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

摘要 拟议的合作协议是为了支持第三阶段随机临床试验(RCT)，以评估 38%氟化银二胺(SDF)的效果。SDF最近在美国推出，而且是非侵入性的， 用于治疗乳牙临床上暴露牙本质的空洞病变，费用低廉，操作简单。 儿童早期龋病(ECC)仍然是美国儿童中最常见的慢性病之一。它也是 贫困儿童(例如，学前班儿童)最常见的未得到满足的医疗需求之一。如果允许进展的话 这种疾病如果长期得不到治疗，可能会对牙科、医疗、社会和生活质量产生广泛的影响。 ECC和严重ECC(例如，前牙的多个空洞病变或至少一个龋损，起病于 早年)预防成本相对较低，但对儿童和家庭造成极大的负担 一旦病变出现空洞，治疗费用昂贵(例如，使用不锈钢牙冠、拔牙术等)。这在年轻的人中尤其如此 需要广泛治疗的儿童，或不合作和/或认知功能不成熟的儿童，或 医疗条件，其中在全身麻醉下治疗，大多数情况下在医院手术室，是标准 关心。2016年，FDA向医疗保健提供者发布了一份通知，幼儿全身麻醉可能导致 永久性神经损伤，应避免。因此，需要更好的战略来成功管理 幼儿的空洞性龋损。拟议的随机对照试验将以招收的幼儿为目标 在Head Start计划中，有空洞龋损的人临床上暴露了牙本质。因为 SDF的突破性治疗状态，FDA一直在大力参与这项试验的设计，以确保它将符合 对空洞性龋损的药物索赔的要求，这在美国是创新的。 本申请已由IND 124808持有者Advantage Silver Dental Arcement，LLC提交给美国食品和药物管理局，作为 我们的合作。在资助的第一个月，我们将与NIDCR合作审查所有相关研究文件，并 RCT手册，提交给IRBs，并校准所有研究审查员。在这一研究准备期之后， 经验丰富的研究团队将进行第三阶段、多中心、随机、安慰剂对照的优势试验， 两个平行小组，共涉及1,040名2-5岁儿童，他们将接受为期8个月的跟踪调查 评估：牙齿-目标1(主要研究目标)--两次使用38%SDF，间隔6个月，对阻止空洞的影响 乳牙期的病变(使用ICDAS II严重程度和活动性标准进行评估)。次要目标将进一步 评估自卫队的提供是否影响：儿童目标2[自卫队对儿童疼痛和牙髓感染的影响]， 和家庭目标3[SDF对口腔健康相关生活质量的影响(次级目标3a)，以及治疗满意度和 可接受性(次级目标3b)]。这一创新项目直接影响和意义是 获得一种非侵入性、廉价且易于使用的替代策略来管理空洞龋损 获得护理机会有限的儿童可以通过止损、减轻疼痛、改善口腔健康来深刻改善口腔健康 提高生活质量，显著降低成本，所有这些都有助于大幅减少龋齿方面的差异。

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.