PROJECT SUMMARY The proposed competing renewal project requests support for additional time, particularly due to delays associated with the COVID-19 pandemic, to complete a Phase III, multicenter, randomized, placebo-controlled trial, with two parallel groups, to assess the effectiveness of 38% silver diamine fluoride (SDF) in U.S. diverse children. SDF became available in the U.S. for treatment of hypersensitivity in 2014, and is being used “off label” for management of cavitated lesions. Early childhood caries (ECC) continues to be one of the most prevalent chronic conditions among U.S. children. It also is one of the most common unmet healthcare needs of underserved children. If allowed to progress untreated, the disease can have broad dental, medical, social, and quality of life consequences. Severe-ECC is relatively inexpensive to prevent, yet once lesions cavitate it becomes extremely burdensome and expensive to treat. This is especially true in young children who need extensive treatment, where treatment under general anesthesia (GA), in most cases in hospital operating rooms, is the standard of care.3 In 2016, the FDA issued a notice that GA in young children can result in permanent neurological damage.25 Thus, effective, acceptable, inexpensive and less-invasive strategies are needed to successfully manage cavitated caries lesions in young children. Because of the Breakthrough Therapy Status for SDF, the FDA has been heavily involved in the design of this trial to ensure it meets the requirements for a cavitated caries lesion “arrest” drug claim, which is innovative in the U.S., and important to facilitate implementation. The trial protocol has been submitted by Advantage Silver Dental Arrest, LLC, holder of IND 124808, to the FDA as part of our ongoing collaboration. During this renewal period, our experienced research team will continue enrollment to reach the sample target of 1,144 children, 1-5 years old, who have severe-ECC, and who will be followed over 8 months. Specific aims include to: Assess the impact of 38% SDF applied once, to arrest cavitated lesions that have exposed dentin clinically in the primary dentition at 6 month follow-up (Aim 1, per FDA), and applied twice, approximately 6 months apart, at 8 month follow-up (Aim 2) [Sub-Aim 2a will compare the effect of one application at 3- and 6-month follow-ups]. Aim 3 will assess the impact of 38% SDF applied twice, approximately 6 months apart, on pain [Sub Aim 3a will assess the impact on pain after a single application (assessed at 3 and 6 months)]. Aim 4 will assess the impact of 38% SDF on Family-Level Outcomes [Sub Aim 4a will assess the impact on Oral Health-Related Quality of Life, and Sub Aim 4b on Treatment Satisfaction and Acceptability]. The immediate impact and significance of this innovative project is that resulting data can lead to a cavitated caries lesion “arrest” FDA drug claim for SDF, which can profoundly improve oral health by supporting implementation of an effective, low-cost intervention, while ensuring regulation of efficacy and safety over time, all contributing to substantial reductions in disparities in caries in children.

PROJECT NARRATIVE The University of Michigan, in collaboration with researchers at New York University and Indiana University, and consultants from the University of Iowa and the University of Otago, propose to continue implementation of a Phase III multicenter, randomized clinical trial, to test the effectiveness of 38% Silver Diamine Fluoride (SDF) in stopping the progression of cavities (i.e., large holes which result from dental caries, a common and debilitating disease) in the teeth of young, diverse children with severe disease. Should the trial be successful, the impact would be a change in the standard of care and expanded access to a simple, non- invasive, inexpensive strategy to manage cavitated caries lesions in young, diverse children in the U.S., which otherwise are usually treated with potentially damaging general anesthesia, and with fillings or extractions. Improved access to this simple treatment should result in a reduction of disparities and improvements in oral health, which addresses the NIDCR 2021-2026 Strategic Plan58 Priority 3 [Accelerate the translation of research and the implementation of new discoveries into oral and general healthcare practices that reduce health inequities and disparities and improve oral health outcomes for individuals and communities worldwide].