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

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Summary The proposed Cooperative Agreement is for support for a Phase III randomized clinical trial (RCT) to assess the effectiveness of 38% silver diamine fluoride (SDF). SDF recently became available in the U.S., and is non-invasive, inexpensive and simple to use for management of cavitated lesions exposing dentin clinically (i.e., holes) in primary teeth. 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 poor children (e.g., Head Start children). If allowed to progress untreated for long periods of time, the disease can have broad dental, medical, social, and quality of life consequences. ECC and severe-ECC (e.g., multiple cavitated lesions or at least one caries lesion in the anterior teeth, with onset at an early age) is relatively inexpensive to prevent, yet becomes extremely burdensome on the children and families, and expensive to treat once lesions cavitate (e.g., with stainless steel crowns, extractions, etc.). This is especially true in young children who need extensive treatment, or are uncooperative and/or have immature cognitive functioning, disabilities, or medical conditions, where treatment under general anesthesia, in most cases in hospital operating rooms, is the standard of care. In 2016, the FDA issued a notice to health care providers that general anesthesia in young children can result in permanent neurological damage and should be avoided. Thus, better strategies are needed to successfully manage cavitated caries lesions in young children. The proposed RCT will be accomplished by targeting young children enrolled in Head Start programs who have cavitated caries lesions that have exposed dentin clinically. Because of the Breakthrough Therapy Status for SDF, FDA has been heavily involved in the design of this trial to ensure it will meet the requirements for a cavitated caries lesion “arrest” drug claim, which is innovative in the U.S. The proposed protocol in this application has been submitted by Advantage Silver Dental Arrest, LLC, holder of IND 124808, to the FDA as part of our collaboration. In the first months of funding, we will work with NIDCR to review all relevant study documents and manuals for the RCT, submit to IRBs, and calibrate all study examiners. Following this study preparation period, an experienced research team will conduct a Phase III, multicenter, randomized, placebo-controlled superiority trial, with two parallel groups involving a total of 1,040 children, 2-5 years old, who will be followed over a period of 8 months, to assess: The tooth-Aim 1 (Primary study aim)- the impact of 38% SDF applied twice, 6 months apart, on arrest of cavitated lesions in the primary dentition (assessed using the ICDAS II severity and activity criteria). Secondary aims will further assess whether the provision of SDF impacts: the child-Aim 2 [effects of SDF on children's pain and pulpal infection], and the family-Aim 3 [effects of SDF on oral health-related quality of life (Sub-Aim 3a), and treatment satisfaction and acceptability (Sub-Aim 3b)]. The immediate impact and significance of this innovative project is that provision of and access to a non-invasive, inexpensive, and simple to use alternative strategy to manage cavitated caries lesions for children with limited access to care could profoundly improve oral health by arresting lesions, reducing pain, improving quality of life, and significantly reducing costs, all contributing to substantial reductions in disparities in caries.