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Trial registered on ANZCTR


Registration number
ACTRN12615000341527
Ethics application status
Approved
Date submitted
26/03/2015
Date registered
15/04/2015
Date last updated
27/11/2019
Date data sharing statement initially provided
27/11/2019
Date results information initially provided
27/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of oral probiotics in improving oral hygiene for orthodontic patients
Scientific title
Efficacy of the oral probiotic Streptococcus salivarius in managing
biofilm formation in patients wearing fixed orthodontic appliances: A double-blind randomized placebo-controlled trial
Secondary ID [1] 286419 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
caries 294587 0
enamel demineralization 294710 0
gingivitis 294711 0
gingival inflammation 294712 0
halitosis 294713 0
Condition category
Condition code
Oral and Gastrointestinal 294887 294887 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
The probiotic lozenges that have been demonstrated efficacious in primary-school-aged children and university-aged adults will be used as the treatment intervention.
These probiotic lozenges contain a probiotic strain, S. salivarius M18 (BLIS Technologies Ltd, Dunedin, New Zealand).
The protocol will require the participants to suck two lozenges each day, one after brushing the teeth in the morning and one after teeth brushing at night.
a) the dose administered: 3.6 billion S. salivarius CFUs/lozenge;
b) the duration/frequency of administration: daily for 4 weeks;
c) the mode of administration: taken by mouth;
d) strategy used to monitor adherence to the intervention: unused lozenge return.
Intervention code [1] 291494 0
Prevention
Comparator / control treatment
Placebo-control, which differs only in containing additional sugar substitutes in place of the S. salivarius M18, will be used in the control group. The active and placebo preparations will be identical in appearance and taste.
Control group
Placebo

Outcomes
Primary outcome [1] 294643 0
1. Plaque Index (PI): PI will be used to measure the amount of biofilm formation by using the modified Silness and Loe Plaque Index (PI) and a periodontal probe (Al-Anezi and Harradine, 2012).
Timepoint [1] 294643 0
The duration of the study will be 4 months in total, including a 1-month treatment intervention followed by a 3-month treatment-free follow-up to assess recurrence rates. This means at the baseline, 1st, and 4th month, the participants’ mouths will be examined and samples will be collected for the assessments.
Primary outcome [2] 294752 0
2. Proportion of ‘good’ bacteria and ‘bad’ bacteria in the dental biofilm: Samples for detecting the proportion of probiotics (S. salivarius M18), pathogenic microbes (S. mutans, A. actinomycetemcomitans, P. gingivalis), and other oral microflora in the dental biofilm will be collected from the gingival areas of the upper lateral incisors, using sterilized dental probes. The microbial profiles of biofilm will be analyzed firstly by direct PCR-based amplification of the 16S ribosomal RNA gene followed by sequencing of the PCR products using next-generation DNA sequencing (Ion Torrent) technology. The 16S rRNA gene is considered the ‘gold standard’ for bacterial identification, which is able to identify the known species and possibly identify the microorganisms that cannot be cultured.
Timepoint [2] 294752 0
The duration of the study will be 4 months in total, including a 1-month treatment intervention followed by a 3-month treatment-free follow-up to assess recurrence rates. This means at the baseline, 1st, and 4th month, the participants’ mouths will be examined and samples will be collected for the assessments.
Primary outcome [3] 294753 0
3. Levels of volatile sulphur compounds (VSCs) in mouth: Levels of VSCs will be assessed by patients’ air samples (breath scores) using a halimeter (Interscan Corp., Chatsworth, USA) based on the average of three readings.
Timepoint [3] 294753 0
The duration of the study will be 4 months in total, including a 1-month treatment intervention followed by a 3-month treatment-free follow-up to assess recurrence rates. This means at the baseline, 1st, and 4th month, the participants’ mouths will be examined and samples will be collected for the assessments.
Secondary outcome [1] 313785 0
The side effects, including bloating and flatulence, will also be assessed by asking patient's feedbacks at each monthly orthodontic visit.

No harm to the patients is anticipated, however, if any serious adverse events are observed in any of the participants, the study will be terminated immediately.
Timepoint [1] 313785 0
All measurements will be taken by a blinded investigator at each monthly orthodontic visit from baseline for 4 months.
Secondary outcome [2] 313992 0
Patient's compliance will also be monitored and assessed by using sticker charts. Each patient will be asked to fill in a sticker chart everyday to record the usage of tablets.
Timepoint [2] 313992 0
All measurements will be taken by a blinded investigator at each monthly orthodontic visit from baseline for 4 months.

Eligibility
Key inclusion criteria
Inclusion criteria: age 10-30 years; at least 20 natural teeth (extraction and non extraction patients); wearing conventional stainless steel brackets (3M Unitek) in both arches; using a fluoride toothpaste not containing any supplementary antibacterial agents for daily oral hygiene. The patients will be willing to participate in the study and will be required to sign an informed consent form.
Minimum age
10 Years
Maximum age
30 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria: systemic disease (i.e. diabetes); periodontal diseases; antibiotic therapy; dental fluorosis; smoking; use of powered toothbrushes; lactose intolerant; allergic to dairy products.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Balanced block randomization will be used to ensure equal patient allocation to each treatment group.
Allocation concealment will be used to avoid selection bias.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The computer-generated random numbers will be provided in opaque, sealed envelopes before interventions.
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
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data will be firstly analyzed by descriptive statistics and normality tests. An intention-to-treat analysis will be carried using mixed-models and, where appropriate, nonparametric Kruskal-Wallis. The statistical software SPSS 20 and STATA 13 will be used. Alfa error will be set at 0.05.

Sample size calculation and statistical power are based on our previous RCT research (Peng Y, et al. Effect of visual method vs plaque disclosure in enhancing oral hygiene in adolescents and young adults: A single-blind randomized controlled trial. Am J Orthod Dentofacial Orthop. 2014;145:280-286). Type I error is set at 0.05 and type II error at 0.20 (80% power). At least 27 patients (i.e., a total of 54 for two groups) will be needed to detect a decrease in biofilm formation of about 30%. To account for possible dropouts during the study, we plan to recruit a total of 64 patients.

Recruitment
Recruitment status
Completed
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 outside Australia
Country [1] 6775 0
New Zealand
State/province [1] 6775 0
Dunedin

Funding & Sponsors
Funding source category [1] 290990 0
Charities/Societies/Foundations
Name [1] 290990 0
The New Zealand Dental Association Research Foundation
Address [1] 290990 0
NZDA House, Building 1, 195 Main Highway Ellerslie, Auckland 1051, PO Box 28084, Remuera 1541
Country [1] 290990 0
New Zealand
Primary sponsor type
University
Name
Faculty of Dentistry, University of Otago
Address
310 Great King Street, Dunedin, 9016
Country
New Zealand
Secondary sponsor category [1] 289670 0
None
Name [1] 289670 0
Address [1] 289670 0
Country [1] 289670 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292579 0
University of Otago Ethics Committee
Ethics committee address [1] 292579 0
362 Leith Street, Dunedin, 9016
Ethics committee country [1] 292579 0
New Zealand
Date submitted for ethics approval [1] 292579 0
01/05/2014
Approval date [1] 292579 0
12/08/2014
Ethics approval number [1] 292579 0

Summary
Brief summary
There is an increasing demand for orthodontic treatment due to its benefits in improving smiles, self-esteem and jaw function. However, braces make it more difficult to brush teeth effectively and therefore increase the accumulation of bacterial plaque (dental biofilm) in these hard-to-brush areas. Plaque can lead to problems such as tooth demineralization, bleeding gums and bad breath. These consequences significantly affect orthodontic treatment results and a patient’s quality of life.
The prevalence of these biofilm-related problems, such as enamel demineralization, still remain as high as 72.9% in patients wearing braces. Many dental products are commercially available to prevent plaque buildup, with little effect. These include interdental brushes, specialized orthodontic toothbrushes, antimicrobial mouth rinses and toothpastes. The need for an effective measure of biofilm control is important and it is even greater in patients wearing braces.
Probiotics are live ‘good’ bacteria that can inhibit ‘bad’ bacteria in biofilms. Regular consumption of oral probiotics has been reported as an effective way for managing plaque in preschool children, primary-school children, adolescents, adults and the elderly. However, the effect of oral probiotics on controlling biofilm in patients wearing braces has not been investigated to date.
The probiotic Streptococcus salivarius, developed at the University of Otago, is the world’s first probiotic for the mouth. It has been shown to be effective and beneficial for the prevention and treatment of biofilm-related problems such as dental decay, gum inflammation and bad breath.
We intend to investigate the effect of probiotic Streptococcus salivarius in managing the biofilm in patients wearing braces and see whether it can reduce dental biofilm accumulation, its unwanted side effects and offer patients a new beneficial oral micro-ecology.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56066 0
Dr Li Mei
Address 56066 0
Department of Oral Sciences, Faculty of Dentistry, University of Otago. 310 Great King Street, Dunedin, 9016
Country 56066 0
New Zealand
Phone 56066 0
+64 3 479 7480
Fax 56066 0
Email 56066 0
li.mei@otago.ac.nz
Contact person for public queries
Name 56067 0
Dr Gareth Benic
Address 56067 0
Department of Oral Sciences, Faculty of Dentistry, University of Otago. 310 Great King Street, Dunedin, 9016
Country 56067 0
New Zealand
Phone 56067 0
+64 3 479 7480
Fax 56067 0
Email 56067 0
gzbenic@gmail.com
Contact person for scientific queries
Name 56068 0
Dr Li Mei
Address 56068 0
Department of Oral Sciences, Faculty of Dentistry, University of Otago. 310 Great King Street, Dunedin, 9016
Country 56068 0
New Zealand
Phone 56068 0
+64 3 479 7480
Fax 56068 0
Email 56068 0
li.mei@otago.ac.nz

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?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 5901 0
Ethical approval
Citation [1] 5901 0
Link [1] 5901 0
Email [1] 5901 0
li.mei@otago.ac.nz
Other [1] 5901 0
Attachment [1] 5901 0
Type [2] 5902 0
Ethical approval
Citation [2] 5902 0
Link [2] 5902 0
Email [2] 5902 0
li.mei@otago.ac.nz
Other [2] 5902 0
Attachment [2] 5902 0
Type [3] 5903 0
Ethical approval
Citation [3] 5903 0
Link [3] 5903 0
Email [3] 5903 0
li.mei@otago.ac.nz
Other [3] 5903 0
Attachment [3] 5903 0
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 5900 0
J. Breath Res. 13 (2019) 036010
https://doi.org/10.1088/1752-7163/ab1c81
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary