T 20 ADMINISTERED TO HIV 1+ ADULTS BY SUBCUTANEOUS INFUSION OR INJECTION

这项多中心、随机、II期有效剂量比较研究的目的是评估T-20连续皮下注射(CSI)或皮下注射(SQI)给HIV-1阳性成人28天的安全性、血浆药代动力学和抗病毒活性。尽管含有蛋白酶抑制剂的疗法具有抗病毒效果，但大约20%-50%的受试者将在开始治疗的52周内表现出HIV-1RNA水平的反弹。此外，对有抗逆转录病毒治疗经验的受试者的治疗不如对抗逆转录病毒治疗天真的受试者成功。对于PI失败的抢救方案的6个月成功率从10%到60%不等。挽救方案的失败至少部分是由于RTIs和PIs之间存在广泛的类内交叉耐药性。研究试剂T-20是一种由36个氨基酸组成的合成肽，由天然的L氨基酸残基组成。T-20的一级序列来源于HIV-1 LAI的gp41跨膜糖蛋白中的一个自然产生的基序(氨基酸残基643-678)。非临床作用机制研究的结果表明，T-20通过与gp4l的关键区域结合而显示出有效和选择性的抑制新生感染和细胞间病毒传播的作用，gp4l调控病毒与宿主细胞膜的融合。一项I/II期临床试验的结果表明，T-20在所有剂量水平下都是安全的，并在按BID计划静脉注射100毫克连续14天时显示出强大的抗逆转录病毒活性。符合参加条件的受试者将被随机分到六组中的一组，由CSI以四种剂量水平(12.5毫克、25毫克、50毫克和100毫克)给予T-20；或由SQI每12小时给予两种剂量水平(50毫克和100毫克)的T-20。研究的总参与时间为7周，包括2周的筛查期、28天的治疗期和1周的随访期。大约78名艾滋病毒感染者(13名受试者/ARM)将在12个中心登记。对先前的抗逆转录病毒暴露没有限制。要求两周内没有当前的抗逆转录病毒治疗，或者6周内没有稳定的抗逆转录病毒方案，筛查时病毒载量和病毒载量为5000拷贝/毫升(第15天至第10天)，并且没有活动性机会性感染。疗效终点包括：CD4和HIV RNA较基线的变化，HIV RNA和GT变化的受试者百分比；较基线的1.0log10变化，CSI组(强化治疗第0天，CPSS在第1、4、7、14、21和28天)和SQI治疗组(强化治疗的第0和14天，第1、4、7、21和28天的低谷)的T-20 PK研究，以及安全性(血液学、血清化学、尿液分析和自发不良事件)。

The purpose of this multi-center, randomized, phase II, active dose comparison study is to evaluate the safety, plasma pharmacokinetics, and antiviral activity of T-20 given by continuous subcutaneous infusion (CSI) or subcutaneous injection (SQI) to HIV-1 positive adults for 28 days. Despite the antiviral efficacy associated with protease inhibitor-containing regimens, approximately 20%-50% of the subject population will exhibit a rebound in HIV-1 RNA levels within 52 weeks of initiating therapy. In addition, the treatment of antiretroviral experienced subjects has been less successful than the treatment of subjects who are naive to antiretroviral therapy. The six-month success rate of salvage regimens for PI failures has varied from 10-60%. Failure of salvage regimens is at least partially due to broad intra-class cross-resistance which exists among RTIs and PIs. The investigational agent, T-20, is a 36-amino acid synthetic peptide composed of naturally-occurring L-amino acid residues. The primary sequence of T-20 was derived from a naturally-occurring motif (amino acid residues 643-678) within the gp4l transmembrane glycoprotein of HIV-1 LAI. The results of nonclinical mechanism of action studies indicate that T-20 exhibits potent and selective inhibition of de novo infection and cell to cell virus transmission by binding to a critical region of gp4l which regulates the fusion of virus to host cell membranes. Results of a Phase I/II clinical trial indicate that T-20 was safe at all dose levels evaluated and exhibited potent antiretroviral activity when given as a 100 mg intravenous administration on a BID schedule for 14 days. Eligible subjects who qualify for participation will be randomized to one of six groups, T-20 to be given by CSI at four dose levels (12.5 mg, 25 mg, 50 mg, and 100 mg); or T-20 to be given by SQI every 12 hour at two dose levels (50 mg and 100 mg). The total study participation will be 7 weeks, including a 2-week screening period, a 28-day treatment period, and a 1-week follow-up period. Approximately 78 HIV-infected adults (13 subjects/arm) will be enrolled at 12 centers. There are no limitations on prior antiretroviral exposure. It is required that there be no current antiretroviral therapy for >2 weeks or stable antiretroviral regimen >6 weeks, viral load >5,000 copies/mL at screen (Day -15 to -10), and the absence of active opportunistic infections. Efficacy endpoints include: CD4 and HIV RNA change from baseline, % subjects achieving change in HIV RNA > 1.0 log10 change from baseline, T-20 PK studies in the CSI arms (intensive Day 0 and Cpss at Days 1, 4, 7, 14, 2 1, and 28) and SQI arms (intensive Days 0 and 14, and troughs at Days 1, 4, 7, 2 1, and 28), and safety (hematology, serum chemistry, urinalysis and spontaneous adverse events.