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Trial registered on ANZCTR

Registration number

ACTRN12621000591853

Ethics application status

Approved

Date submitted

18/03/2021

Date registered

18/05/2021

Date last updated

18/05/2021

Date data sharing statement initially provided

18/05/2021

Type of registration

Retrospectively registered

Titles & IDs

Public title

The effect of gels containing high concentrations of calcium with and without fluoride on the cosmetic appearance of white spots on tooth enamel and tooth sensitivity.

Scientific title

Concealment of white spot lesions in enamel and occlusion of dentinal tubules following topical application of gels containing high concentrations of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) with and without added fluoride in healthy adults, in situ.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1266-2731

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

dental caries

dentinal hypersensitivity

Condition category

Condition code

Oral and Gastrointestinal

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, four-way crossover design to assess the effects of topical application of two gels, one solution, and not applying either gel or solution, on the cosmetic appearance of white spot lesions on enamel surfaces (early enamel decay) and occlusion of open dentinal tubules in tooth root dentine, using an established intra-oral caries model.

Four 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 and two slabs of human dentine attached. The enamel and dentine slabs will be pre-sterilized. The enamel slabs will contain subsurface lesions created in the laboratory and the dentine slabs will have open tubules. The appliances will be fabricated under the direct supervision of a registered prosthetist/dental technician at the Royal Dental Hospital of Melbourne. Though participants were not recruited on the basis that they had participated in previous in situ studies, at least some of the participants had recently participated in an in situ study registered with the ANZCTR (ACTRN12620000747921) and all had participated in other studies not registered with the ANZCTR. A qualified dentist on the research team will ensure the appliance fits correctly one week prior to commencement of the first intervention in this project. The enamel and dentine slabs will be also be attached to the appliances by the research team one week prior to the first intervention in this project. Participants will wear the appliances for 24 hours a day over four 14 consecutive-day treatment periods (including weekends). At the end of each treatment period participants will rest from the study for one week before commencing the next treatment period. During the rest period, the research team will replace the slabs on the appliances with new pre-sterilized slabs.

One of four treatments will each be randomly allocated to one of the four treatment periods. For three treatments, a gel or solution will be applied to the surfaces of each slab on the appliance. For the fourth treatment nothing will be applied to the slabs. The three treatments applied to the slabs will be: 1) gel containing 60% (w/v) casein phosphopeptide-amorphous calcium phosphate and 1100 mg/L fluoride as stannous fluoride; 2) gel containing 60% (w/v) casein phosphopeptide-amorphous calcium phosphate but not containing stannous fluoride; 3) solution containing 1100 mg/L fluoride as stannous fluoride. The solution will be the positive control for the gels. The fourth treatment where neither gel nor solution is applied to the slabs on the appliance will be the negative control.

The gels will be prepared by the research team using distilled de-ionized water and will be slightly alkaline when prepared so will have a small amount of dilute hydrochloric acid added by the research team to bring the pH to 7.0. Therefore, the gels will contain a small concentration of chloride ions. The stannous fluoride solution will also be prepared by the research team using distilled de-ionized water. It will have a pH of approximately 4.0 and will not have its pH adjusted to 7.0 due to precipitation of stannous hydroxide ions when hydroxide ions are added so will only contain stannous fluoride in distilled de-ionized water.

For each of the three treatment periods a gel or the solution is allocated, once each weekday participants will present to the research department at the Melbourne Dental School and give their appliances to the research team who will paint one of the gels or the solution on the surface of each slab on the appliance and then heat the gel or solution on the slabs using a white light used in clinical dental practice to set white filling materials. This will all be done with the appliance out of participants' mouths. Once the gel or solution has cooled, the appliance will be returned to the participants for them to wear again. Each participant will wait approximately 10 to 15 minutes during each visit the gel or solution is applied to the slabs. During the treatment period that no gel or solution is applied to the slabs on the appliance, participants will not need to attend the research department at the Melbourne Dental School on those days. Participants will be instructed not to drink water with the appliance in their mouth within 40 minutes of the gel or solution being applied to the slabs. The research team will prepare the gels and solution every second day using distilled de-ionized water, will store the gels and the solution in a secure refrigerator in the research department, and will be experienced in painting and heating the gels and the solution on the slabs.

During each of the two weekends during the three treatment periods a gel or the solution is allocated, participants will paint their allocated gel or solution on the slabs at home once on Saturday and once on Sunday. They will be given tubes of their allocated gel or solution in tubes by the research team on the preceding Fridays and will be instructed to keep the tubes in a refrigerator at home when not being used. Once on each of the two weekend days, prior to painting their allocated gel or solution on the slabs, participants will remove a tube of gel or solution from their refrigerator and allow it to warm to room temperature. They will then remove their appliance, rinse it briefly with distilled de-ionized water (supplied), and then paint the gel or solution on the surface of the slabs as instructed by the research team but will not heat the gel or solution. All the gel or solution in the tube (no more than 1 mL) will be painted on the surface of the slabs by the participants each time using a small brush used in clinical dentistry to apply solutions or gels to teeth. After the gel or solution is painted on the slabs by the participants on weekends, participants will then insert their appliances into their mouths. As for weekdays, participants will be instructed not to drink water with the appliance in their mouth within 40 minutes of the gel or solution being applied to the slabs on weekends.

During the fourth treatment when neither gel nor solution is painted on the slabs, participants will wear their appliance in exactly the same way as they will wear their appliance during the other three treatment periods.

Participants will be randomly allocated to one of the four treatments during each treatment period and cross over to another treatment for the following treatment period. Each participant will complete all four 14-day treatment periods. The entire study period, including rest periods, will comprise a total of 11 weeks in total. The order of treatments allocated to each participant will be unknown to the researchers analyzing the results. Participants will not know the identities of the two gels.

During the treatment periods, participants will only leave their appliances out of their mouths when eating, drinking (except water), when brushing their teeth and cleaning their appliance twice a day as instructed, or when participating in sporting activities. Participants will brush their teeth with a standard fluoride toothpaste (supplied) twice daily. 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 the enamel and dentine slabs but will be instructed to rinse the slabs with distilled de-ionized water (supplied). When the appliances are removed they will be placed in snap-sealed bags (supplied) with several drops of distilled de-ionized water (supplied) to prevent them drying. Participants will be asked to not use any toothpaste other than the standard fluoride toothpaste given to them by the research team and will be asked to refrain from using any mouthrinses for the duration of the study. Participants will otherwise maintain normal dietary and oral hygiene practices during the study 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 remove the appliance and, if applicable to that treatment period, when the gel or solution is painted on the slabs on their appliance. 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.

Following the initial screening dental examination, participants will be examined eight times by a qualified dentist on the research team over the course of the study period. These will comprise four dental examinations at the start of each treatment period and four dental examinations at the completion of each treatment period. These examinations, will be conducted to ensure no dental caries or periodontal disease is present. Again, no radiographs will be taken during any of these examinations. After the final dental examination at the end of fourth treatment period, participants will be given the option of having a standard fluoride treatment (fluoride gel in trays) administered by the qualified dentist.

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

Intervention code [1]

Treatment: Other

Comparator / control treatment

There will be a positive control solution and a negative control treatment.

The positive (active) control will be a solution of stannous fluoride containing 1100 parts per million fluoride in distilled de-ionized water. This pH of this solution will be approximately 4.0 and will not be adjusted to be the same as the pH of the two gels (pH 7.0) as adding hydroxide ions to this solution leads to precipitation of stannous hydroxide; therefore, no other chemicals other than stannous fluoride will be present in this solution.

The negative control treatment will be a no gel/solution treatment, which will involve nothing being painted on the slabs but participants just wearing the appliance in exactly the same way as for the other three treatments. There will not be a placebo gel or solution (not containing active ingredients) included as a negative control

Each participant will also act as his/her own control as they will each crossover to each of the four treatments.

Control group

Active

Outcomes

Primary outcome [1]

Change in the colour of or concealment of white spot lesions on tooth enamel surfaces using image analysis of standardised photographs.

Timepoint [1]

Each white spot lesion will be photographed before each two-week treatment period commences and immediately upon completion of that two-week treatment period.

Primary outcome [2]

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 [2]

Sections of each white spot lesion, with its matched control lesion, will be radiographed approximately two weeks after completion of each two-week treatment period.

Primary outcome [3]

Occlusion of dentinal tubules following the experiment. A scanning electron microscope will be used to scan the surfaces of dentine slabs that were attached to the appliances and their control paired untreated dentine slabs that were not attached to the appliance but stored in a humid environment during the study period.

Timepoint [3]

Slabs of dentine with treated white spot lesions and their matched untreated control slabs for all four treatments will be assessed approximately two weeks after completion of the fourth (last) treatment period.

Secondary outcome [1]

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]

Sections of each white spot lesion, with its matched control lesion, will be radiographed approximately two weeks after completion of each two-week treatment 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;
• 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

1) Advanced gum disease (such as active infection, loose teeth or severely receded
gums);
2) Active treatment for advanced gum disease;
3) 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;
4) Untreated dental decay (cavities);
5) History of allergic or other adverse reactions to milk or milk proteins;
6) History of allergic or other adverse reactions to tin or tin-containing products;
7) Pregnancy, plans to become pregnant during the study, or lactation;
8) Existing dental work which prevents the potential participant wearing the appliance used in the study including orthodontic appliances and removable dentures;
9) Treatment with antibiotics or anti-inflammatory medicines in the month prior to starting the study;
10) Use of drugs that may interact with the gels or the solution tested in this project or which may affect salivary flow rate;
11) History of health conditions requiring antibiotic coverage prior to dental treatment;
12) Serious infectious disease;
13) Any other diseases or conditions that might interfere with examination procedures or the participants safely completing the study;
14) 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;
15) History of allergic or adverse reactions to toothpaste or toothpaste ingredients;
16) 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)

Allocation is not concealed.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomization using a randomization table created by a random number generator.

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 required sample size was calculated using a repeated measured ANOVA model with GPower 3.1 (Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175-191.) using estimates from previous studies and predicted amounts of repair following use of the gels. Assuming a 90% probability of detecting a true significant difference between the effects of the four treatments and, conversely, a 5% probability of falsely detecting a difference with correlation coefficient of 0.7 and a nonsphericity correction of 0.5, an effect size of 2.89 was calculated and a sample size of three was calculated. To compensate for errors in estimates of the standard deviations and potential participant attrition, a sample size of four was deemed sufficient for the purposes of this study.

The experimental unit will be the participant. Standardized photographs of the enamel lesions before and after the four treatments will be taken and changes in colour of the white spots will be analysed using imaging software. Measurements of changes in the mineral content of the white spots will be determined in the enamel slabs in the appliance worn by each participant over each treatment period by analysing x-rays of the slabs. Changes in the depth of the white spot lesion, mineral content change and percent mineral content change in the white spot lesions after the four treatments will be calculated by comparing x-rays of lesions after treatment with their paired control lesions and the results averaged for each treatment period for each participant.

Descriptive statistics (mean and standard deviation) will be calculated for all outcome measures and tabulated by treatment. The data for change in colour of the lesions, change in mineral content (percent remineralization) and lesion depth will be analysed using a linear mixed modelling approach for a crossover design. All statistical tests will be two-sided and will employ a significance level of a = 0.05. All analyses will be performed using either SPSS (IBM Corporation. Armonk NY, USA) or Stata (StataCorp LP, College Station, TX, USA) statistical software.

Occlusion of dentinal tubules on treated dentine slabs and their paired untreated slabs will be assessed visually from images obtained using a scanning electron microscope.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

Actual

8/03/2021

Date of last participant enrolment

Anticipated

Actual

1/04/2021

Date of last data collection

Anticipated

3/08/2021

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment postcode(s) [1]

3052 - Melbourne University

Funding & Sponsors

Funding source category [1]

Other

Name [1]

University of Melbourne Centre for Oral Health Research

Address [1]

Melbourne Dental School
720 Swanston Street Carlton VIC 3052

Country [1]

Australia

Primary sponsor type

University

Name

The University of Melbourne

Address

Parkville Vic 3010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Melbourne Human Ethics, Science, Technology, Engineering, Mathematics, and Medicine (STEMM) 1 Committee

Ethics committee address [1]

Office of Research Ethics and Integrity
Research, Innovation & Commercialisation
Level 5, Alan Gilbert Building, 161 Barry Street, Carlton
The University of Melbourne, Victoria 3010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/07/2020

Approval date [1]

20/10/2020

Ethics approval number [1]

14357

Summary

Brief summary

This project will compare the change in colour or concealment of unsightly white spots (early decay) on human tooth enamel and closure of open microscopic holes (tubules) in human tooth roots (dentine), which can relieve tooth root sensitivity, after application of either: 1) gel containing the major milk protein casein, calcium and tin fluoride; 2) gel containing casein and calcium without fluoride; 3) solution containing tin fluoride; 4) no gel or solution, to the surfaces of enamel white spots and open dentine tubules. To test these treatments, pieces of pre-sterilized human enamel with white spots and root dentine with open tubules will be attached to custom-made removable denture-like appliances that will be worn by four human participants for 24 hours a day for each of four 14-consecutive day treatment periods, with a different treatment allocated to each period. Each treatment period will be separated by a one-week washout period when the participants will rest from the study while new pieces of enamel and dentine are attached to their appliances before they cross-over to another treatment. For three treatment periods, a different gel or the solution will be painted on the pieces of enamel and dentine, with the appliance out of the mouth, by the research team once daily on weekdays and by the participants once daily on weekends. Participants will only wear their appliance for the fourth treatment. The order of treatments will be random. The hypothesis is that the gel containing casein and calcium with or without tin fluoride will change the colour of or conceal the white spots and close the dentine tubules more effectively than the other treatments.

Trial website

Trial related presentations / publications

Public notes

Screening
Before being eligible to participate, potential participants will be screened to ensure they fulfill all inclusion criteria. Participants will fill in a medical questionnaire and have their mouths examined by a qualified dentist on the research team to identify dental caries and periodontal disease by visual inspection and gentle probing. No intra-oral radiographs will be taken. In addition, potential participants will each provide two 2-minute saliva samples allowing saliva accumulating in their mouths to flow into a sterile tube. One sample will be collected at rest and the other while chewing sugar-free gum.

Although ethics approval had originally been obtained on 20/10/2020 prior to the first participant being recruited, there were two amendments to the project that needed to approved. Final ethics approval for these amendments was obtained on 12/03/2021, four days after recruitment of the first participant. The amendments were necessary to strengthen the project and are described as follows. The project was originally designed to test three different gels. It was amended to test two gels, a solution, and a no-gel or solution treatment..Therefore, four instead of three treatment were tested. The solution was included as the positive control for the two gels and the no gel/solution treatment was included as the negative control for the gels. The other amendment was to expand the pool of potential participants to include anyone interested in participating in the project and not just staff and students of the Melbourne Dental School and Melbourne Dental Clinic. The reason for this change was to potentially provide a wider and potentially less skewed cross-section of potential participants from which to recruit.

Contacts

Principal investigator

Name

Prof Eric C. Reynolds

Address

Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052

Country

Australia

Phone

+61 3 9341 1547

Fax

e.reynolds@unimelb.edu.au

Contact person for public queries

Name

Eric C. Reynolds

Address

Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052

Country

Australia

Phone

+61 3 9341 1547

Fax

e.reynolds@unimelb.edu.au

Contact person for scientific queries

Name

Eric C. Reynolds

Address

Melbourne Dental School University of Melbourne Level 6 720 Swanston Street Carlton, Victoria 3052

Country

Australia

Phone

+61 3 9341 1547

Fax

e.reynolds@unimelb.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.	Type	Citation	Link	Email	Other Details	Attachment
11055	Informed consent form					381613-(Uploaded-17-03-2021-16-05-13)-Study-related document.pdf
11056	Ethical approval					381613-(Uploaded-17-03-2021-16-05-40)-Study-related document.pdf

Results publications and other study-related documents

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No additional documents have been identified.

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