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.

该主题项目是利用NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是针对该中心的，这不是调查人员的机构。 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（PIS）的剂量修饰是否可以改善PI-经验受试者的病毒学反应。比对PI敏感的HIV在体外，耐PI抗抗毒的HIV需要更高的PI水平。 A5146将使用治疗药物监测（TDM）来优化PI药物浓度。最佳药物水平将通过确定在第1步研究条目中启动的受试者打捞方案中每个PI的归一化抑制引号（NIQ）来计算。 NIQ考虑了有关受试者病毒对该药物的抗药性程度的引起血浆PI药物水平困扰的受试者（请参见下面的计算）。目的是让受试者血浆PI药物水平高于抑制受试者病毒所需的药物水平。 > 1的NIQ意味着智商比对同一PI有良好响应的受试者的智商高。 NIQ = 1表示受试者的智商低于对同一PI有良好反应的受试者的智商。低药物水平或高水平的病毒耐药性可能导致NIQ较低（= 1）。对于所有PI，这项研究的目标NIQ为1.0。筛查：经验丰富的治疗经验的受试者在至少一个含PI的抗逆转录病毒组合方案中将进行筛查耐药性测试，同时使用虚拟表型进行筛查测试。 A5146分为以下三个步骤：步骤1：步骤1是确定哪些受试者具有NIQS = 1或>1。在进入步骤1时，受试者将根据筛选时执行的虚拟表型启动新的打捞方案。进入两周后，所有受试者将在新的打捞方案上获得PI故障水平的定时等离子体样本。该故障级别将与IC50中的倍数变化一起从筛选虚拟表型中用于计算NIQ。所有受试者都将在第4周之前收到NIQ结果，以确定其在步骤2条目中进行随机化或ARM分配的资格。步骤2：在步骤2条目下，总共有180名NIQ = 1的受试者将被随机分配为护理标准（SOC）（ARM A）或TDM+SOC（ARM B）。此外，将在观察臂（ARM C）中遵循50名NIQ> 1的受试者。注意：到达目标振准后，ARM C C于07/28/04关闭。第2周NIQ> 1的受试者将永久停止研究。 NIQS = 1的受试者将根据预先指定的剂量调整算法接受PI剂量升级。 PI剂量算法是由A5146研究团队药理学家得出的，并定期更新，以包括其他Triple-PI组合方案，新近FDA批准的PI代理以及基于新的可用安全信息的修订剂量建议。研究团队将使用这些剂量调整算法来确定是否应在有资格接收TDM的受试者中为NIQ = 1升级PI剂量。 PI剂量调整建议将在电子报告中传输到该站点。步骤2中第24周或更晚的病毒性衰竭的受试者将继续在第48周的原始分配治疗组的步骤2中继续遵循。在第24周或更晚时，患有病毒性衰竭的受试者可能会选择输入步骤3。在第2步中，在24或第24周之后具有确认的等离子HIV-1 RNA浓度为= 1000拷贝/mL的受试者都有资格进入步骤3并接受第二次虚拟表型耐药性测试。电阻测试的结果将用于设计步骤3打捞方案。将在此步骤3打捞方案上获得重复PI药物水平，并且所有受试者将为第3步挽救方案中任何PI的NIQ值提供。所有具有NIQS = 1的受试者都将使用相同的剂量调整算法接受剂量调整后的PI治疗，该算法在第2步，TDM+SOC ARM中用于受试者。步骤3中的PI剂量调整不能比研究参与的第44周更晚。在注册步骤3后，步骤3最多将遵循24周的受试者，但在研究进入后不超过48周（第0周，步骤1）。请参见此模式末尾的图。步骤2进入ARM A或B或分配给ARM C的受试者将在第1步条目后48周进行。在第4周，具有NIQ = 1的受试者将随机分配为A臂A或B，并且NIQ> 1的受试者将被分配给ARMC。C。ARM A：ARM A：SOC ARM B：TDM+SOC ARM C：ARM C中的观察受试者C（观察）的观察受试者（观察）将以与对象相同的方式与ARM A（SOC 2）的单位相同的方式= SOC a（soc）在第2周之后的ARM A ARM A ARM A ARM A ARM A ARM（SOC）24 ni ni 2; soc a ni ni ni ni; NIQ> 1）。注意：到达目标振准后，ARM C C于07/28/04关闭。根据虚拟表型抗性测试的结果，将由受试者的临床选择和处方抗逆转录病毒方案。 A5146将不提供任何抗逆转录病毒药物。