This clinical trial was submitted to and approved by the Research Ethics Committee of Bauru School of Dentistry under CAAE number 14958719.5.0000.5417 and was registered in the clinical studies database (Brazilian Registry of Clinical Trials Universal Trial Number U1111-1237-6720). This protocol follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) guidelines for randomized trials of nonpharmacological treatments [26].

Participants will be included after their parents or guardians have signed an informed consent form containing detailed information about the research. The children will receive an assent term, with age-appropriate language, explaining how the research will be conducted and that they will be free to accept or reject participation in the study. Participant confidentiality will be guaranteed, and only researchers will have access to the data. At the end of the study, the researchers are committed to offering treatment with the product that demonstrates the best result, regardless of which experimental group the child was in.

This is a double-blind randomized controlled clinical study, conducted with three parallel groups, with a duration of 6 months (Figure 1). The participants and their parents/guardians, as well as the examiners, will not be aware of the group allocation of any patients.

Examiner calibration will be performed using 35 original photographs of teeth with MIH with different degrees of severity and other developmental enamel defects. The photographs will be evaluated based on the MIH index [27]. All photographs will be reevaluated by the two examiners after 15 days to assess inter- and intraexaminer agreement (κ>0.85).

The study participants will be selected from the city of Bauru, São Paulo, Brazil, which has a population of 371,690 inhabitants and a Human Development Index of 0.801. Participants aged 6-10 years will be selected from an epidemiological survey in municipal schools. These schools are located in an urban area, in different zones (north, south, east, and west), and will be selected by a draw according to each zone. In the selected schools, all children aged 6-10 years will be evaluated. Children with potential for inclusion in the research will be referred for a clinical examination at the pediatric dentistry clinic of Bauru School of Dentistry, University of São Paulo, and those that have at least one first permanent molar affected by MIH with hypersensitivity complaint and without loss of structure will be invited to participate. The sensitivity complaint will be confirmed by applying a 1-second air jet at a distance of 1 centimeter from the occlusal surface of the tooth; a score of 2 or 3 on the Schiff Cold Air Sensitivity Scale (SCASS) will be considered as a positive result. Patients with orthodontic appliances, syndromes that involve enamel malformation, or behavioral problems during the clinical examination will be excluded.

The sample size was calculated considering analysis of variance, performed in SigmaPlot (version 12.3; SPSS Inc), and it was considered a minimally detectable difference of 1 on the SCASS scores between groups. A standard deviation of 0.9 was used based on a previous study [28], α error was 5%, β error was 20%, and a dropout rate of 18% was used, which resulted in a total of 60 children (20 per group). The first 60 children who meet the inclusion criteria will be selected to be part of the study, while others who also present with sensitivity but cannot be included will receive the necessary treatment.

Recruitment will take place from October 2019 to December 2021. After allocation and treatment for 4 weeks, the patients will be followed up for 6 months.

The included patients will be allocated to one of the 3 treatment options by stratified block randomization: (1) the control group (sodium fluoride varnish; Duraphat, Colgate), (2) experimental group I (4% TiF₄), and (3) experimental group II (S-PRG resin coating; PRG Barrier Coat, Shofu). The randomization sequence will be generated using Microsoft Excel 365 (Microsoft Corp) by an examiner who will not be involved in any of the clinical trial phases. To ensure allocation concealment, the randomly generated sequence will be sealed in opaque envelopes that will be opened only after the child is ready to receive treatment. The randomization procedure will be done per block of 3 children with the same SCASS scores to guarantee similar scores among groups at baseline.

The analysis unit will be the child and will be considered one tooth per child. If more than one permanent first molar has the condition, all will undergo the same treatment so that there is no interference from different treatments and other factors such as saliva, and one tooth will be selected by a draw to be included in the data analysis. The order of treatment among affected teeth in a patient will also be defined by a draw.

All children will receive instructions on noncariogenic diet and oral hygiene. Furthermore, the participants will receive an oral hygiene kit with toothbrush and fluoride toothpaste (both Colgate-Palmolive Company). Immediately before treatment, a supervised toothbrushing will be performed with a fluoride-free toothpaste to standardize the treatment phase and to follow the instructions of the S-PRG resin manufacturer. The study risks for participants are minimal and related to the sensitivity due to MIH.

In the control and experimental I groups, the fluoride varnishes will be applied once per week for 4 consecutive weeks. For the experimental II group, the product will be applied the first week and the application will be simulated the following 3 weeks for patient blinding.

All children in the control and experimental I groups will be treated according to the same protocol:

For the experimental II group, the treatment protocol according to the manufacturer is as follows:

Sensitivity will be assessed before and after treatment (for all groups) using three instruments: the Wong-Baker FACES Pain Rating Scale (WBFPS), SCASS, and FLACC (Face, Legs, Activity, Cry, Consolability) scale, as described below.

First, the researcher will ask whether the child feels any discomfort in his/her teeth. The researcher will also carefully explain that their WBFPS face choice should be related to the toothache and not the child’s mood at that moment. The child will then be shown the WBFPS, and the child will be guided to choose the most representative face.

Second, sensitivity will be clinically assessed by applying a 1-second air jet 1 centimeter from the buccal and occlusal surfaces of the tooth. The adjacent teeth will be protected with cotton rolls and the patient’s response to the stimulus will be evaluated according to the SCASS. The child's reaction will be recorded according to the codes described in Multimedia Appendix 1.

Third, the examiner will also record the patient's reaction using the FLACC scale (Multimedia Appendix 2). This scale has 5 categories and the responses to each one will be scored from 0 to 2. In each category, the numbers obtained will be summed to obtain the total pain score (0-10). Finally, the child will be asked about discomfort in their teeth again following the use of the air jet and the WBFPS will be applied again.

A single trained, calibrated, and blinded examiner (not involved in the treatment application) will assess the sensitivity effectiveness of treatment in all groups at different moments: (1) before the application of each material, (2) immediately after application or simulation, (3) one month after the last application/simulation, (4) two months after the last application/simulation, (5) four months after the last application/simulation, and (6) six months after the last application/simulation. For all evaluations, the WBFPS, SCASS, and FLACC scale will be used as previously described.

Parental satisfaction and child self-reported discomfort will be evaluated immediately after the fourth week of application or application simulation. Children and their guardians will be asked to rate their satisfaction with the treatment received as very satisfied, partially satisfied, neither satisfied nor dissatisfied, partially dissatisfied, or very dissatisfied. Furthermore, parents will be asked about the importance attributed to the treatment performed on their children (ie, how important it is to treat the tooth affected by MIH) through 5 questions. Concerning discomfort, the questionnaire will assess the child’s acceptability of the treatment, especially the taste of the material, burning sensation, appearance, and duration of the procedure. The questions will be asked by an examiner who did not participate in the treatment stage and is not aware of the type of treatment received by the patient.

Considering that hypersensitivity can impact toothbrushing, the child’s oral hygiene condition will be evaluated using the visible plaque index (IPV) [29] and gingival index (GI) [30] at different times: (1) before the treatment, (2) before each material application/simulation, and (3) at each follow-up visit (1, 2, 4, and 6 months).

Patients will be assessed regarding sensitivity 1, 2, 4, and 6 months after the treatment and will receive preventive instructions concerning diet and biofilm control. At the follow-up appointments, if a tooth displays posteruptive breakdown restricted to enamel, the patient will be kept in the study, but if the breakdown affects dentin (or in the case of a cavitated carious lesion), the patient will receive restorative treatment and be excluded from the study. If the patient has relapsed sensitivity, the initial treatment protocol will be maintained according to each group.

Statistical analysis will be performed with SigmaPlot (version 12.3; SPSS Inc). For the WBFPS, SCASS, and FLACC scale, the three groups and evaluation time will be compared by 2-way repeated measures analysis of variance followed by a Tukey test, based on the recommendation of Cohen [31], to allow for interaction analysis between study factors and to avoid an inflated α error. A Spearman correlation test will be performed to determine if there is a significant correlation among the WBFPS, SCASS, and FLACC scale. The significance level will be set at 5%. Poisson regression will be used to assess the influence of IPV, GI, and discomfort on the outcome. The satisfaction of parents/guardians and participants will be analyzed descriptively.