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

T 20 通过皮下输注或注射给药于 HIV 1 成人

• 批准号: 6309223
• 负责人: ROBERTO CLAUDIO ARDUINO
• 金额: $ 1.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6309223
• 关键词: AIDS therapy; CD4 molecule; HIV envelope protein gp41; HIV infections; antiAIDS agent; antiviral agents; clinical research; clinical trial phase I; drug administration rate /duration; drug screening /evaluation; human immunodeficiency virus; human subject; human therapy evaluation; injection /infusion; intravenous administration; longitudinal human study; opportunistic infections; pharmacokinetics; protease inhibitor; virus RNA

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.

这项多中心、随机、II期、活性剂量比较研究的目的是评价T-20通过连续皮下输注（CSI）或皮下注射（SQI）给予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。 尽管含蛋白酶底物的治疗方案具有抗病毒疗效，但约20%-50%的受试者人群在开始治疗后52周内会出现HIV-1 RNA水平反弹。此外，与未接受过抗逆转录病毒治疗的受试者相比，对有抗逆转录病毒治疗经验的受试者的治疗不太成功。 PI失败的挽救治疗方案的6个月成功率为10- 60%。挽救治疗方案的失败至少部分是由于RTI和PI之间存在广泛的类内交叉耐药。 研究药物T-20是一种由天然L-氨基酸残基组成的36个氨基酸合成肽。 T-20的一级序列源自HIV-1 LAI的gp 4l跨膜糖蛋白内天然存在的基序（氨基酸残基643-678）。非临床作用机制研究的结果表明，T-20通过与调节病毒与宿主细胞膜融合的gp 4l的关键区域结合，对从头感染和细胞间病毒传播表现出强效和选择性抑制。一项I/II期临床试验的结果表明，T-20在评价的所有剂量水平下都是安全的，并且在以BID方案静脉内给予100 mg持续14天时表现出强效抗逆转录病毒活性。 有资格参与研究的合格受试者将被随机分配至6个组之一，由CSI以4个剂量水平（12.5 mg、25 mg、50 mg和100 mg）给予T-20;或由SQI以2个剂量水平（50 mg和100 mg）每12小时给予T-20。 总研究参与期为7周，包括2周筛选期、28天治疗期和1周随访期。 将在12家临床试验机构入组约78例HIV感染成人（13例受试者/组）。 对先前的抗逆转录病毒暴露没有限制。 要求当前无抗逆转录病毒治疗>2周或稳定的抗逆转录病毒方案>6周，筛选时病毒载量> 5，000拷贝/mL（第-15天至第-10天），并且不存在活动性机会性感染。 疗效终点包括：CD 4和HIV RNA较基线的变化，HIV RNA较基线变化> 1.0 log 10的受试者百分比，CSI组的T-20 PK研究（强化第0天和第1、4、7、14、21和28天的Cpss）和SQI组（强化第0和14天，以及第1、4、7、21和28天的谷值）和安全性（血液学、血清化学、尿分析和自发不良事件）。