Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000747921
Ethics application status
Approved
Date submitted
23/05/2020
Date registered
21/07/2020
Date last updated
21/07/2020
Date data sharing statement initially provided
21/07/2020
Date results information initially provided
21/07/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
The abilities of different toothpastes to prevent and repair early tooth decay.
Scientific title
Evaluation of Efficacy of Experimental Dentrifice Formulations with Different Forms of Fluoride and/or Other Agents to Remineralize Enamel and Dentine Subsurface Lesions in Healthy Adults: a Double-Blind Randomized In Situ Clinical Trial
Secondary ID [1] 301354 0
Nil Known
Universal Trial Number (UTN)
U1111-1252-5399
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dental Caries 317573 0
Condition category
Condition code
Oral and Gastrointestinal 315660 315660 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Public Health 315835 315835 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This randomized controlled study will use a double-blind, five-way crossover design to assess the effects of rinsing with five dentifrice formulations on the promotion of enamel and dentine remineralization and/or preventing enamel and dentine demineralization, using an established intra-oral caries model.

Ten human volunteers will be selected from staff and students of the Melbourne Dental School, University of Melbourne 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 and contain subsurface lesions created in the laboratory. Participants will wear the appliances for 24 hours a day over five 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.

During each treatment period participants will rinse with a sucrose solution and then a slurry of one of five dentrifices four times a day while they are wearing their appliances.
Five different dentifrice formulations containing widely-used, commercially-available ingredients will be tested. Two dentifrices will act as controls; one positive control will be a commercially available fluoride dentifrice and the other negative control will be identical to the first control except it will not contain fluoride (the active ingredient). The active ingredient in the positive control will be 1100 parts per million fluoride as sodium fluoride (0.243% sodium fluoride). There will also be three experimental dentifrice formulations with only one of these (experimental formulation 1) containing an active ingredient (sodium monofluorophosphate). Ingredients in the other two experimental formulations are widely-used excipients and not actives. Experimental formulation 1 will contain 1500 parts per million fluoride as sodium monofluorophosphate (1.14% (w/v) sodium monofluorophosphate) as the active agent. The other two experimental dentifrice formulations will not contain fluoride and will act as placebos for the experimental dentifrice formulation containing sodium monofluorophosphate. These two experimental dentrifice formulations (Experimental formulation 2 and Experimental formulation 3) do not contain active ingredients but only excipients. Experimental formulation 2 will contain 1% (w/v) Betaine (derived from coconut oil), which is an excipient and not an active. Betaine is an alternative and milder detergent than sodium lauryl sulphate usually used in toothpaste. Experimental formulation 3, the other placebo, will not contain Betaine but will contain the detergent sodium lauryl sulphate instead (also an excipient and not an active).

Participants will be randomly allocated to one of the dentrifice slurries during each treatment period and cross over to another dentrifice slurry for the following treatment period. Each participant will rinse with all five dentrifice slurries over the study period. Therefore, participants will complete five 14-day treatment periods each separated by a one-week washout period during which the participants will rest from the study. The entire study period will comprise a total of 14 weeks in total.

Tubes containing 5 mL of 10% sucrose and tubes containing 5 mL of dentrifice slurry both diluted in distilled de-ionized water and prepared by the research team, will be given to the participants by the research team. The sucrose solutions will also be filtered by the research team prior to being dispensed. The dentrifice slurries will be prepared by diluting 1 gram of dentrifice in 4 mL of distilled de-ionized water. Four times a day on each day of each treatment period, when wearing their appliances, participants will rinse with the sucrose solutions and dentrifice slurries as follows. At 9:30 am, 11:00 am, 1:30 pm and 3:30 pm, participants will rinse with all 5 mL of the sucrose solution in one of the tubes for 60 seconds. Participants will then expectorate the sucrose solution and then, 40 minutes later (at 10:10 am, 11:40 am, 2:10 pm and 4:10 pm), they will shake a tube containing their allocated dentrifice slurry and immediately rinse with all 5 mL of the slurry for 60 seconds. They will then expectorate the slurry and continue wearing their appliance. On weekdays, the solutions and slurries will be stored at room temperature. On weekends, the solutions and slurries will be stored in a refrigerator at home and participants will be instructed to allow the solutions and slurries to warm to room temperature prior to rinsing.

During the treatment periods, participants will only leave their appliances out of their mouths when eating, drinking (except water), and when brushing their teeth and cleaning their appliance twice a day as instructed. 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 or rinsing the troughs holding the enamel and dentine slabs. 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 fluoride toothpaste given to them by the research team and will be asked to refrain from using any mouthrinses (other than the sucrose solutions and allocated dentrifice slurries at the specified times) for the duration of the study. They will also be instructed to refrain from consuming antibacterial mints or lozenges or chewing any gum products during the entire study period. Participants will otherwise maintain normal dietary and oral hygiene practices during the study period.

Participants will also provide 15 post-rinse saliva samples during the study by expectorating the dentrifice slurry and accumulated saliva immediately after one of the rinses with the slurries on three different weekdays during each treatment 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 rinse with the sucrose solutions and dentrifice slurries. 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.

Following the initial screening dental examination, participants will be examined ten times by a qualified dentist on the research team over the course of the study period. These will comprise five dental examinations at the start of each treatment period and five 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 final 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] 317652 0
Treatment: Other
Comparator / control treatment
There will be a positive control dentrifice and a negative control dentrifice. The positive (active) control will be a commercially-available dentrifice containing 1100 parts per million fluoride as sodium fluoride. The negative control will be a dentrifice containing the same ingredients as the positive control but will not contain fluoride. The negative control dentrifice will contain sorbitol, water, hydrated silica, sodium lauryl sulphate, trisodium phosphate, sodium phosphate, cellulose gum, flavor, sodium saccharin, Carbomer 956, mica, titanium dioxide and Blue 1. Each participant will act as his/her own control as they will each rinse with all five dentrifice slurries.
Control group
Active

Outcomes
Primary outcome [1] 323897 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.
Timepoint [1] 323897 0
This outcome will be assessed at the end of each treatment period. As the radiographs will include images of lesions from the same enamel that is attached to the appliances but not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each treatment period.
Secondary outcome [1] 383239 0
Percent remineralization of dentine 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 dentine 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.
Timepoint [1] 383239 0
This outcome will be assessed at the end of each treatment period. As the radiographs will include images of lesions from the same dentine that is attached to the appliances but not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each treatment period.
Secondary outcome [2] 383240 0
Change in the mineral content of enamel and dentine subsurface lesions from baseline to that following treatment. This is a composite secondary outcome. Mineral content will be measured by analysing images of transverse microradiographs of enamel and dentine 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.
Timepoint [2] 383240 0
This outcome will be assessed at the end of each treatment period. As the radiographs will include images of lesions from the same enamel and dentine that is attached to the appliances but not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each treatment period.
Secondary outcome [3] 383242 0
Change in the depth of enamel and dentine subsurface lesions from baseline to that following treatment. This a composite secondary outcome. Lesion depth will be measured by analysing images of transverse microradiographs of enamel and dentine lesions. A microradiography unit will be employed to take the radiographs and scans of the radiographic images of the lesions will enable the depth of each lesion to be calculated.
Timepoint [3] 383242 0
This outcome will be assessed at the end of each treatment period. As the radiographs will include images of lesions from the same enamel and dentine that is attached to the appliances but not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each treatment period.
Secondary outcome [4] 383275 0
Occlusion of dentinal tubules following the experiment. A scanning electron microscope will be used to scan the surfaces of dentine surfaces that were attached to the appliances and control dentine that was not exposed.
Timepoint [4] 383275 0
This outcome will be assessed at the end of each treatment period. As the dentine surfaces that were exposed to the dentrifice formulations will be scanned with their matched dentine surfaces not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each treatment period.
Secondary outcome [5] 383276 0
Distribution of chemical elements within the enamel and dentine lesions following the experiment. This will be investigated using a scanning electron microscope with energy-dispersive X-ray spectroscopy.
Timepoint [5] 383276 0
This outcome will be assessed at the end of each treatment period. As the enamel and dentine surfaces that were exposed to the dentrifice formulations will be scanned with their matched enamel and dentine surfaces not exposed to the dentrifice formulations, this outcome measure will not be assessed at the beginning of each 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;
• 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 time;
• Be willing to refrain from using non-study dentifrice, mouth rinse, chewing gum, and other non-study oral care products during the study;
• Be willing to postpone all elective dental procedures until the study has been completed;
• Be willing to refrain from chewing gums while using the test products;
• 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.
• Only staff and students of the Melbourne Dental School, University of Melbourne will be eligible to participate.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Advanced periodontal disease, as characterized by purulent exudate, generalized mobility, and/or severe recession;
• Active treatment for periodontitis;
• Medical condition which requires premedication prior to dental visits/procedures;
• Untreated dental caries (e.g. cavities);
• Self-reported pregnancy or plans to become pregnant during the study;
• Existing dental work which prevents wearing of the appliance including orthodontic appliances or removable dentures;
• Chronic disease such as diabetes or use of medications that cause gum swelling;
• Any diseases or conditions (including sensitivity to dentifrice ingredients) that might interfere with examination procedures or the participant safely completing the study;
• Treatment with antibiotics or anti-inflammatory medicines in the month prior to starting the study;
• Use of drugs that may interact with the dentrifice slurries or which may affect salivary flow rate;
• History of health conditions requiring antibiotic coverage prior to dental treatment;
• Serious infectious disease;
• Any other medical or dental conditions deemed to put the health and well being of the participant or research team at risk if the potential participant participated in the study.

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 not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to one of ten treatment sequences according to a computer-generated randomization plan. These sequences are based on the size 5 Williams (1949) design and ensures that each experimental product will follow the other experimental products the same number of times, thus allowing any carry-over effects to be balanced.
The site will keep the Treatment Sequence Schedule while the study is on-going. Should a subject miss a treatment period, that treatment in the sequence will be skipped .
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
Safety/efficacy
Statistical methods / analysis
Descriptive statistics (mean, standard deviation and range) will be calculated for all continuous variables and frequencies for all discrete variables. All statistical tests will be two-sided and employ a significance level of alpha equal to 0.05. All analyses will be performed using either SPSS (IBM Corporation. Armonk NY, USA), Stata (StataCorp LP, College Station, TX, USA) statistical software or SAS .

The unit of analysis will be the participant. Measurements will be determined for the demineralized and remineralized/treated enamel and dentine lesions and the results will then be averaged to obtain an outcome measure 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 all outcome measures (percent remineralization, mineral loss or gain, and lesion depth change) will be analyzed using a linear mixed modelling approach for a crossover design. Treatment and period will be included in the model as fixed effects and subject will be a random effect. Carryover effects will also be assessed and eliminated from the final model if the p-value is greater than 0.1. For the absolute loss/gain measures, the values of the responses prior to treatment (initial mineral content or initial lesion depth) might be used as covariates for their respective analyses.

No adjustment will be made for multiple comparison tests. Assumption of normality of residuals will be checked using normal probability plots and the Shapiro-Wilk test and assumption of homogeneity of variance will be tested on the residuals using Levene’s test.

The incidences of adverse events will be compared between the five treatment groups. The safety analysis population will include all participants who received any of the test dentrifices and who have follow-up data.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
22/05/2020
Date of last participant enrolment
Anticipated
Actual
25/06/2020
Date of last data collection
Anticipated
31/12/2020
Actual
Sample size
Target
10
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 30362 0
3010 - University Of Melbourne

Funding & Sponsors
Funding source category [1] 305794 0
Commercial sector/Industry
Name [1] 305794 0
The Procter & Gamble Company
Country [1] 305794 0
United States of America
Primary sponsor type
University
Name
The University of Melbourne
Address
Parkville, Victoria 3010
Country
Australia
Secondary sponsor category [1] 306232 0
None
Name [1] 306232 0
Address [1] 306232 0
Country [1] 306232 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306065 0
University of Melbourne Medicine and Dentistry Human Ethics Sub-Committee
Ethics committee address [1] 306065 0
Office of Research Ethics & Integrity
Level 5, 161 Barry Street
The University of Melbourne
VIC 3010
Ethics committee country [1] 306065 0
Australia
Date submitted for ethics approval [1] 306065 0
22/01/2020
Approval date [1] 306065 0
22/04/2020
Ethics approval number [1] 306065 0
1955501

Summary
Brief summary
The purpose of this study is the investigate the abilities of five toothpastes, three of which will be experimental formulations, to prevent and repair tooth decay. It is hypothesized that some of the experimental formulations will be more effective in preventing decay and repairing early decay. Volunteers will will wear custom-made removable denture-like appliances with sterilized human tooth slabs attached for 24 hours a day except when eating, drinking and cleaning their teeth and their appliance for five 14-consecutive day treatment periods. During each treatment period they will rinse with a sugar solution and a slurry of one of the five toothpastes each for one minute four times a day while wearing the appliance. They will rest for a week between each 14-day treatment period and will rinse with a different toothpaste slurry and with new tooth slabs attached to their appliances during each treatment period.
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.

Contacts
Principal investigator
Name 102574 0
Prof Eric C. Reynolds
Address 102574 0
Melbourne Dental School
The University of Melbourne
720 Swanston Street
Melbourne, Victoria 3010
Australia
Country 102574 0
Australia
Phone 102574 0
+61 3 9341 1547
Fax 102574 0
Email 102574 0
[email protected]
Contact person for public queries
Name 102575 0
Prof Eric C. Reynolds
Address 102575 0
Melbourne Dental School
The University of Melbourne
720 Swanston Street
Melbourne, Victoria 3010
Australia
Country 102575 0
Australia
Phone 102575 0
+61 3 9341 1547
Fax 102575 0
Email 102575 0
[email protected]
Contact person for scientific queries
Name 102576 0
Prof Eric C. Reynolds
Address 102576 0
Melbourne Dental School
The University of Melbourne
720 Swanston Street
Melbourne, Victoria 3010
Australia
Country 102576 0
Australia
Phone 102576 0
+61 3 9341 1547
Fax 102576 0
Email 102576 0
[email protected]

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
8057Informed consent form    379879-(Uploaded-23-05-2020-21-04-59)-Study-related document.docx
8058Ethical approval    379879-(Uploaded-23-05-2020-21-05-33)-Study-related document.pdf



Results publications and other study-related documents

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