligibility
Key inclusion criteria
a) Diagnosis of periodontitis patients non-responsive to initial periodontal therapy will be determined by the presence of at least 4 sites with probing depth equal to or greater than 6 mm on at least two non-adjacent teeth with bleeding on probing at the recall visit after initial periodontal debridement.
b) patients in the age range of 30 to 75 years
c) Presence of at least 16 natural teeth.

Minimum age
30 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
c) history of cardiac arrhythmias or history of myocardial infarction
c) current smokers( equal to or greater than 10 cigarettes/day)
d) Pregnant women
e) patients with uncontrolled type II diabetes mellitus


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 randomization list will be used for the purposes of randomization. The code for randomization will be held by the compounding pharmacy.
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 or greater than 2 mm with bleeding on probing at any site, will be considered an exit criterion for the study. A person not 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).
Adverse effects: Possible adverse effects seen in patients due to the administration of azithromycin will be recorded.
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
With at least 17 subjects per arm, we will be able to detect an effect size (mean divided by standard deviation) of 1.25 mm at 90% power and a two-sided alpha level of 0.01. It is proposed to enroll 40 (20 control and 20 intervention) patients to compensate for drop-outs.

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 CAL levels 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
Not yet 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)
QLD
Recruitment postcode(s) [1] 23180 0
4000 - Brisbane
Recruitment postcode(s) [2] 21931 0
4006 - Herston
Recruitment postcode(s) [3] 25838 0
4122 - Mount Gravatt

Funding & Sponsors
Funding source category [1] 298877 0
University
Name [1] 298877 0
School of Dentistry, University of Queensland
Address [1] 298877 0
School of Dentistry,
University of Queensland
Herston, Qld
4006
Country [1] 298877 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
School of Dentistry, University of Queensland
Oral Health Center, Herston
Qld, 4006
Country
Australia
Secondary sponsor category [1] 301983 0
None
Name [1] 301983 0
Address [1] 301983 0
Country [1] 301983 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299819 0
Bellberry Limited
Ethics committee address [1] 299819 0
129 Glen Osmond Road
Eastwood
South Australia 5063
Ethics committee country [1] 299819 0
Australia
Date submitted for ethics approval [1] 299819 0
26/04/2016
Approval date [1] 299819 0
22/06/2018
Ethics approval number [1] 299819 0
2016-03-262-A-1

Summary
Brief summary
Few cases of periodontitis continue to have residual periodontal pockets with bleeding on probing despite well performed non-surgical periodontal therapy. It is unclear if the use of adjunctive systemic antimicrobials can provide clinical benefits in these cases. If the adjunctive systemic antimicrobial has additional anti-inflammatory properties it may help in the modulation of the host response. Azithromycin is one such antimicrobial with additional anti-inflammatory and host-modulating properties. Although the anti-microbial properties of azithromycin have been studied extensively, there are few studies on its host-modulating and anti-inflammatory properties in the treatment of periodontitis. It is hypothesized that adjunctive administration of azithromycin results in a gain in clinical attachment levels, decreased probing depths, decrease in Periodontal Inflammatory Surface Area (PISA) scores, decreased levels of pro-inflammatory cytokines and decrease in the number of pathogenic bacteria in the periodontal pockets among patients non-responsive to initial periodontal therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81662 0
Prof Saso Ivanovski
Address 81662 0
Prof Saso Ivanovski
Professor of Periodontics, Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81662 0
Australia
Phone 81662 0
+61733658064
Fax 81662 0
Email 81662 0
s.ivanovski@uq.edu.au
Contact person for public queries
Name 81663 0
Prof Saso Ivanovski
Address 81663 0
Prof Saso Ivanovski
Professor of Periodontics, Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81663 0
Australia
Phone 81663 0
+61733658064
Fax 81663 0
Email 81663 0
s.ivanovski@uq.edu.au
Contact person for scientific queries
Name 81664 0
Prof Saso Ivanovski
Address 81664 0
Prof Saso Ivanovski
Professor of Periodontics, Director of Research
School of Dentistry,
University of Queensland
Herston, Qld, 4006
Australia
Country 81664 0
Australia
Phone 81664 0
+61733658064
Fax 81664 0
Email 81664 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] 1675 0
Ethical approval
Citation [1] 1675 0
Link [1] 1675 0
Email [1] 1675 0
Other [1] 1675 0
Type [2] 1676 0
Study protocol
Citation [2] 1676 0
Link [2] 1676 0
Email [2] 1676 0
Other [2] 1676 0
Type [3] 1677 0
Informed consent form
Citation [3] 1677 0
Link [3] 1677 0
Email [3] 1677 0
Other [3] 1677 0
Type [4] 1678 0
Other
Citation [4] 1678 0
Link [4] 1678 0
Email [4] 1678 0
Other [4] 1678 0
Participant Information Sheet
Summary results
No Results