Study to Evaluate Safety and Toxicity of Polyphenon E (EGCG) in HIV-1-Infected Individuals
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine the safety, toxicity, dosing, and antiviral effects
      of epigallocatechin gallate (EGCG) in capsule form (Polyphenon® E), administered orally twice
      daily at three different doses in HIV-1-infected clinically stable, treatment-naïve and
      treatment-experienced adults not on concomitant antiretroviral (ARV) therapy.
    

Detailed description: 
      HIV-1 infection ultimately results in impaired specific immune function by virtue of the
      initial binding of the HIV-1 virion envelope glycoprotein 120 (gp120) to the CD4 receptor in
      complex with a chemokine receptor on the T-cell surface1. Even though gp120 elicits
      virus-neutralizing antibodies, HIV-1 eludes the immune system and leads to the onset of AIDS.
      Ever since the discovery of the virus as the causative agent, there has been an intense
      effort to develop therapeutic methods to inhibit or prevent infection.2-4 CD4, a cell surface
      glycoprotein expressed on T cells, plays an important role in the recognition of antigens by
      T cells and in their activation.5 It also acts as a receptor for HIV-1 as gp120 binds to it
      via its D1 domain and, uses this interaction to infect CD4+ T cells.5 Therefore, there has
      been interest in finding molecules that block the binding of gp120 to CD4 (entry inhibitors)
      as a way of reducing HIV-1 infectivity.

      Studies have demonstrated evidence of high affinity binding of EGCG to the CD4 molecule with
      a Kd of 10nM with subsequent inhibition of gp120 binding to human CD4+ T cells. EGCG binds in
      the same molecular pocket on CD4, as does HIV-1-gp120 at physiologically relevant
      concentrations.

      This is a phase I, placebo-controlled, dose-blinded, randomized study of Polyphenon® E as
      monotherapy in participants who are HIV-1-infected with a CD+ T lymphocyte count of at least
      250 cells/mm3 and are ARV-naïve or ARV-experienced. There will be 3 dose levels and for each
      dose level, there will be 6 subjects who will receive the study drug and 2 subjects who will
      be randomized to take placebo. Dosing will be escalated sequentially contingent on the safety
      profile of previous doses. Safety data from all participants receiving Polyphenon® E in the
      preceding dose level will be evaluated and considered acceptable prior to escalation to the
      next higher dose. PK analyses will be also performed as each dose level is completed. If at
      least 4 subjects on the active drug in each dose level have evaluable PK data, subjects will
      not be replaced. As the inability to achieve adequate EGCG concentrations that are necessary
      to inhibit HIV-1 replication is a major concern in this study, it is necessary to confirm
      EGCG pharmacokinetics in the event that the primary outcome measure of virologic response is
      not observed for each dose level. For each PK visit on Study Days 1 and 14, a total of 10
      blood samples will be obtained per subject. If only a few samples cannot be used (this
      depends on the individual subject's pharmacokinetic profile, although one or two unevaluable
      samples will not likely cause a subject's data to be unevaluable), PK analyses can still be
      performed and will not require subjects to be deemed unevaluable and replaced.
    

Intervention name(s): Polyphenon E; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): There will be 3 dose levels and for each dose level, there will be 6 subjects who will receive the study drug and 2 subjects who will be randomized to take placebo. Dosing will be escalated sequentially contingent on the safety profile of previous doses. Safety data from all participants receiving Polyphenon® E in the preceding dose level will be evaluated and considered acceptable prior to escalation to the next higher dose. PK analyses will be also performed as each dose level is completed. It is necessary to confirm EGCG pharmacokinetics in the event that the primary outcome measure of virologic response is not observed for each arm. For each PK visit on Study Days 1 and 14, a total of 10 blood samples will be obtained per subject.
Other intervention name(s): EGCG; epigallocatechin gallate; green tea catechin; green tea extract
Intervention MeSH terms: Epigallocatechin gallate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: HIV; safety; toxicity; pharmacokinetics; Polyphenon E; EGCG; green tea; CD4; viral load