Sparking Advancements in Genomic Medicine

项目摘要 作为IGNITE II网络的一部分，两项前瞻性随机实用基因型指导临床试验， GUARDD-US和ADOPT-PGx分别自2019年7月和2021年2月开始实施。这些 试验将有助于确定实施基因检测对高血压、抑郁症和疼痛的影响 治疗GUARDD-US：慢性肾脏病（CKD）与高血压相关。非洲人 祖先（AA）的CKD和肾衰竭风险最高，高血压患病率最高， 血压（BP）控制率最低。虽然这种差异部分是由于社会决定因素造成的， 祖先具有生物学基础和APOL 1高风险遗传变异，几乎只在AA中发现， 肾衰竭风险增加10倍我们提出了一个基因型指导的试验，以确定早期与早期的影响。 延迟获知3个月收缩压（SBP）的阳性APOL 1基因分型结果。审判 旨在招募患有高血压（伴或不伴CKD）的非裔美国人，随机分为即刻组和 APOL 1基因检测延迟返回。对于APOL 1呈阴性的人，我们还将进行一项试点研究 检测药物遗传学（PGx）检测对SBP的影响。ADOPT-PGx：疼痛和抑郁是 影响了相当大一部分美国人口。急性和慢性疼痛的治疗受到挑战 由于很难找到有效的治疗方法，同时最大限度地减少副作用或阿片类药物成瘾的风险。为 抑郁症，很少有临床相关的成功治疗的预测，这导致不充分的 治疗许多患者。我们提出了一个前瞻性的随机实用基因型指导的临床试验， 测试了基因型指导治疗在三种情况下的效果：急性术后疼痛，慢性疼痛， 疼痛和抑郁对于每种情况，受试者将被随机分配到基因型指导的药物治疗组 与通常的药物治疗选择方法相比。代表疼痛的患者报告结局的变化 和抑郁控制使用标准PROMIS量表定义的主要终点。次要分析 包括安全性终点、总体健康状况的变化以及 保健利用。目前的行政补充申请主要反映了5/9年级的试验需求 由于ADOPT-PGx和GUARDD-US试验的意外网络范围延迟以及由于以下原因而关闭 新冠肺炎。此外，这一行政要求反映了UF临床组（CG）的100名入组 急性疼痛试验的额外参与者，使UF的招募目标达到850名参与者。

Project Summary As part of the IGNITE II network, two prospective randomized pragmatic genotype-guided clinical trials, GUARDD-US and ADOPT-PGx, have been underway since July 2019 and February 2021, respectively. These trials will help to determine the impact of implementing genetic testing on hypertension, depression, and pain therapies. GUARDD-US: Chronic kidney disease (CKD) is associated with hypertension. People with African ancestry (AAs) have the highest risk of CKD and kidney failure, the highest prevalence of hypertension, and the lowest rate of blood pressure (BP) control. While this disparity is in part due to social determinants, ancestry has biological underpinnings and APOL1 high-risk genetic variants, nearly exclusive found in AAs, increase kidney failure risk 10-fold. We propose a genotype-guided trial to determine the effect of early vs. delayed knowledge of a positive APOL1 genotyping result on 3-month systolic blood pressure (SBP). The trial aims to recruit African Americans with hypertension, with or without CKD, randomized to immediate versus delayed return of APOL1 genetic testing. In those who are APOL1 negative, we will also conduct a pilot study to test the impact of pharmacogenetic (PGx) testing on SBP. ADOPT-PGx: Pain and depression are conditions that impact substantial proportions of the US population. The treatment of acute and chronic pain is challenged by the difficulty of finding effective therapies while minimizing the risk of adverse effects or opioid addiction. For depression, there are few clinically relevant predictors of successful treatment, which results in inadequate therapy for many patients. We propose a prospective randomized pragmatic genotype-guided clinical trial that tests the effect of genotype-guided therapy in three scenarios of patients: acute post-surgical pain, chronic pain, and depression. For each scenario, participants will be randomized to genotype-guided drug therapy versus usual approaches to drug therapy selection. Changes in patient reported outcomes representing pain and depression control using standard PROMIS scales define the primary endpoints. Secondary analyses include safety endpoints, changes in overall well-being, and economic impact represented by differences in healthcare utilization. The current administrative supplement request reflects trial needs for Year 5/9 largely due to unanticipated network-wide delays with the ADOPT-PGx and GUARDD-US trials and shutdowns due to COVID-19. In addition, this administrative request reflects the UF Clinical Group’s (CG) enrollment of 100 additional participants for the Acute Pain Trial, bringing UF’s enrollment goal to 850 participants.