Clinical trial NCT04054635: A Clinical Trial of Silver Diamine Fluoride to Arrest Early Childhood Caries in Young Children
Official title: A Randomized Clinical Trial of Silver Diamine Fluoride to Arrest Early Childhood Caries in Young Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Early Childhood Caries
Keywords: silver diamine fluoride
randomized clinical trial
early childhood caries
severe early childhood caries
oral microbiome
treatment
arrest
application
frequency
regimen
cariogenic bacteria
early childhood oral health impact scale
oral health-related quality of of life
caries
oral bacteriome
oral mycobiome
cavitated lesions
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Children's Hospital Research Institute of Manitoba
First posted: 2019-08-13
Enrollment: 84
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are randomly assigned to one of three application regimens of silver diamine fluoride (SDF) to cavitated caries lesions in primary teeth during the duration of the study. Regimen 1 will be two applications of SDF four months apart. Regimen 2 will be two applications of SDF six months apart. Regimen 3 will be two applications of SDF one month apart.
Primary purpose: TREATMENT

Brief summary: Silver diamine fluoride (SDF) is an antibiotic liquid that has the potential to arrest Early Childhood Caries in young children and delay treatment until children can be seen in outpatient settings. While SDF received approval for clinical use in Canada in 2017 (i.e. Advantage Arrest TM/38% SDF), there has been little guidance on the frequency and duration of applications. This study evaluates the use of SDF at different frequencies to manage dental caries in young children. Potential oral microbiome changes in children receiving SDF treatments are also studied. The investigators hypothesize that two applications of SDF at different frequencies will yield similar arrest rates, and that SDF negatively influences the population of cariogenic bacteria in the oral microbiome. The investigators propose a randomized clinical trial to study the use of SDF to arrest cavitated lesions in primary teeth at different application regimens. Regimen 1 will be two applications of SDF four months apart. Regimen 2 will be two applications of SDF six months apart. Regimen 3 will be two applications of SDF one month apart. Arrest of caries lesions will be determined by assessing clinical hardness, colour change and size of lesions at baseline, at second visit, and at the final study visit. Children \< 72 months of age with active caries will be recruited from community-based dental clinics or who are currently on a wait list for dental surgery under general anesthesia in Winnipeg, Manitoba. SDF will be applied on the day of recruitment to cavitated lesions involving dentin followed by 5%NaFV. Depending on which frequency regimen children are randomized to, participants will return for a second visit. At the second visit, caries lesions treated with SDF at baseline will be assessed to see if caries is arrested. A second application of SDF will be applied to these initially treated caries lesions followed by 5%NaFV. Participants will return for a third and final study visit according to the schedule of their randomized grouping. Caries lesions previously treated by SDF will be assessed once again. To investigate SDF's influence on the human oral microbiome, children from each regimen will have plaque samples collected. Samples will be obtained prior to SDF application at baseline, at the first follow-up visit, and at the final visit. Following nucleic acid isolation from plaque samples and amplicon sequencing, data analysis will be performed in lab using established methods.

Detailed description: Good oral health during early childhood sets the foundation for a lifetime of optimal dental health. Unfortunately, many Canadian children develop Early Childhood Caries (ECC), defined as caries in the primary dentition in those \< 72 months of age. ECC is a significant concern as not only can it increase the risk for caries throughout childhood and adolescence, but severe forms can impact health and well-being. Many with ECC suffer from an aggressive subtype, called severe ECC (S-ECC), which frequently requires rehabilitative dental surgery under general anesthesia (GA).

There is an urgent need to implement public health strategies to reduce the proportion of children developing ECC, especially S-ECC, and to manage effectively children who already have the disease. The challenge is that there are few effective interventions. Traditional primary prevention modalities have had little impact on reducing the incidence and severity of ECC in North America. Until recently there have been no effective non-surgical products for secondary prevention available. Though primary prevention is always preferred, secondary prevention can reduce the morbidity from caries and preserve the function of affected teeth until exfoliation.

Recent reports highlight the anti-caries effects of silver diamine fluoride (SDF). One systematic review and meta-analysis reported that 38% SDF is safe and effective in arresting dentin caries in primary teeth resulting in the arrest of 81% of active caries lesions. The recent American Dental Association (ADA) report on non-restorative management of caries prioritizes the use of SDF over other products to manage cavitated caries lesions. Despite this evidence, true consensus on the frequency of SDF applications in children with ECC is lacking. Further, the current American Academy of Pediatric Dentistry (AAPD) Clinical Practice Guidelines on SDF emphasize that research is needed on the use of SDF to arrest caries lesions in both primary and permanent teeth, specifically urging researchers to undertake randomized clinical trials (RCTs). SDF has the potential to arrest ECC in young children and delay treatment until children can be seen in outpatient settings, thereby reducing the need for rehabilitative dental surgery under GA.

While Advantage Arrest TM (38% SDF) received approval for clinical use in Canada in 2017, there has been little guidance on the frequency and duration of applications. Some proposed SDF protocols may not easily translate into dental public health clinical settings or work well in remote Indigenous communities, where access to care is often limited. Recommendations for frequent reapplication are not practical or realistic in these programs or remote regions where follow-up visits may be several months away and not within a matter of weeks. Since there was no clear protocol for dental professionals to follow for arresting caries in young children when SDF was approved for use in Canada in 2017, The investigators undertook a mixed-methods pilot feasibility study of SDF. Data from 40 children 40.2 ± 14.9 months of age are encouraging. Children with 239 active caries lesions in primary teeth underwent treatment with 38% SDF (followed by 5% sodium fluoride varnish/5%NaFV) at baseline and 4 months later. Treated lesions were assessed 4 and 8 months after baseline to determine arrest. The early childhood oral health impact scale (ECOHIS) questionnaire was completed at second and third visits to assess oral health related quality of life (OHRQoL). ECOHIS is a validated tool for use with parents/caregivers of children \< 72 months of age. Arrest rates after one and two applications of SDF were 74.1% and 96.2%, respectively. OHRQoL was not found to be adversely affected by the success of SDF treatment. From these pilot data the investigators concluded that SDF is a promising agent to manage ECC, but at least two applications are recommended.

The purpose of this current study is to investigate the effectiveness of using SDF to arrest ECC in very young children randomized to different application frequency regimens. The investigators will also study potential oral microbiome changes in children receiving SDF treatment. The investigators hypothesize that two applications of SDF at different frequencies will yield similar arrest rates, and that SDF will negatively influence the population of cariogenic bacteria in the oral microbiome.

The investigators propose a RCT to study the use of SDF to arrest cavitated caries lesions in primary teeth at different application regimens. This study is novel, as this would be the first RCT of SDF conducted in Canada. Regimen 1 will be two applications of SDF four months apart, which is the protocol frequency adopted by the Winnipeg Regional Health Authority's (WRHA) Clinical Guideline on SDF. Regimen 2 will be two applications of SDF six months apart (ADA recommendation). Regimen 3 will be two applications of SDF one month apart, which is proposed in the AAPD's clinical practice guideline. The ADA recently indicated that SDF should be prioritized over 5%NaFV for non-restorative management of cavitated lesions. Thus, a control group receiving solely fluoride varnish will not be included as this would now be considered unethical and substandard care. However, the investigators will attempt to follow as a comparison group those children whose parents/caregivers do not consent to SDF to manage their child's caries and only choose 5%NaFV.

Arrest of caries lesions will be determined by assessing clinical hardness, colour change, and size of lesions at baseline, at second visit, and at the final study visit. Children will be recruited over eight months. The investigators will perform block randomization by site in order to achieve equal proportions in each regimen by clinic site of recruitment. Following informed consent the child's parent/caregiver will complete a short questionnaire (via interview) on general and dental health, oral hygiene, dietary intake of sugars, and family demographics along with the ECOHIS to assess OHRQL. SDF will be applied on the day of recruitment to cavitated lesions involving dentin followed by 5%NaFV. Depending on which frequency regimen children are randomized to, participants will return for a second visit. During this second visit, caries lesions treated with SDF at baseline will be assessed to see if caries is arrested as determined through measures of hardness, colour change, and size. At this same visit a second application of SDF will be applied to these initially treated caries lesions followed by 5%NaFV. Children and parents will return for the third and final study visit according to the schedule of their randomized grouping. Parents/caregivers will complete a follow-up questionnaire similar to the baseline tool. Caries lesions previously treated by SDF will be assessed for clinical hardness, colour change and size to determine if they have arrested.

As ECC is age specific, participants will be \< 72 months of age with active caries and their parents/caregivers. The majority will be recruited from community-based dental clinics in Winnipeg or who are currently on a wait list for dental surgery under GA in Winnipeg. The investigators found that these were ideal sites for the recently completed feasibility trial of SDF. Participation will be restricted to children living in the Winnipeg region or within a one hour drive of Winnipeg to minimize the risk of loss-to-follow-up. Eligibility criteria are designed to select young children who have active caries, and thus are at an increased risk of morbidity from existing caries and onset of new caries.

Sample size for this pilot study has been determined in discussion with a collaborator. The intent of the study is not to compare arrest rates between groups to see which yields higher and more significant arrest rates. Rather, the investigators are interested in determining whether the three different regimens will yield arrest rates within a range of what is determined to be clinically acceptable. Based on the recent pilot feasibility study of SDF with 40 children (with 239 lesions), the investigators reported an arrest rate of approximately 96% following two applications of SDF. Results from a recent systematic review state that 80% of lesions can arrest because of SDF. The investigators believe that a range of arrest rates from 80% to 96% yield similar beneficial outcomes in the clinical setting. Based on the pilot study, 40 children had 239 lesions (average 6 lesions/child). With the pilot sample of 239 lesions, it is possible to estimate an arrest rate with a 95% confidence interval to be accurate within ± 6.5%. With 400 lesions anticipated in the proposed recruitment sample, the 95% confidence interval for the arrest rate would be ± 5.0%. The investigators propose three SDF regimen groups and anticipate that each group will have 22 children anticipating an average of six lesions. This would mean 396 lesions would be followed in this study. The investigators anticipate that with 400 lesions the percent of arrest will be within ± 5% if 22 children are in each group. To deal with potential drop-outs and loss-to-follow-up of up to 20% the investigators will over recruit by 22.7% into each group and recruit 27 per group. The investigators anticipate the successful recruitment of 10 children each month.

Clinical outcomes assessed will include the proportion of lesions arrested (i.e., "arrest rate" = total number lesions arrested / total number of lesions treated), the number of children with arrested caries, and the number of children requiring dental surgery under GA. The investigators will also record dmft and dmfs scores for each child at baseline and at subsequent study visits. The dmft and dmfs scores are cumulative counts of the total number of primary teeth or surfaces decayed, missing due to, or filled because of caries.

Caries activity will be determined according to hardness and colour of the caries lesion. Hardness is the best indicator of dentinal tissue caries activity. The hardness of caries lesions will be assessed by applying light force to the lesion with a ball ended probe and by classifying the lesion into one of three hardness categories: 1) very soft; 2) medium; or 3) very hard. The investigators will record these ratings of hardness of lesions on the Clinical Record Forms at the baseline visit, second visit, and third (final) clinical visit. The Clinical Record Forms will be those used in the pilot feasibility study of SDF. The colour of caries lesions will also be assessed. Dentin colour of each caries lesion will be classified as: 1) yellow; 2) brown; or 3) black. The colour black is associated with arrested caries. The size of caries lesions will also be measured (in mm) at the baseline, second, and third clinical visits.

To investigate SDF's influence on the human oral microbiome, ten children from each regimen will have plaque samples collected. Samples will be obtained prior to SDF application at baseline, at the first follow-up visit, and at the final visit. Following nucleic acid isolation from plaque samples and amplicon sequencing, data analysis will be performed in lab using established methods.

Problems and adverse events will be recorded and reported to the University of Manitoba's ethics office.

Eligibility criteria: Inclusion Criteria:

1. Child is \< 72 months of age with early childhood caries (ECC) with active lesions (International Caries Detection and Assessment System codes 5 or 6).
2. Child has ≥ 1 primary tooth with caries that is eligible to receive SDF. Eligible primary teeth must: a) have soft cavitated caries lesions extending into dentin; b) the cavitated lesions must allow for direct application of silver diamine fluoride (SDF). Teeth that meet any of the PUFA (pulpal involvement, ulceration, fistula, and abscess) index criteria (i.e. spontaneous pain due to caries, pulp exposure, mobility, signs of pulpal infection such as abscess, fistula, or swelling) will be excluded. However, a child would still be eligible even if they have at least one tooth that meets PUFA criteria, but other eligible teeth with caries do not.

Exclusion Criteria:

1. Child is allergic or has a sensitivity to silver or other heavy metal ions.
2. Child has hereditary generalized developmental defects of enamel (e.g. Amelogenesis Imperfecta, Dentinogenesis Imperfecta)
3. Child has severe medical problems that limit participation.
4. Child requires immediate rehabilitation under general anesthesia (GA) because of severe infection or pain.
5. Antibiotic use within the last 2 weeks.

Primary outcomes:
measure: Overall Arrest Rates
timeFrame: 8 months, 12 months, and 2 months
measure: Anterior Teeth Arrest Rates
timeFrame: 8 months, 12 months, and 2 months
measure: Posterior Arrest Rates
timeFrame: 8 months, 12 months, and 2 months
Secondary outcomes:
Other outcomes:
Locations:
city: Winnipeg
country: Canada
facility: Children's Hospital Research Institute of Manitoba
state: Manitoba
Study officials:
affiliation: University of Manitoba
name: Robert J Schroth
role: PRINCIPAL_INVESTIGATOR
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