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

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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.