ANTIRETROVIRAL ACTIVITY OF HYDROXYUREA ALONE AND IN COMBINATION WITH DDI

羟基脲单独和与 DDI 组合的抗逆转录病毒活性

• 批准号: 6415298
• 负责人: CAROL S DUKES-HAMILTON
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415298
• 关键词: 2'3' dideoxyinosine; AIDS therapy; HIV infections; clinical research; clinical trial phase I; combination chemotherapy; dosage; drug adverse effect; drug screening /evaluation; human subject; hydroxyurea; pharmacokinetics

Purpose: The purpose of this study is to determine whether hydroxyurea is safe and well tolerated at the two doses that will be examined alone and in combination with ddI, and whether there will be a more favorable antiviral effect when ddI and hyroxyurea are used in combination as compared to either one used as monotherapy Rationale Deoxyribonucleotide triphosphates (dNTPs) are the building blocks for cellular DNA and are synthesized de novo within the cell. Therefore, cellular DNA synthesis is dependent on the enzyme ribonucleotide reductase (RR), which catalyzes all four ribonucleotides to the reduced deoxy-form. HIV replication can be decreased by interfering with the concentration of dNTPs. Hydroxyurea inhibits RR activity and thus halts cellular DNA synthesis, and decreases the efficiency of HIV reverse transcription. This activity is synergistic with nucleoside RT inhibitor. In vitro testing shows greater synergy between hydroxyurea and DDI than with ZDV. Methods: This is a 24 week, phase I/II, randomized, double-blind, dose-ranging study in HIV-infected adults, whose CD4 lymphocyte count is between 200-500. There will be two 12-week treatment periods and 5 study arms. Pharmacokinetic monitoring will be performed on all subjects. Specimens for quantitative HIV RNA levels, CD4+/CD8+ lymphocyte counts, and dATP measurements will be obtained on weeks 2, 4, 8, 12 and 24. The initial 12-week portion of the study is designed to gather data that will be used to perform an antiretroviral activity analysis. The principal comparison used in the antiretroviral activity analysis will be between the hydroxyurea + ddI combination therapy arms and the ddI monotherapy arm. The Week 8 plasma HIV RNA levels will be used in this comparison. After the completion of Week 12, subjects on combination therapy will remain on their current therapy; and subjects on ddI monotherapy will remain on ddI and have hydroxyurea added at an assigned dose (1:1 randomization) of 1000 mg qd or 1500 mg qd. Randomization of subjects in the ddI monotherapy arm to low or high dose hydroxyurea + ddI combination therapy at Week 12 will have occurred at study entry. Therefore, all subjects will receive combination therapy during Weeks 12 to 24, with half receiving hydroxyurea at a dose of 1000 mg qd and half receiving hydroxyurea at a dose of 1500 mg qd. During Weeks 12 to 24, all study medication will be open label with no placebos. The following clinical and laboratory evaluations will be performed at scheduled intervals. Targeted physical exam based on new and ongoing signs or symptoms at Weeks 4, 8, 12, 18, and 24; weight at Weeks 4, 12, 24; Karnofsky status, urinalysis with microscopic examination, and serum beta-HCG test for women of child-bearing potential at Weeks12 and 24; CBC with MCV, differential and platelets; electrolytes, liver function tests, amylase, alkaline phosphatase and total bilirubin will be done at Weeks 2, 4, 8, 12, 18 and 24. Results and Future Plans: The study is ongoing and treatment arms remain blinded, therefore study conclusions and significance can not yet be discussed. The study is currently closed to accrual, though patients are continuing to be followed. A longer-term follow-up phase is being contemplated.

目的：本研究的目的是确定单独使用和与ddI联合使用两种剂量的羟基脲是否安全且耐受良好，以及ddI和HYROxyurea联合使用时是否比单独使用任何一种时具有更有利的抗病毒效果。是细胞DNA的基石，在细胞内重新合成。因此，细胞DNA合成依赖于核糖核苷酸还原酶（RR），该酶将所有四种核糖核苷酸催化为还原的脱氧形式。可以通过干扰dNTPs的浓度来减少艾滋病毒的复制。羟基脲抑制RR活性，从而停止细胞DNA合成，并降低HIV逆转录的效率。该活性与核苷RT抑制剂具有协同作用。体外试验显示，与ZDV相比，羟基脲和DDI之间具有更大的协同作用。研究方法：这是一项为期24周、I/II期、随机、双盲、剂量范围研究，受试者为HIV感染的成人，其CD 4淋巴细胞计数在200-500之间。将有两个12周的治疗期和5个研究组。将对所有受试者进行药代动力学监测。将在第2、4、8、12和24周采集用于定量HIV RNA水平、CD 4 +/CD 8+淋巴细胞计数和dATP测量的标本。研究的最初12周部分旨在收集将用于进行抗逆转录病毒活性分析的数据。抗逆转录病毒活性分析中使用的主要比较将在羟基脲+ ddI联合治疗组和ddI单药治疗组之间进行，该比较将使用第8周血浆HIV RNA水平。第12周完成后，接受联合治疗的受试者将继续接受当前治疗;接受ddI单药治疗的受试者将继续接受ddI治疗，并以1000 mg qd或1500 mg qd的指定剂量（1：1随机化）添加羟基脲。第12周时，ddI单药治疗组中的受试者将在研究入组时随机分配至低或高剂量羟基脲+ ddI联合治疗组。因此，所有受试者将在第12 - 24周期间接受联合治疗，一半受试者接受1000 mg qd剂量的羟基脲，一半受试者接受1500 mg qd剂量的羟基脲。第12 - 24周期间，所有研究药物均为开放标签，不含安慰剂。将在计划的时间间隔进行以下临床和实验室评价。第4、8、12、18和24周时基于新的和持续的体征或症状进行有针对性的体格检查;第4、12、24周时的体重;第12和24周时有生育能力的女性的Karnofsky状态、尿分析和显微镜检查以及血清β-HCG检测; CBC和MCV、分类计数和血小板;将在第2、4、8、12、18和24周进行电解质、肝功能检查、淀粉酶、碱性磷酸酶和总胆红素检查。结果和未来计划：该研究正在进行中，治疗组仍保持盲态，因此尚不能讨论研究结论和意义。该研究目前已停止招募，但患者仍在继续接受随访。正在考虑一个较长期的后续阶段。