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

该项目的目标是：1）招募少数民族和服务不足的患者参加IGNITE II实用临床 试验（PCT）网络; 2）测试基因型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。印第安纳州大学和目前的调查人员先前开展了研究 基础设施和方案，以便从不同的临床环境中有效招募研究参与者， 印第安纳州。全州范围内的地理编码电子医疗保健记录和社区相关数据使我们能够识别 并招募少数民族研究参与者和那些谁住在联邦指定的服务不足的地区。在 与我们的医疗机构合作伙伴协调，我们的多学科团队处于理想的位置， IGNITE I实施广泛的基因组医学协议的经验教训，有助于 网络范围的分析，与其他临床小组合作，并帮助影响基因组临床实践， 政策认识到滥用阿片类药物处方已成为一个国家危机，我们提出了一个PCT， 药物遗传学指导的阿片类药物选择和给药，目标是优化疼痛控制和增加 在临床实践中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名死于吸毒过量在印第安纳州发现的农村和医疗服务不足的地区是其中最 影响。然而，尽管存在相关风险，阿片类药物仍然是管理许多严重病例的宝贵工具。 痛苦最常用的阿片类药物（羟考酮、氢可酮、可待因或曲马多） 通过肝酶CYP2D6抑制活性代谢物。然而，近10%的患者 编码极低或极高CYP2D6活性的等位基因，阻止阿片类药物剂量改变，或 选择.尽管有强有力的证据和临床指南使用CYP2D6基因检测来指导阿片类药物 治疗，它是在很少的诊所实施。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和进行临床CYP2D6基因分型的能力， OPTIMIZE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）， 一项实用、前瞻性、随机临床试验，旨在检验实施CYP2D6 基因分型提高阿片类药物的有效性并降低相关的毒性。使用群集随机化 研究设计（按诊所），研究受试者（n = 1333）将入组两个研究组之一，CYP2D6- 指导阿片类药物选择和给药（干预）或标准治疗（对照）。我们将招募个人， （1）计划进行通常需要术后阿片类药物的手术，或（2）开具CYP2D6- 代谢的阿片类药物，具有基于阿片类药物剂量递增的不受控制的慢性疼痛的证据。初级 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。我们预计 向提供者提供的药物遗传学建议将改善这些结果， 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.