Effectiveness of Silver Diamine Fluoride (SDF) in Arresting Cavitated Caries Lesions

Study Overview
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Brief Summary
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This trial is a Phase III, multisite, randomized, placebo-controlled trial, with two parallel groups. The groups are SDF or placebo and they are applied every 6 months. The primary hypothesis of the trial is that SDF is better than placebo for stopping cavities with dentin exposed in baby teeth when assessed at 6 months after initial application.

Detailed Description
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This trial is a phase III, multicenter, randomized, placebo-controlled superiority trial, with two parallel groups (placebo vs. SDF applied to cavitated lesions) involving a total of 1144 children with the primary outcome assessed at 6 months after initial treatment. One thousand one hundred forty four children, 12-71 months of age, from early childhood education programs, such as Head Start centers, Early Head Start centers, and equivalent city/state subsidized preschool programs, or children attending dental clinics associated with the clinical trial sites, will be randomized, in two cohorts. Trial visits will occur at baseline, 3 months, 6 months, and 8 months. SDF/placebo will be applied at baseline and 6 months. Parents/legal guardians will be called 24 to 48 hours after the SDF/placebo application to assess adverse events and unanticipated problems and in-person visits for safety exams will be available for all child participants approximately 24 to 48 hours after SDF/placebo application. This visit could happen before or after the 24- to 48-hour call with the parent or legal guardian, but every attempt will be made so that the call occurs prior to the 24- to 48-hour visit. Additionally, intermediate contacts at 1.5 months, 4.5 months, and 7 months will occur to determine if the child needs an additional visit to assess pain, lesion progression, etc. and to maintain contact with the participant. Randomization to SDF application (treatment) or placebo (control) will be at the participant-level; all teeth within a participant that meet the inclusion criteria will receive the same trial product. Both treatment and control will be dispensed from identical unit-dose ampules coded and labeled to ensure masking of all trial personnel. The number of ampules required to treat all carious lesions in the participant's mouth will be recorded. No caries removal will be performed. Teeth will be cleaned with a toothbrush and will be dried with cotton/gauze, and the solution will be painted on the dentin of each targeted cavitated lesion using a standardized applicator. Following application, the tooth will be blotted dry with gauze. At each clinical visit International Caries Detection and Assessment System (ICDAS) examinations, including cavitated lesion hardness assessments, soft tissue assessments and questionnaires on dental discomfort, family impact and treatment satisfaction and acceptability will be collected.

Official Title
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Phase III RCT of the Effectiveness of Silver Diamine Fluoride in Arresting Cavitated Caries Lesions

Conditions
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Cavities of Teeth

Intervention / Treatment
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* Drug: Silver Diamine Fluoride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Child: Male or female, between 12-71 months of age at baseline, up to the day the child turns 6 years old. Must allow examination of the oral cavity and application of treatment by the examiners at baseline. Must have S-ECC [defined as: In children younger than age 3, any sign (non-cavitated or cavitated lesion) of caries in any tooth surface (i.e., most common for this age group will be on erupted smooth surfaces). From ages 3 through 5, ≥1 dmfs in maxillary anterior teeth; or a dmfs score of ≥4 (age 3), ≥5 (age 4), or ≥6 (age 5) constitutes S-ECC. Note: The d component of the dmfs index is defined as including cavitated and non-cavitated lesions, thus ICDAS>1]. Have at least one SDF-target tooth with Soft cavitated caries lesions extending into dentin [ICDAS 5 or 6]; Cavitated lesion(s) that allow for direct hardness assessment and application of SDF (microbrush applicator must fit the cavity and be able to access all exposed dentin). Parent/Legal Guardian: Provide written informed consent for the child and her/himself prior to participation. Must be at least 18 years old, or an emancipated minor who provides documentation of emancipation. Must be willing and able to participate in trial activities. Exclusion Criteria: Child: Hereditary generalized developmental dental defects such as Amelogenesis Imperfecta and Dentinogenesis Imperfecta. Known allergy/sensitivity to silver or other heavy metal ions. Presence of any gingival or peri-oral ulceration, abscess or stomatitis. Participating in the foster care system at trial initiation. Toothache pain at baseline (based on Dental Discomfort Questionnaire score of 1 or higher). Note: If toothache pain occurs after baseline, the child remains eligible to continue in the trial as long as he/she has at least one trial tooth that meets tooth inclusion/exclusion criteria. Demonstrated inability to comply with trial protocol requirements (determination is at the Clinical Site Investigator's discretion). Rickets. Osteopenia or osteoporosis (e.g., Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Marfan Syndrome, etc.). Chronic diseases such as chronic kidney disease, leukemia, lymphoma, rheumatic disorders, etc. Metabolic bone disease (e.g., Galactosemia, Glycogen Storage Disease Type 1, etc.). Chronic glucocorticoid, anticonvulsants, chemotherapy, bisphosphonate administration. Hypothyroidism, hyperparathyroidism, impaired glucose tolerance, hypocalcemia or hypophosphatemia. Tooth: Pain due to caries (based on DDQ score of 1 or higher). Note: If toothache pain occurs after baseline, the tooth is removed from the study. Pulpal exposure, or signs of pulpal infection (abscess, fistula, swelling). Mobility not associated with expected exfoliation patterns. Parent/Legal Guardian: Demonstrated inability to comply with trial protocol requirements (determination is at the Clinical Site Investigator's discretion). Inability to read and comprehend the consent document or trial questionnaires in the translated languages available.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 71 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Silver Diamine Fluoride (SDF)<br>SDF will be applied to the affected teeth twice during the study. Once at screening/baseline and again at the 6-month visit. | Drug: Silver Diamine Fluoride<br>* SDF will be applied twice during the study<br>* Other names: Diammine Silver Fluoride;|
| Placebo Comparator: Placebo<br>The placebo will be applied to the affected teeth twice during the study. Once at screening/baseline and again at the 6-month visit. | Drug: Placebo<br>* This is being compared to the SDF and will also be applied twice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of arrested trial lesions per child in each treatment arm after one treatment with SDF or Placebo | Arrested trial lesions will be assessed by determining if the lesion is hard or soft by pressing on the lesion using a standard probe as assessed by calibrated examiners. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of arrested trial lesions per child in each treatment arm after two treatments with SDF or Placebo | Arrested trial lesions will be assessed by determining if the lesion is hard or soft after two SDF applications by pressing on the lesion using a standard probe as assessed by calibrated examiners. | 8 months | 
| Change in proportion of arrested trial lesions per child in each treatment arm after one treatment with SDF or Placebo | Change in proportion of arrested trial lesions will be assessed by determining if the lesion is hard or soft by pressing on the lesion using a standard probe as assessed by calibrated examiners. The effect of a single application will be assessed at 3-month follow-up versus the 6-month follow-up post initial treatment. | 3 months and 6 months | 
| Proportion of Children in Each Treatment Arm experiencing Toothache Pain | The presence of pain associated with a trial tooth will be defined as a score of 1 or higher using the Dental Discomfort Questionnaire (DDQ), which can be associated with a trial tooth during a clinical visit. The DDQ is a validated tool that assesses pain in children 5 and younger, as reported by parents/legal guardians as proxies, based on the observation of toothache pain-related behaviors by the child. It consists of two parts. The first part includes a question concerning the occurrence of toothache and when (if no pain DDQ score of 0, best). The second part consists of 8 validated questions about different behaviors associated with toothache or discomfort due to caries. Each item can be answered on a three-point scale: 0 'never', 1 'sometimes', and 2 'often'. If there is toothache the total score is calculated by adding the scores to the 8 questions in part two, and ranges from 0 (no pain) to 16 (worse score). | Baseline, 24-48 hour call, 1.5 month, 3 month, 4.5 month, 6 month, 24-48 hours after 6 month, 7 month, 8 month |