A Phase I/IIa AERAS-456 in HIV-Negative Adults With & Without Latent Tuberculosis Infection (C-035-456)
Condition: Latent Tuberculosis Bacteriology and Histology Unknown; Latent Tuberculosis
MeSH terms: Tuberculosis; Latent Tuberculosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a Phase I/IIa, double-blind, randomized, placebo-controlled, dose- and
      regimen-finding study in healthy adults with and without LTBI, who are BCG-vaccinated, HIV
      negative, and have no history or evidence of TB disease. The investigational product is
      AERAS-456 at 3 dose levels: 5, 15, and 50ug of H56 antigen with 500 nmol IC31. The vaccine is
      administered by IM injection.
    

Detailed description: 
      This is a Phase I/IIa, double-blind, randomized, placebo-controlled, dose- and
      regimen-finding study in healthy adults with and without latent Tuberculosis (TB) Infection,
      who are Bacille Calmette Guerin (BCG)-vaccinated, HIV negative, and have no history or
      evidence of TB disease. The investigational product is AERAS-456 at 3 dose levels: 5, 15, and
      50ug of H56 antigen with 500 nmol IC31. The vaccine is administered by intramuscular (IM)
      injection. The study will be conducted at two sites in South Africa.

      A total of 98 subjects will be enrolled in 2 phases into 4 groups based on Latent TB
      Infection (LTBI) status. The initial phase will be a dose ranging study of a 2-dose regimen
      at 3 dosage levels in LTBI(-) subjects, to select a dosage for the second phase. In the
      second phase, the study will be expanded to evaluate both 2-dose and 3-dose regimens and to
      include LTBI(+) subjects. In the first phase, 50 LTBI(-) subjects will be enrolled in Group 1
      and randomized at a ratio of 3:3:3:1 to receive 2 doses of 5/500, 15/500, or 50/500 of
      AERAS-456, or placebo given at Study Days 0 and 56 (Table 0 1).

      One dose level of AERAS-456 will be selected by the sponsor and SSI for the second phase of
      the study, based on analysis of unblinded safety and immunogenicity data through 28 days
      after the second dose in the first phase, in conjunction with safety and immunogenicity data
      from study C-032-456. The criteria for dose-selection will be specified in a statistical
      analysis plan to be finalized prior to the unblinded review. The selected dose, in
      conjunction with the unblinded safety and immunogenicity data, will be submitted to the SMC
      for review. In the second phase, 48 subjects will be enrolled concurrently into Group 2
      (LTBI[-]) and into Groups 3 and 4 (LTBI[+], Table 0 2). In each of Groups 2 and 4, 16
      subjects will be randomized at a ratio of 3:1 to receive 3 doses of AERAS-456 or placebo
      given at Study Days 0, 56, and 112. In Group 3, 16 subjects will be randomized at a ratio of
      3:1 to receive 2 doses of AERAS-456 or placebo given at Study Days 0 and 56.

      All subjects will stay on the study for 292 days after receiving the first vaccination. The
      subjects in Groups 1 and 3 will be followed up for 236 days after the second vaccination and
      subjects in Groups 2 and 4 will be followed up for 180 days after the third vaccination. The
      sample size for each study cohort was selected because it was judged to be adequate for
      preliminary safety and immunogenicity evaluations for a Phase I/IIa study rather than for
      statistical reasons. Given 12 and 15 subjects in individual AERAS-456 dosing groups, the
      study will have an 80% probability of detecting at least 1 specified event which occurs at a
      rate of 12.5% and 10.0%, respectively. If no such events are observed among 12 and 15
      subjects receiving active study vaccine, an approximation to the upper one-sided 95%
      confidence bound on the rate of occurrence for that event would be 22% and 18%, respectively.
    

Intervention name(s): H56ug/IC31nmol; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): H56:IC31 (designated as AERAS-456 for Aeras-sponsored clinical development) contains a fusion protein (referred to as H56 antigen, or H56) of 3 mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant.; Sterile buffer consisting of 10mM Tris and 169mM NaCl at pH 7.4
Other intervention name(s): AERAS-456
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: A 2 phase study based on LTBI status. Phase 1 is a dose ranging study of a 2 dose regimen at 3 dosage levels and placebo in LTBI negative participants. The second phase evaluated 2 and 3 dose regimens and included + and - LTBI participants.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: BCG Vaccinated; HIV Negative