ACTG A5146: THERAPEUTIC DRUG MONITORING ON VIRAL LOAD, PI-EXPERIENCED HIV-1 PTS

ACTG A5146：对病毒载量、PI 经历过的 HIV-1 PTS 进行治疗药物监测

• 批准号: 7378021
• 负责人: ROBERT C KALAYJIAN
• 金额: $ 2.7万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378021
• 关键词: ACTG; A5146; THERAPEUTIC; DRUG; MONITORING

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A5146 is an open-label, randomized, multicenter trial. The goal of A5146 is to determine whether dose modification of protease inhibitors (PIs) improves virologic response in PI-experienced subjects. PI-resistant HIV needs higher PI levels to be suppressed than PI-sensitive HIV in vitro. A5146 will use therapeutic drug monitoring (TDM) to optimize PI drug concentrations. Optimal drug levels will be calculated by determining the normalized inhibitory quotient (NIQ) for each PI in the subjects salvage regimen that is initiated at Step 1 study entry. An NIQ takes into account the subjects trough plasma PI drug level in relation to the degree of resistance of the subjects virus to that drug (see calculation below). The goal is to have the subjects plasma PI trough level be higher than the drug level required to inhibit the subject¿s virus. An NIQ of > 1 means that the subjects IQ is more than the IQ of subjects who had a good response to the same PI. An NIQ = 1 means that the subjects IQ is lower than the IQ of subjects who had a good response to the same PI. Either a low drug level or a high level of viral resistance can cause an NIQ to be low (= 1). The target NIQ in this study is 1.0 for all PIs. Screening: Treatment-experienced subjects who have virologically failed at least one PI-containing antiretroviral combination regimen will have a screening resistance test performed using a virtual phenotype while they remain on their failing regimen. A5146 is divided into three steps as follows: Step 1: Step 1 is to determine which subjects have NIQs = 1 or > 1. At entry to Step 1, subjects will initiate a new salvage regimen based on the virtual phenotype performed at screening. Two weeks after entry, all subjects will have a timed plasma sample obtained for PI trough levels on the new salvage regimen. This trough level will be used with the fold-change in IC50 from the screening virtual phenotype to calculate an NIQ. All subjects will receive NIQ results before week 4 in order to determine their eligibility for randomization or arm assignment at Step 2 entry. Step 2: At Step 2 entry, a total of 180 subjects with NIQs = 1 will be randomized to standard of care (SOC) (Arm A) or to TDM+SOC (Arm B). In addition, 50 subjects with NIQs > 1 will be followed in an Observational Arm (Arm C). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Subjects with a week 2 NIQ > 1 will be permanently discontinued from the study. Subjects with NIQs = 1 will receive PI dose escalations according to pre-specified dose adjustment algorithms. The PI dosing algorithms were derived by the A5146 study team pharmacologists and are updated periodically to include additional triple-PI combination regimens, newly FDA-approved PI agents, and revised dosing recommendations based on new available safety information. These dose adjustment algorithms will be used by the study team to determine whether a PI dose should be escalated for an NIQ = 1 in a subject who is eligible to receive TDM. The PI dose adjustment recommendation will be transmitted in an electronic report to the site. Subjects in Step 2 without virologic failure at week 24 or later will continue to be followed in Step 2 on their original assigned treatment arms through week 48. Subjects with virologic failure at week 24 or later may choose to enter Step 3. Step 3: Step 3 is to provide the option of TDM to subjects who failed their initial regimen on Step 2, independent of their original treatment arm randomization or assignment. Subjects in any of the Step 2 arms who have a confirmed plasma HIV-1 RNA concentration of = 1000 copies/mL at or after week 24 will be eligible to enter Step 3 and receive a second virtual phenotype drug resistance test. The results of the resistance test will be used to design a Step 3 salvage regimen. Repeat PI drug level(s) will be obtained on this Step 3 salvage regimen, and NIQ values for any PIs in the Step 3 salvage regimen will be provided for all subjects. All subjects with NIQs = 1 will be given the option to receive dose-adjusted PI therapy, using the same dose adjustment algorithms that were used for subjects in the Step 2, TDM+SOC arm. PI dose adjustments in Step 3 cannot occur any later than week 44 of study participation. After registering to Step 3, subjects will be followed for a maximum of 24 weeks on Step 3 but not more than 48 weeks after study entry (week 0, Step 1). See diagram at the end of this schema. Subjects randomized at Step 2 entry to Arm A or B, or assigned to Arm C, will be followed for 48 weeks after Step 1 entry. At week 4, subjects with NIQ = 1 will be randomized to Arms A or B, and subjects with NIQ >1 will be assigned to Arm C. Arm A: SOC Arm B: TDM+SOC Arm C: Observational Subjects in Arm C (Observational) will be treated in exactly the same manner as subjects randomized to Arm A (SOC) after Step 2 entry through week 24, the only difference being their week 2 NIQ result (Arm A: NIQ = 1; Arm C: NIQ >1). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Antiretroviral regimens will be selected and prescribed by the subject's clinician based on the results of virtual phenotypic resistance testing. A5146 will not provide any antiretroviral drugs.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。A5146是一项开放标签、随机、多中心试验。A5146的目的是确定蛋白酶抑制剂（PI）的剂量调整是否改善PI经历受试者的病毒学应答。在体外，PI耐药HIV比PI敏感HIV需要更高的PI水平才能被抑制。A5146将使用治疗药物监测（TDM）来优化PI药物浓度。将通过确定在第1步研究入组时开始的受试者挽救治疗方案中每个PI的归一化抑制商（NIQ）来计算最佳药物水平。 NIQ考虑了受试者血浆PI药物谷水平与受试者病毒对该药物耐药程度的关系（见下文计算）。目标是使受试者血浆PI谷水平高于抑制受试者病毒所需的药物水平。NIQ> 1意味着受试者的智商高于对相同PI有良好反应的受试者的智商。NIQ = 1意味着受试者的IQ低于对相同PI有良好反应的受试者的IQ。低药物水平或高水平病毒耐药性均可导致NIQ较低（= 1）。本研究中所有PI的目标NIQ均为1.0。 筛选：至少一种含PI的抗逆转录病毒联合治疗方案病毒学失败的有治疗经验的受试者，在继续接受失败的方案时，将使用虚拟表型进行筛选耐药试验。A5146分为以下三个步骤：步骤1：步骤1是确定哪些受试者NIQ = 1或> 1。在进入第1步时，受试者将根据筛选时进行的虚拟表型启动新的挽救治疗方案。入组后2周，所有受试者将获得一份定时血浆样本，用于测定新挽救治疗方案的PI谷水平。该谷水平将与筛选虚拟表型的IC 50倍数变化一起用于计算NIQ。所有受试者将在第4周前收到NIQ结果，以确定其是否有资格在第2步入组时接受随机化或分组。 第2步：在第2步入组时，共180例NIQ = 1的受试者将随机分配至标准治疗（SOC）（A组）或TDM+SOC（B组）。此外，将在观察组（C组）中随访NIQ> 1的50名受试者。注：C组在达到目标增加后于2004年7月28日关闭。第2周NIQ > 1的受试者将永久终止研究。 NIQ = 1的受试者将根据预先规定的剂量调整算法接受PI剂量递增。 PI给药算法由A5146研究团队药理学家制定，并定期更新，以纳入额外的三联PI联合方案、FDA新批准的PI药物以及基于新的可用安全性信息修订的给药建议。研究团队将使用这些剂量调整算法来确定对于有资格接受TDM的受试者，NIQ = 1时是否应递增PI剂量。PI剂量调整建议将以电子报告形式发送给研究中心。 在第24周或之后无病毒学失败的第2步受试者将继续在第2步中接受其原始分配治疗组的随访，直至第48周。第24周或之后病毒学失败的受试者可选择进入步骤3。 第三步：第3步是为第2步初始方案失败的受试者提供TDM选择，与其初始治疗组随机化或分配无关。 第24周或之后，任何步骤2组中确认血浆HIV-1 RNA浓度≥ 1000拷贝/mL的受试者将有资格进入步骤3并接受第二次虚拟表型耐药试验。耐药试验的结果将用于设计第3步挽救治疗方案。将获得第3步挽救治疗方案的重复PI药物水平，并将提供所有受试者第3步挽救治疗方案中任何PI的NIQ值。 NIQ = 1的所有受试者将可选择接受剂量调整的PI治疗，使用与第2步TDM+SOC组中受试者相同的剂量调整算法。第3步中的PI剂量调整不得晚于参与研究的第44周。登记至第3步后，受试者将在第3步接受最长24周的随访，但不超过研究入组后48周（第0周，第1步）。请参见此模式末尾的图表。 在第2步入组时随机分配至A组或B组或分配至C组的受试者将在第1步入组后接受48周随访。在第4周，NIQ = 1的受试者将被随机分配至A组或B组，NIQ >1的受试者将被分配至C组。 A组：SOC B组：TDM+SOC C组：C组（观察性）中的观察性受试者将以与在第2步进入后至第24周随机分配至A组（SOC）的受试者完全相同的方式进行治疗，唯一的差异是其第2周NIQ结果（A组：NIQ = 1; C组：NIQ >1）。注：C组在达到目标增加后于2004年7月28日关闭。 抗逆转录病毒治疗方案将由受试者的临床医生根据虚拟表型耐药检测结果选择和处方。A5146不会提供任何抗逆转录病毒药物。