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

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
1060 children with the primary outcome assessed at 6 months after initial treatment.

One thousand sixty children, 23-61 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. The plan to enroll in two cohorts, one at the
beginning of each school year, is intended to address the feasibility and ability to recruit
the total number of participants required. Each cohort will be followed for 8 months. Trial
enrollment will occur over a course of 2 ½ years. 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.

Inclusion Criteria:

- Child:

- Male or female, between 23-61 months of age at baseline.

- 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.

- 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.