PACTG P1038

PACTG P1038

• 批准号: 7604657
• 负责人: Deborah Persaud
• 金额: $ 0.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604657
• 关键词: Acyclovir; Adolescent; Affect; Algorithms; Analysis of Variance; Anti-Retroviral Agents; Antiviral Agents; Benign; Biological Assay; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Candida; Cell Count; Chemotherapy-Oncologic Procedure; Child; Chronic; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Computer Retrieval of Information on Scientific Projects Database; Data; Deglutition; Dose; Drug Kinetics; Drug usage; Drug-sensitive; Enrollment; Failure; Fluconazole; Funding; Goals; Grant; Growth; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Immune system; Immunologics; In Vitro; Institution; Investigation; Label; Lead; Life; Lopinavir; Lopinavir/Ritonavir; Medical; Methods; Multi-Drug Resistance; Numbers; Opportunistic Infections; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Progress Reports; Protocols documentation; Publications; RNA; Relative (related person); Research; Research Design; Research Personnel; Resistance; Resources; Risk; Safety; Saquinavir; Site; Source; Specialist; Specific qualifier value; Standards of Weights and Measures; Symptoms; Textbooks; Time; Toxic effect; Treatment Failure; Treatment Protocols; United States National Institutes of Health; Vaccination; Viral; Viral load measurement; Viremia; Virion; Virus; Virus Replication; Week; antiretroviral therapy; cancer cell; capsule; chemotherapy; concept; drug resistant virus; experience; improved; non-nucleoside reverse transcriptase inhibitors; oncology; prevent; response; success; tumor

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. -Goals and Methods (provide the page reference to the research design/statistical analysis section of the full protocol) - Goals: Pages 37-38 This is a "proof of concept" study, designed to examine the feasibility of treating subjects who have failed PI-containing HAART therapy with high doses of LPV/r. The primary objectives of the study are to estimate pharmacokinetic parameters for LPV/r and SQV (see section 9), and to examine the safety of LPV/r and SQV at the doses specified in section 5 of this protocol. PACTG P1038 is a Phase I/II, open label study of high dose lopinavir/ritonavir (LPV/r) to assess the safety, tolerability, and pharmacokinetics of LPV/r with or without saquinavir (SQV) in HIV-infected children and adolescents who have at least six months of prior PI experience and are failing their current antiretroviral therapy (plasma HIV RNA 5000 copies/mL). The study will seek to enroll 48 subjects = 2 years to 15. Each of these factors is intertwined with other effects which may affect treatment success: some subjects currently on an NNRTI will be treated at higher doses of LPV/r to compensate for the reduction of LPV/r concentrations when co-dosed with NNRTIs, and subjects failing to achieve IQ = 15 will have saquinavir added to their regimens, provided that they can swallow the saquinavir capsules (see schema). In the analyses described below, the extent to which achieving an IQ = 15 predicts long term virologic and immunologic success may be confounded by use of NNRTIs or saquinavir, which may successfully compensate for failure to achieve a LPV/r IQ = 15, thereby eliminating the potential virologic advantage of those who do meet this criteria. Co-variance analyses will be used in an attempt to control for these potentially confounding factors, but complete adjustment for confounding will not be possible This study will use a higher than standard dose of lopinavir. The rationale for this is that "resistance" to most antivirals is a relative phenomenon, i.e. even in vitro "resistant" strains of HIV-1 are rarely 100% resistant. If higher doses of the drug are used, viral replication can be suppressed even in "resistant" clones. The net result will be the suppression of a greater number of virions. This strategy has been successfully employed in other infectious diseases (higher doses of fluconazole to treat candida, higher acyclovir doses for longer chronic suppression) and oncology (multi-drug resistant cancer cells can be eliminated with higher doses). In fact "dose intensity" (i.e. the amount of drug given per unit time) is a fundamental principle in cancer chemotherapy (50, 51). Standard oncology textbooks warn "ad hoc adjustment of dosing is a major reason for treatment failure in patients with drug-sensitive human tumors undergoing their first chemotherapy treatment" (50). The goal of therapy is long-lasting control of HIV replication to prevent or reverse HIV-related symptoms, or immune system suppression. Combination therapy with three or more antiretroviral medications is better than therapy with monotherapy or therapy with only 2 antiretrovirals (5-12), and triple-drug therapy is currently recommended for treatment of patients with HIV infection (13-18). Potent multi-drug therapy can decrease virus replication (4, 19, 20), reduce plasma virus load to below limits of quantitation on sensitive assays (BLQ), reverse symptoms of HIV infection (21-26), improve growth (27-31), and lead to improved immune system function, including increased CD4+ cell count, decreased CD8+ cell count, and improved response to vaccination (32-37). While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of treated subjects will have regimen failure and return of detectable plasma virus within one year (8, 9, 38, 39). Loss of control of HIV replication can be benign in some subjects, who will have sustained high or rising CD4+ cell counts, no risk of opportunistic infection, and no symptoms of HIV infection (40-43). However, in other subjects, return of plasma viremia may be associated with a decrease in CD4+ cell count, selection of drug-resistant virus, and return of symptoms of HIV or opportunistic infection (38). Progress report will be made available to the participating sites. The safety data from the first six subjects enrolled in P1038 will be reviewed when the sixth subject has been on treatment for 4 weeks. The following algorithm will be applied to determine whether an intensive review of safety data, with the potential for stopping accrual to the study or stopping study treatment for all subjects enrolled in the study, should be performed: 1) Fail, if 1 or more subjects have drug related life threatening toxicity 2) Fail, if 3 or more subjects have drug related, non-life-threatening Grade 3 or 4 toxicity If either of the criteria for safety failure is met, accrual to the study will be suspended, pending a thorough investigation of the safety data by a committee which will include: the Chair, Vice Chairs, Medical Officers, Statisticians, Clinical Trials Specialist from P1038, a representative from the Primary Therapy RAC, and Abbott and Roche representatives There are no publications to date that have resulted from this study.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 - 目标和方法（提供完整方案的研究设计/统计分析部分的页面参考） - 目标：第37-38页 这是一项“概念验证”研究，旨在检查用高剂量LPV/r治疗含PI的HAART治疗失败的受试者的可行性。 本研究的主要目的是估计LPV/r和SQV的药代动力学参数（见第9节），并检查LPV/r和SQV在本方案第5节规定剂量下的安全性。 PACTG P1038是一项在既往至少有6个月PI经验且当前抗逆转录病毒治疗失败（血浆HIV RNA 5000拷贝/mL）的HIV感染儿童和青少年中开展的高剂量洛匹那韦/利托那韦（LPV/r）的I/II期、开放标签研究，旨在评估LPV/r联合或不联合沙奎那韦（SQV）的安全性、耐受性和药代动力学。 本研究将招募48例受试者= 2岁至15岁。 这些因素中的每一个都与可能影响治疗成功的其他效应交织在一起：目前正在接受NNRTI的一些受试者将接受更高剂量的LPV/r治疗，以补偿与NNRTI联合给药时LPV/r浓度的降低，而未能达到IQ = 15的受试者将在其治疗方案中添加沙奎那韦，前提是他们可以吞咽沙奎那韦胶囊（见图表）。在下文描述的分析中，达到IQ = 15预测长期病毒学和免疫学成功的程度可能会受到NNRTI或沙奎那韦的混淆，这可能会成功补偿未能达到LPV/r IQ = 15的情况，从而消除符合该标准的患者的潜在病毒学优势。 将使用协方差分析试图控制这些潜在的混杂因素，但不可能对混杂因素进行完全调整 本研究将使用高于标准剂量的洛匹那韦。其理由是，对大多数抗病毒药物的“耐药性”是一种相对现象，即即使是HIV-1的体外“耐药”菌株也很少有100%的耐药性。 如果使用更高剂量的药物，即使在“耐药”克隆中也可以抑制病毒复制。 最终结果将是抑制更多数量的病毒体。 这一策略已成功应用于其他感染性疾病（更高剂量的氟康唑治疗念珠菌，更高剂量的阿昔洛韦治疗更长时间的慢性抑制）和肿瘤学（可以用更高剂量消除多药耐药癌细胞）。 事实上，“剂量强度”（即每单位时间给予的药物量）是癌症化疗的基本原则（50，51）。 标准肿瘤学教科书警告说：“剂量的临时调整是首次接受化疗的药物敏感性人类肿瘤患者治疗失败的主要原因”（50）。 治疗的目标是长期控制HIV复制，以预防或逆转HIV相关症状或免疫系统抑制。 三种或三种以上抗逆转录病毒药物的联合治疗优于单药治疗或仅使用两种抗逆转录病毒药物的治疗（5-12），目前推荐三联药物治疗HIV感染患者（13-18）。 有效的多药物治疗可以减少病毒复制（4，19，20），将血浆病毒载量降低至低于灵敏测定的定量限（BLQ），逆转HIV感染的症状（21-26），改善生长（27-31），并导致改善的免疫系统功能，包括增加的CD 4+细胞计数，减少的CD 8+细胞计数，和对疫苗接种的反应改善（32-37）。 虽然强效治疗方案最初可将大多数HIV感染者的病毒载量降低至检测定量限以下，但30%至80%的治疗受试者将在1年内出现治疗方案失败和可检测到的血浆病毒恢复（8，9，38，39）。 HIV复制失控在某些受试者中可能是良性的，这些受试者将具有持续的高或上升的CD 4+细胞计数，没有机会性感染的风险，并且没有HIV感染的症状（40-43）。 然而，在其他受试者中，血浆病毒血症的恢复可能与CD 4+细胞计数减少、耐药病毒的选择以及HIV或机会性感染症状的恢复有关（38）。 将向参与研究中心提供进度报告。当第6例受试者接受治疗4周后，将审查入组P1038的前6例受试者的安全性数据。 将应用以下算法确定是否应对安全性数据进行密集审查，可能会停止入组研究或停止所有入组研究的受试者的研究治疗： 第一章 失败，如果1例或多例受试者发生药物相关危及生命的毒性 （二） 如果3例或以上受试者发生药物相关、非危及生命的3级或4级毒性，则为失败 如果符合安全性失败的任一标准，则将暂停研究入组，等待委员会对安全性数据进行彻底调查，委员会将包括：主席、副主席、医学官员、统计员、P1038的临床试验专家、主要治疗RAC的代表以及Abbott和Roche代表 迄今为止，本研究尚未发表任何出版物。