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Trial registered on ANZCTR


Registration number
ACTRN12621001416886
Ethics application status
Approved
Date submitted
7/09/2021
Date registered
20/10/2021
Date last updated
20/10/2021
Date data sharing statement initially provided
20/10/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A comparison of the effects of two sugar-free chewing gums to repair early tooth decay.
Scientific title
A comparison of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) prepared using microbial or porcine trypsin/chymotrypsin to remineralize subsurface enamel lesions in healthy adults in situ.
Secondary ID [1] 296827 0
Nil Known
Universal Trial Number (UTN)
U1111-1268-9724
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dental Caries 321615 0
Condition category
Condition code
Oral and Gastrointestinal 319356 319356 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
This randomized controlled study will use a double-blind, two-way crossover design to assess the effects of chewing two sugar-free gums on the remineralization of artificially-created subsurface enamel lesions (early enamel decay), using an established in situ caries model.

Ten (10) human volunteers will be selected to participate. Potential participants will be given a Plain Language Statement detailing what they will be asked to do and a consent form to sign and date if they agree to participate.

Each participant will wear a custom-made removable palatal acrylic appliance with four slabs of human enamel attached. The enamel slabs will be pre-sterilized and will contain subsurface lesions created in the laboratory. The appliances will be fabricated for the participants under the direct supervision of a registered prosthetist/dental technician at the Royal Dental Hospital of Melbourne. The appliances will either have been previously fabricated for the participants for previous in situ projects they have participated in or, in the case of participants who have not participated in these projects before, will be newly fabricated for them. One week prior to commencement of the first intervention in this project, a qualified dentist on the research team will ensure the appliance fits correctly and then the enamel slabs will be attached to the appliances by the research team.

Participants will wear the appliances four times a day for 40 minutes each time over two 10 consecutive-weekday treatment periods (excluding weekends). There will be two one-week washout periods; one before the first treatment period commences and one between the two treatment periods. During the washout periods participants will not wear their appliance but will brush their teeth only with a standard fluoride toothpaste that they will use throughout the entire project period. During the second washout period, the research team will replace the slabs on the appliances with new pre-sterilized enamel slabs.

The two gums will each be randomly allocated to one of the two treatment periods. The two gums will both contain exactly the same ingredients including 1% (by weight) casein, the major protein in milk, combined with calcium (called casein phosphopeptide-amorphous calcium phosphate or CPP-ACP). One gum will contain CPP-ACP manufactured using an enzyme called trypsin/chymotrypsin originating from pigs and the other will contain CPP-ACP made with trypsin/chymotrypsin originating from a fungus.

The chewing gums will be supplied in this coded packages by the sponsor of this study. At the start of each treatment period the participants will present to the research department at the Melbourne Dental School to receive their appliances and enough gum to chew over that treatment period.

Participants will be randomly allocated to one of the two gums to chew during the first treatment period and cross over to the other gum to chew during the second treatment period. The order the gums are allocated to each participant will be random and unknown to the participants or the researchers analyzing the results. Each participant will complete both 10-day treatment periods and the entire project period will comprise a total of six weeks in total.

During the treatment periods, participants will not eat or drink anything when wearing their appliance and will not wear their appliance when participating in sporting activities. They will clean their appliance using a toothbrush and fluoride-free toothpaste (both supplied) and then rinse their appliance with distilled de-ionized water (supplied). They will be instructed to avoid brushing and rinsing the enamel slabs and the trough areas surrounding the enamel slabs. When the appliance is not being worn it will be placed in a snap-sealed bag (supplied) with several drops of distilled de-ionized water (supplied) to prevent them drying. During the entire six-week project period they will be instructed to brush their teeth twice a day with a toothbrush and a standard fluoride toothpaste (both supplied) with the appliance out of their mouths during the treatment periods. They will also continue other normal oral hygiene practices throughout the project period. For the duration of the entire project period, participants will be asked to not use any toothpaste other than the standard fluoride toothpaste given to them by the research team, refrain from using any mouthrinses, and will also be instructed not to chew any gum other than chew their allocated gum at the specified times during the treatment periods. Participants will otherwise maintain normal dietary and oral hygiene practices during the project period.

Each participant will be requested to inform the research staff if they experience any discomfort wearing the appliance. The qualified dentist on the research team will then assess the problem and adjust the appliance if needed.

All participants will be given a diary at the commencement of each treatment period and will be asked to fill in the times they wear the appliance and chew the gum. Participants will also be asked to inform the research team of any adverse events that occur during the treatment periods and note these in the diary. They will return the diary at the conclusion of each treatment period.

Participants will be assured they will be free to withdraw from the study at any time without prejudice.

Intervention code [1] 320311 0
Treatment: Other
Comparator / control treatment
The "comparator" is the gum that will contain CPP-ACP manufactured using an enzyme called trypsin/chymotrypsin originating from pigs.
Control group
Active

Outcomes
Primary outcome [1] 327222 0
Percent remineralization of enamel subsurface lesions (the percent change in mineral content values relative to the baseline mineral content). Mineral content will be measured by analysing images of transverse microradiographs of enamel lesions. A microradiography unit will be employed to take the radiographs and a computer program that measures grey values on the radiographs will calculate the mineral content of scans of each lesion. The percent remineralization will be calculated by measuring the percentage difference in mineral content of each lesion in each slab that was attached to the appliance compared with the mineral content of each paired lesion in the corresponding untreated paired slab that was not attached to the appliance but stored in a humid environment during the study period..
Timepoint [1] 327222 0
Sections of each enamel slab containing two subsurface enamel lesions, with its matched control enamel slab containing two matched subsurface enamel lesions, will be radiographed approximately two weeks after completion of each two-week treatment period.
Secondary outcome [1] 394278 0
Depth of enamel subsurface lesions. Depth will be measured by analysing images of transverse microradiographs of enamel lesions. A microradiography unit will be employed to take the radiographs. The change in depth of lesions after treatment will be measured by subtracting the depth of each lesion in each slab attached to the appliance from the depth of its paired lesion in the corresponding paired untreated slab that was not attached to the appliance but stored in a humid environment during the study period..
Timepoint [1] 394278 0
Sections of each enamel slab containing two subsurface enamel lesions, with its matched control enamel slab containing two matched subsurface enamel lesions, will be radiographed approximately two weeks after completion of each two-week treatment period.
Secondary outcome [2] 401387 0
Adverse events related to chewing the two different gums. This will be assessed by identifying and comparing any adverse events self-reported by the participants during the two two-week treatment periods in the diaries given to them.
Timepoint [2] 401387 0
Any adverse events self-reported by the participants in the diaries will be identified at the end of each two-week treatment period and at the end of the study period..

Eligibility
Key inclusion criteria
• Aged 18-75 years of age;
• Provide written informed consent prior to participation and be given a signed copy of the informed consent form;
• Be in good general health based on medical/dental history and oral exam without a history of allergic or adverse reactions to milk, milk products, tin or tin-containing products;
• Agree not to participate in any other oral study for the study duration;
• Have a reasonable functional dentition as determined by the oral examiner and sufficient teeth to support the fabricated dental appliance;
• Be willing to participate in the study, able to follow the study directions, successfully tolerate/perform all study procedures, and willing to return for all specified visits at their appointed times;
• Able to chew gum;
• Be willing to refrain from using non-study dentifrice and mouthrinse during the study period;
• Be willing to postpone all elective dental procedures until the study has been completed;
• Be willing and able to refrain from wearing a nightguard (occlusal splint) for the entire course of the study (for nightguard wearers only).

In addition, to be eligible to participate in this study, an individual will need to meet all the following criteria:
• Ability to understand, and ability to read and sign, the informed consent form;
• Have at least 22 natural teeth;
• Have a gum-stimulated whole salivary flow rate at least 1.0 mL/minute and unstimulated whole salivary flow rate at least 0.2 mL/minute.
• Willingness to comply with all study procedures and be available for the duration of the study
• Able to clean their teeth with a manual toothbrush.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Advanced gum disease (such as active infection, loose teeth or severely receded
gums);
• Active treatment for advanced gum disease;
• Medical conditions such as those which require premedication prior to dental visits/procedures, chronic disease such as diabetes or use of medications that cause gum swelling chronic diseases;
• Untreated dental decay (cavities);
• History of allergic or other adverse reactions to milk or milk proteins;
• History of allergic or other adverse reactions to ingredients in sugar-free chewing gums such as artificial sweeteners;
• Pregnancy, plans to become pregnant during the study, or lactation;
• Existing dental work which prevents the potential participant wearing the appliance used in the study including orthodontic appliances and removable dentures;
• Treatment with antibiotics or anti-inflammatory medicines in the month prior to starting the study;
• Use of drugs that may interact with the gums tested in this project or which may affect salivary flow rate;
• History of health conditions requiring antibiotic coverage prior to dental treatment;
• Serious infectious disease;
• Any other diseases or conditions that might interfere with examination procedures or the participants safely completing the study;
• Any other medical or dental conditions deemed to put the health and well being of the participant or the research team at risk if the potential participant did participate in the study;
• History of allergic or adverse reactions to toothpaste or toothpaste ingredients;
• History of head and neck radiation treatment (radiotherapy).

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size calculation was performed using Minitab statistical software for an equivalence study using a 2 x 2 cross-over design (Minitab statistical software (version 19, Minitab, LLC: State College, PA)). The standard deviation for the percent remineralization (%R) in a previous chewing gum study was 1.7%. Assuming the standard deviation for each participant group is 1.7% in this proposed project, and the correlation between groups is 0.3, then the standard deviation of the mean difference in %R is 2%. Using an equivalence acceptance interval for %R = {-2.8%, +2.8%}, which is ±15% of the expected %R value, with an assumed within-subject standard deviation = 2% and an alpha value = 0.05, the required sample size was calculated as follows:
1) for a target power = 0.80, a sample size of 6 was calculated, with actual power = 0.88;
2) for a target power = 0.90, a sample size of 7 was calculated, with actual power = 0.93.
To allow for inaccuracy in estimation of the standard deviation and to allow for potential participant withdrawal, a sample size of 10 participants was deemed sufficient for the purposes of this project.

The microradiographs will be analyzed using image analysis software to measure the depth of the enamel lesions and the mineral content of the lesions. The percentage change in mineral content (%R) after chewing the gums will be calculated. The experimental unit will be the participant. All statistical tests will be two-sided and will employ a significance level of a = 0.05. Descriptive statistics (mean and standard deviation) will be calculated for all lesion parameters before and after chewing with each of the gums. A two-sided equivalence test for a two-period crossover trial will be performed on %R values after chewing the gums to determine whether the efficacies of the two chewing gums to remineralize enamel subsurface lesions are statistically equivalent using an equivalence acceptance interval of (-2%, +2%) for %R, an hypothesized mean difference in %R between after chewing the two gums = 0, power = 0.80 and a = 0.05.

Differences in mean values for initial lesion depth, initial mineral content and %R will also be assessed using repeated measures analysis of variance, which has been used to analyze data from similar projects in the past. This statistical test enables any variation in baseline lesion depth and mineral content to be accounted for when measuring change in lesion depth and both mineral content change and %R, respectively. Pairwise comparisons of the marginal means will be performed using a Sidak post hoc adjustment (Sokal and Rohlf, 1969). Assumptions for the statistical tests will be tested using Levene's test, normal probability plots and the Shapiro-Wilk test on the residuals.

All analyses will be using Stata statistical software (version 14, StataCorp: College Station, TX) or Minitab statistical software (version 19, Minitab, LLC: State College, PA).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
4/08/2021
Date of last participant enrolment
Anticipated
Actual
9/08/2021
Date of last data collection
Anticipated
26/11/2021
Actual
Sample size
Target
10
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 33731 0
3052 - Melbourne University

Funding & Sponsors
Funding source category [1] 301401 0
Self funded/Unfunded
Name [1] 301401 0
Country [1] 301401 0
Primary sponsor type
University
Name
The University of Melbourne
Address
Parkville Victoria 3010
Country
Australia
Secondary sponsor category [1] 310514 0
None
Name [1] 310514 0
Address [1] 310514 0
Country [1] 310514 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302136 0
STEMM 3 Committee Human Ethics University of Melbourne
Ethics committee address [1] 302136 0
Ethics committee country [1] 302136 0
Australia
Date submitted for ethics approval [1] 302136 0
03/05/2021
Approval date [1] 302136 0
03/08/2021
Ethics approval number [1] 302136 0
20842

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

Contacts
Principal investigator
Name 89246 0
Prof Eric C. Reynolds
Address 89246 0
Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052
Country 89246 0
Australia
Phone 89246 0
+61 3 9341 1547
Fax 89246 0
Email 89246 0
e.reynolds@unimelb.edu.au
Contact person for public queries
Name 89247 0
Eric C. Reynolds
Address 89247 0
Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052
Country 89247 0
Australia
Phone 89247 0
+61 3 9341 1547
Fax 89247 0
Email 89247 0
e.reynolds@unimelb.edu.au
Contact person for scientific queries
Name 89248 0
Eric C. Reynolds
Address 89248 0
Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052
Country 89248 0
Australia
Phone 89248 0
+61 3 9341 1547
Fax 89248 0
Email 89248 0
e.reynolds@unimelb.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
IPD data will not be available due to privacy concerns as this study involves only a small number of participants and the potential for data matching with previous studies conducted by the Institution.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11412Informed consent form    376547-(Uploaded-25-08-2021-17-32-25)-Study-related document.pdf
12995Ethical approval    376547-(Uploaded-25-08-2021-17-49-05)-Study-related document.pdf



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.