This is a randomised, double-blind, active-controlled clinical trial. The design and report of this protocol follow the Standard Protocol Items: Recommendations for Interventional Trials statement (Appendix 1) . The schedule of this study is shown in Fig. 1.
This trial will be conducted in kindergartens in Hong Kong. The objectives and procedures of this study will be explained to the kindergarten headmasters. After their confirmation is received, an invitation letter and informed consent form will be sent to the parents of eligible children (Appendix 2). The written consent will be collected from the parents before the trial takes place.
All first-year children from the participating kindergartens will be invited to take part in the study. The inclusion criteria will be children who are aged 3 to 4 years old and those who are generally healthy. Children will be excluded from this study if they are uncooperative with dental procedures; suffer from major systemic diseases; receive long-term medications; have abnormal dentition, such as amelogenesis imperfect; or have tooth anomalies, such as double teeth.
Baseline and follow-up dental examinations
Baseline and follow-up dental examinations will be conducted in an outreach setting in the participating kindergartens. World Health Organization Community Periodontal Index (CPI) probes (405/WHO probe, Otto Leibinger, Mühlheim, Germany) and light-emitting diode intra-oral illuminations attached to disposable dental mirrors (MirrorLite, Kudos Crown Limited, Hong Kong, China) will be used in the examinations.
A trained dentist will perform dental examinations using visual inspection. No radiography will be taken. The six upper anterior teeth of each child will be studied carefully. The child’s caries status will be evaluated after the tooth surfaces are cleaned and dried with a gauze sponge. All of the surfaces of the six upper anterior teeth will be diagnosed as sound or carious (active or arrested). Surfaces that are free of caries will be recorded as sound. Surfaces with cavitated lesions will be deemed carious. The carious lesions will be explored gently in the lesion’s centre using a CPI probe. If a carious lesion is soft upon gentle probing, it will be diagnosed as active. Meanwhile, if a carious lesion is hard upon gentle probing, it will be diagnosed as arrested [12, 14].
Apart from the six upper anterior teeth, the child’s caries experience at the tooth level will be assessed using the decayed, missing (due to caries) and filled primary tooth (dmft) index. Other dentition problems, such as hyper-mobility, tooth discoloration, abscess and fistula, will be recorded as well. The visible plaque index (VPI) will be used to measure the child’s oral hygiene status . The presence of visible plaque on the buccal and lingual surfaces of six index teeth (55, 51, 63, 71, 75 and 83) will be examined. A single examiner will conduct the baseline and 12-month follow-up dental examinations using the same diagnostic criteria, equipment and procedure. Duplicate tests in 10% of the children regarding caries diagnosis will be conducted at both stages of the study to assess the intra-examiner reliability.
The two intervention groups are the 38% SDF solution group (Advantage Arrest, Elevate Oral Care, FL, USA) and the 5% NaF varnish group (Duraphat Varnish, Colgate-Palmolive, NY, USA). No placebo-controlled group will be used in this study due to ethical concerns. An independent operator will use micro-brushes (MICROBRUSH, Grafton, WI, USA) to apply the fluoride therapies according to the assigned intervention group on all surfaces of the six upper anterior teeth at baseline. The children will not be allowed to drink or eat for half an hour after the fluoride therapies. Because a dentist is completing this one-off intervention, no special criteria for modifying or discontinuing the intervention, improving the adherence and monitoring the adherence will be issued. Implementing fluoride therapies will not require any alterations to the children’s usual dental care.
Randomisation, intervention allocation and allocation concealment
This study will use the stratified randomisation method for intervention allocation. The enrolled children will first be classified into two strata: i) low caries risk – having no caries experience (dmft = 0), or ii) high caries risk – having caries experience (dmft > 0). Children in each stratum will be randomly allocated to two intervention groups using a computer-generated random number with a block size of eight. A research assistant will keep the random number sheet. The allocation sequence will be sealed in opaque envelopes.
The examiner, the participating children and their parents will not know the intervention allocation throughout the whole study. The blinding will be permissible only when the parents request their children’s treatment histories. The research assistant working with the intervention allocation will disclose the treatment group to the parents. Then, these children will be excluded from this trial.
Caries-preventive and caries-arresting effect
The caries-preventive effect will be determined based on the number of carious surfaces developed in the six anterior upper teeth at the 12-month follow-up. The caries-arresting effect will be determined based on the number of arrested carious surfaces in the six anterior upper teeth at the 12-month follow-up.
An independent examiner will pay another visit to each kindergarten one day after the baseline dental examination and fluoride therapy. The presence of any short-term adverse effects in the hard and soft tissues in the oral cavity will be recorded. At the 12-month follow-up, the examiner will determine the presence of any long-term adverse effects. In addition, the investigator’s contact will be left with the parents. If the parents have any concern or notice adverse effects, they can reach the investigators at their own convenience. Follow-ups will be provided on a case-by-case base.
Children’s and parents’ acceptance
At baseline, an independent research assistant will observe the child’s reaction during the dental examination and fluoride therapy. The child’s acceptance of the dental procedures will be measured using interval rating scales for children’s uncooperative behaviour . Their behaviour will be classified as follows:
0 – Total cooperation, best possible working conditions, no crying or physical protest.
1 – Mild, soft verbal protest or (quiet) crying as a signal of discomfort, but does not obstruct progress. Appropriate behaviour for procedure.
2 – Protest more prominent. Both crying and hand signals. May move hand around, thus making it hard to administer treatment. Protest more distracting and troublesome. However, child still complies with request to cooperate.
3 – Protest presents real problem for dentist. Complies with demands reluctantly, requiring extra effort by dentist. Body movement.
4 – Protest disrupts procedure, requires that all of the dentist’s attention be directed towards the child’s behaviour. Compliance eventually achieved after considerable effort by dentist, but without much actual physical restraint. (May require holding child’s hands, or the like, to start.) More prominent body movement.
5 – General protest: no compliance or cooperation. Physical restraint is required.
It is not noteworthy that the children classified as level 5 will be excluded from this study.
A parental questionnaire asking about the parents’ satisfaction levels and concerns about the fluoride therapies will be distributed at the 12-month follow-up to assess parents’ acceptance of the fluoride therapies.
Children’s oral hygiene behaviours (e.g., tooth brushing), use of fluoride products (e.g., toothpaste), diet behaviours (e.g., bottle feeding and snacking habits), dental visit behaviours and demographic backgrounds (e.g., parental educational level and monthly family incomes) will be collected through a parental questionnaire administered at baseline.
Sample size calculation
The data utilised for the sample size calculation is from a previous study conducted in Hong Kong . The mean number of decayed teeth of 3-year-old children was 5. The mean numbers of newly developed carious surfaces in SDF and NaF groups were 0.47 (SD 0.87) and 0.70 (SD 0.84), respectively. The difference in the preventive effects between the two groups was 33%. When the statistical power was set at 0.9 and the type I error was set at 5%, 292 children were required in each group. With the dropout rate estimated at 15%, 688 children should be enrolled at baseline, with 344 children in each group.
An experienced statistician will oversee the data handling procedures. Two research assistants will enter the data into a Microsoft Excel file independently (double entry). The two datasets will be compared to identify errors. This study will adopt an intention-to-treat analysis. If the quantities of children who withdraw from the study significantly differ between the two intervention groups at the 12-month follow-up, a per-protocol analysis will be conducted. In this case, only the children who have completed the entire trial will be counted in the results. The statistical software products of SPSS for Windows (IBM Corporation, USA) and SAS for Windows (SAS Institute Inc., USA) will be used for the data analyses. The intra-examiner reliability of caries diagnoses will be assessed using Cohen’s Kappa statistics at baseline and the 12-month follow-up. The results at both the subject level and the tooth surface level will be analysed. The statistical significance level will be set at 0.05 for two-sided tests.
Chi-square tests will be performed to study the between-group differences in the proportion of children with new caries development (subject level) and in the proportion of tooth surfaces with new cavitations (tooth surface level). T-tests will be conducted to study the between-group differences in the mean number of newly developed carious surfaces, the number of arrested carious surfaces, the dmft index, and the numbers of non-vital teeth and hyper-mobile teeth at the 12-month follow-up. Descriptive analysis will be used to study the adverse effects as well as the children’s and parents’ acceptance of the fluoride therapies. In addition, this study will explore whether patient characteristics affect the treatment effects (effect modification). Independent variables, such as demographic background, dental hygiene practices and other clinical parameters that may modify the outcome variables, will be studied. Because the outcome variables may not be normally distributed, the Poisson model or negative binomial regression model will be considered to investigate the effect modification .
Ethical approval has been obtained from the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW20-397). A written consent form will be collected from the parents or guardians of each child. All of the participating children have the right to withdraw from this trial at any time for any reason by informing the investigators of their children to do so. Withdrawal from this trial will not influence the children’s right to receive other dental services from the Faculty of Dentistry of The University of Hong Kong. Because the clinical procedures performed in this study will be simple and non-invasive, this study will cause minimal risk to the participants. Moreover, professional training sessions will be provided to the field investigators to further minimise the risk. If one life-threatening case appears, or if more than 30% of the children present severe systemic side effects, the study will be stopped. All of the data and related information will be kept in a personal computer confidentially. Only the investigators will have the authority to assess the dataset.