Implementing genomic medicine through pragmatic trials in diverse and underserved populations across Indiana.

该项目的目标是1)招募少数族裔和服务不足的患者到IGNITE II务实临床 试验(PCT)网络；以及2)测试基因指导的阿片类药物治疗对疼痛控制和阿片类药物治疗的影响。 相关不良事件。印第安纳大学和目前的调查人员之前已经开发了一项研究 用于从不同临床环境中高效招募研究参与者的基础设施和协议 印第安纳州。全州范围内地理编码的电子医疗记录和社区相关数据使我们能够识别 并招募少数族裔研究参与者和那些生活在联邦指定的服务不足地区的人。在……里面 与我们的医疗保健机构合作伙伴协调，我们的多学科团队处于理想的地位，适用于 从IGNITE I中吸取的经验教训，以实施广泛的基因组医学方案，有助于 全网络分析，与其他临床小组协作，并帮助影响基因组临床实践和 政策。认识到滥用阿片类药物处方已成为一种国家危机，我们建议对 药物遗传学指导的阿片类药物选择和剂量，目标是优化疼痛控制和增加 临床使用阿片类药物的安全性。就人均阿片类药物处方而言，印第安纳州在全国排名第九 第17位是服药过量死亡。印第安纳州的农村和医疗服务不足的地区是最多的 受影响。然而，尽管有相关的风险，阿片类药物对于处理许多严重的 疼痛。最常见的处方类阿片(羟可酮、氢可酮、可待因或曲马多)被转换 通过肝脏酶CYP2D6对药理活性代谢物的作用。然而，近10%的患者有 编码极低或极高的CYP2D6活性的等位基因，证明改变阿片类药物的剂量或 选择。尽管有强有力的证据和临床指南表明使用CYP2D6基因检测来指导阿片类药物 这种疗法在极少数诊所中得到了应用。利用我们在阿片类药物遗传学方面的专业知识，以及 我们建议，在印第安纳州识别阿片类药物处方并进行临床CYP2D6基因分型的能力 优化研究(阿片类药物遗传学指导的治疗实施以最大限度地提高疗效)，a 一项务实、前瞻性、随机的临床试验，旨在检验实施细胞色素P4502D6的假设 基因分型可提高阿片类药物的有效性，并减少相关毒性。使用集群随机化 研究设计(通过临床)，研究参与者(n=1333)将被登记到两个研究分支之一，CYP2D6- 指导阿片类药物的选择和剂量(干预)或护理标准(对照)。我们将招募符合以下条件的个人 或者(1)安排进行手术，通常需要术后阿片类药物，或(2)开出CYP2D6- 代谢的阿片类药物，根据阿片类药物剂量的增加，有证据表明慢性疼痛失控。主要 结果将是自我报告的疼痛控制和阿片类药物相关的不良事件。我们期待着 给予提供者的药物遗传学建议将改善这些结果，并因此 降低与阿片类药物治疗相关的风险。

The goals of this project are 1) to recruit minority and underserved patients to the IGNITE II pragmatic clinical trials (PCT) network; and 2) to test the effects of genotype-guided opioid therapy on pain control and opioid- related adverse events. Indiana University and the current investigators have previously developed research infrastructure and protocols for efficiently recruiting study participants from diverse clinical settings across Indiana. State-wide geocoded electronic health care records and community-related data allow us to identify and recruit minority study participants and those who live in federally-designated underserved areas. In coordination with our healthcare institutional partners, our multi-disciplinary team is ideally positioned to apply lessons learned from IGNITE I to implement a wide range of genomic medicine protocols, contribute to network-wide analyses, collaborate with other clinical groups, and help influence genomic clinical practice and policy. Recognizing that abuse of opioid prescriptions has become a national crisis, we propose a PCT of pharmacogenetic-guided opioid selection and dosing with a goal of optimizing pain control and increasing the safety of using opioids in clinical practice. Indiana is 9th in the nation in terms of opioid prescriptions per capita and 17th in overdose deaths. Rural and medically underserved areas found in Indiana are amongst the most affected. Despite the associated risks, however, opioids are still invaluable to managing many cases of severe pain. The most commonly prescribed opioids (oxycodone, hydrocodone, codeine, or tramadol) are converted to pharmacologically active metabolites by the liver enzyme, CYP2D6. However, nearly 10% of patients have alleles encoding either extremely low or extremely high CYP2D6 activity, warranting altered opioid dosing or selection. Despite strong evidence and clinical guidelines for using CYP2D6 genetic testing to guide opioid therapy, it is implemented in very few clinics. Leveraging our expertise in opioid pharmacogenetics, as well as the ability to identify opioid prescriptions across Indiana and perform clinical CYP2D6 genotyping, we propose the OPTIMIZE study (Opioid Pharmacogenetics-guided Therapy Implementation to MaximIZe Effectiveness), a pragmatic, prospective, randomized, clinical trial designed to test the hypothesis that implementing CYP2D6 genotyping improves opioid effectiveness and reduces associated toxicities. Using a cluster randomization study design (by clinic), study participants (n=1333) will be enrolled into one of two study arms, CYP2D6- guided opioid selection and dosing (intervention) or standard of care (control). We will recruit individuals who are either (1) scheduled for surgeries typically requiring post-operative opioids, or (2) prescribed a CYP2D6- metabolized opioid with evidence of uncontrolled chronic pain based on escalating opioid dose. Primary outcomes will be self-reported pain control and opioid-related adverse events. We expect the pharmacogenetic recommendations given to the provider will improve these outcomes, and consequently reduce the risks associated with opioid treatment.