Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001140448
Ethics application status
Approved
Date submitted
15/08/2016
Date registered
22/08/2016
Date last updated
11/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Manuka Honey with Cyclopower (Trademark) Chewable Tablets on Oral Health in Young Adults
Scientific title
Effect of MGO400+ Manuka Honey with Cyclopower (Trademark) Chewable Tablets on Oral Health Including Dental Plaque Activity and Gingival Health in Young Adults
Secondary ID [1] 289936 0
none known
Universal Trial Number (UTN)
U1111-1186-4730
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
oral health 299917 0
Condition category
Condition code
Oral and Gastrointestinal 299813 299813 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Alternative and Complementary Medicine 299841 299841 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1
12 participants will each chew or rinse five times for one minute each time with a one week washout period between each test. For each test product used, the pH of dental plaque will be measured over the next 40 minutes to measure the effect of the test product on the acidity produced in the plaque. They will chew one MGO400+ Manuka Honey tablet (food supplement) with 2.16g honey and 3.93g xylitol; one xylitol tablet with 4g xylitol, 2.5g of Manuka honey, and two rinses with 20ml of 10% sucrose solution - the standard for determining dental plaque pH. The honey and xylitol test interventions will be compared with the sucrose interventions to determine if they result in the same, more or less acidity in dental plaque.

Part 2
15 participants will chew MGO400+ Manuka Honey tablets (food supplement) with 2.16g honey and 3.93g xylitol three times daily for 28 days and 15 participants will chew xylitol tablets with 4g xylitol three times daily for 28 days. The oral health status of each group including the dental plaque pH, the growth of dental plaque, the health of the gingival tissues and the saliva will be recorded at time 0, 14 days, 28 days and then at 56 days to look for any residual effects when compared with baseline and the end of the intervention. At 14 and 28 days, participants will be asked to return unused tablets to allow determination of how reliably the tablets were chewed.
Intervention code [1] 295618 0
Prevention
Intervention code [2] 295641 0
Treatment: Other
Comparator / control treatment
Part 1
The comparison tests are sucrose solution, honey and xylitol.

Part 2
The control group is an active control chewing xylitol tablets (4.0g xylitol). This is within the usual xylitol range in tablets and chewing gum on the market. Xylitol has a known benefit in improving oral health. Xylitol is also included in the MGO400+ Manuka Honey tablets ( 3.93g xylitol). The xylitol group will allow an assessment of any improvement or decrease of effect on oral health from the MGO400+ Manuka Honey tablets.
Control group
Active

Outcomes
Primary outcome [1] 299288 0
Part 1
The acidity of dental plaque will be determined by measuring the changes in the pH of dental plaque over 40 minutes following chewing or rinsing with the test products: MGO400+ Manuka Honey tablet (food supplement) with 2.16g honey and 3.93g xylitol; xylitol tablet with 4g xylitol, 2.5g of Manuka honey, and two rinses with 20ml of 10% sucrose solution on five different occasions with a one week wash out between measurements. This will be done on samples of dental plaque removed from the teeth in the normal way with a dental instrument.
Timepoint [1] 299288 0
Part 1
The dental plaque pH will be measured at time 0, then 1, 5, 10, 20 and 40 minutes following chewing or rinsing with each test product.
Primary outcome [2] 299289 0
Part 2
Oral health will be assessed by examining the mouth and recording the health of teeth, soft tissues and the gingival (gum) tissues at the beginning of the study - Day 1,, 14 days, 28 days and 56 days. At each time point, the acidity of dental plaque will be determined by measuring the changes in the pH of dental plaque over 40 minutes following rinsing with 20 ml of a 10% sucrose solution. This will be done on samples of dental plaque removed from the teeth in the normal way with a dental instrument.
Timepoint [2] 299289 0
Part 2
Oral health assessments will take place on Days 1, 14, 28 and 56 days with the intervention starting following the assessment on Day 1.
Secondary outcome [1] 326738 0
Part 2
Gingival (gum) health will be assessed by measuring the dental plaque build up and health of the gums. This is done by noting how much of the teeth surfaces are covered by dental plaque and by grading the colour of the gingival tissues which reflects any inflammation that may be present.
Timepoint [1] 326738 0
Days 1, 14, 28 and 56.
Secondary outcome [2] 326837 0
Part 2
Salivary health will be assessed by measuring salivary buffering capacity, pH and salivary flow rates. This involves having the participant spit saliva into a measuring cup for two minutes to work out the flow rate. The pH is measured using a pH electrode and the buffering capacity is measured by adding acid to the saliva and measuring how much acid can be neutralised.
Timepoint [2] 326837 0
Days 1, 14, 28 and 56.
Secondary outcome [3] 326838 0
Soft tissue health will be measured by recording any visible changes that occur in the tissues during the intervention and 28 days after ceasing the intervention. This will be done as part of the dental examination.
Timepoint [3] 326838 0
Days 1, 14, 28 and 56.
Secondary outcome [4] 326842 0
Changes in the dental plaque biofilm will be assessed by analysing changes in the bacteria in the biofilm.
Timepoint [4] 326842 0
Days 1, 14, 28 and 56.

Eligibility
Key inclusion criteria
1. 16-30 years of age
2. Written consent
3. Able to understand and follow instructions
4. Healthy with no conditions impacting on oral health
5. Evidence (including radiographic) of dental caries progression within the last 2 years
6. DMFT >4 (to show caries in more than the occlusal surfaces of the first molars)
7. No antibiotic use in the past 28 days
8. Not allergic to Manuka honey or xylitol
Minimum age
16 Years
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Medical condition that impacts on the study
2. Unable to commit for the number of appointments required
3. Dry mouth conditions

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)
Numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation using a computer generated randomisation table
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We have consulted a consulting biostatistician (Andrew Gray) who is available to provide guidance on statistical issues throughout the project.

For the Part 1 sample size, he recommend the following:. I’ve used a higher correlation coefficient than we’d talked about (0.7 rather than 0.5) on reflection and this means that the cross-over design is more “powerful” than the equivalent parallel study.
The number of participants in the first study was determined in part by how many it would be feasible to recruit and follow-up. With n=6, this would provide 80% power for detecting differences between any two groups of 0.35 for pH (using a SD of 0.5 estimated from the literature) or 2.8 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level and assuming r=0.7 or higher for the repeated measures. Both are around 0.7 SD and so could be described as “large” effects.
The number of participants in the first study was determined in part by how many it would be feasible to recruit and follow-up. With n=9, this would provide 80% power for detecting differences between any two groups of 0.27 for pH (using a SD of 0.5 estimated from the literature) or 2.2 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level and assuming r=0.7 or higher for the repeated measures. Both are around 0.5 SD and so could be described as “medium” effects.
The number of participants in the first study was determined in part by how many it would be feasible to recruit and follow-up. With n=12, this would provide 80% power for detecting differences between any two groups of 0.23 for pH (using a SD of 0.5 estimated from the literature) or 1.9 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level and assuming r=0.7 or higher for the repeated measures. Both are around 0.5 SD and so could be described as “medium” effects.

A multiple of 3 for Part 1 would be useful in allowing you to balance the first order carry-over effects (this couldn’t be done exactly with 10 participants). I’d suggest 12 if you think that’s feasible but n=9 would also allow detecting “medium” effect sizes so either could be justified.

For Part 2 sample size, the following was provided:
With n=10/group, and allowing for 10% loss to follow-up within each group, this would provide 80% power for detecting differences between any two groups at any time point of 1.20 for pH (using a SD of 0.5 estimated from the literature) or 9.6 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level.
With n=15/group, and allowing for 10% loss to follow-up within each group, this would provide 80% power for detecting differences between any two groups at any time point of 0.90 for pH (using a SD of 0.5 estimated from the literature) or 7.2 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level.
With n=20/group, and allowing for 10% loss to follow-up within each group, this would provide 80% power for detecting differences between any two groups at any time point of 0.71 for pH (using a SD of 0.5 estimated from the literature) or 5.7 for AUC(5.7) (using a SD of 4 estimated from the literature) using a two-sided test at the 0.05 level.

For Part 2, the two versus three groups options depend entirely on the research question(s) of interest. In general terms, a better answer to a more precise question (so with two groups) is usually a good thing so I think the two groups of 15 would be sensible if the total number is limited to 30.

For statistical methods, He has recommended:
· You are going to allocate participants in Study 1 to one of three orders that are balanced for first order carry over and period effects (ABC BCA and CAB)
· For Part 1, while linear mixed models could be used, a simpler approach of performing multiple paired t-tests for each of the three combinations of treatment will be performed. As this is an exploratory study to identify any risk of harm, no adjustment for multiple comparisons will be performed.
· For Part 2, as missing data would make repeated measures ANOVAs inappropriate, separate ANOVAs will be used for each time point to compare the intervention groups.
· All results will be presented along with 95% confidence intervals to help interpret the study’s findings in terms of clinical significance as well as statistical significance.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/09/2016
Actual
13/10/2016
Date of last participant enrolment
Anticipated
7/11/2016
Actual
30/01/2017
Date of last data collection
Anticipated
16/01/2017
Actual
11/04/2017
Sample size
Target
42
Accrual to date
Final
44
Recruitment outside Australia
Country [1] 8099 0
New Zealand
State/province [1] 8099 0
Otago

Funding & Sponsors
Funding source category [1] 294309 0
Commercial sector/Industry
Name [1] 294309 0
Manuka Health New Zealand Limited
Country [1] 294309 0
New Zealand
Primary sponsor type
Individual
Name
Mandy Suddes PhD, PMP
Address
Head of Research and Development
Manuka Health New Zealand Limited
Level 4
123 Carlton Gore Road
Newmarket
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 293149 0
None
Name [1] 293149 0
None
Address [1] 293149 0
None
Country [1] 293149 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295735 0
Health and Disability Research Ethics Committee
Ethics committee address [1] 295735 0
Ethics committee country [1] 295735 0
New Zealand
Date submitted for ethics approval [1] 295735 0
26/08/2016
Approval date [1] 295735 0
02/09/2016
Ethics approval number [1] 295735 0
16/STH/132

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

Contacts
Principal investigator
Name 68270 0
Prof Bernadette K Drummond
Address 68270 0
Department of Oral Sciences
University of Otago Faculty of Dentistry
PO Box 647
Dunedin 9054
Country 68270 0
New Zealand
Phone 68270 0
+6434797128
Fax 68270 0
Email 68270 0
bernadette.drummond@otago.ac.nz
Contact person for public queries
Name 68271 0
Bernadette Drummond
Address 68271 0
Department of Oral Sciences
University of Otago Faculty of Dentistry
PO Box 647
Dunedin 9054
Country 68271 0
New Zealand
Phone 68271 0
+6434797128
Fax 68271 0
Email 68271 0
bernadette.drummond@otago.ac.nz
Contact person for scientific queries
Name 68272 0
Bernadette Drummond
Address 68272 0
Department of Oral Sciences
University of Otago Faculty of Dentistry
PO Box 647
Dunedin 9054
Country 68272 0
New Zealand
Phone 68272 0
+6434797128
Fax 68272 0
Email 68272 0
bernadette.drummond@otago.ac.nz

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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