Study of Pre-clearance of Latent Tuberculosis Infection And BCG Revaccination
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this research is to further study the tuberculosis (TB) vaccine, Bacillus
      Calmette Guérin (BCG). The goal of this study is to evaluate whether the BCG vaccine is more
      effective in preventing TB in adults if it is given after 6 months of treatment with a widely
      used anti-TB drug, isoniazid (INH). Participants will include 82 healthy, tuberculin skin
      test positive (TST+), HIV-uninfected, male and female volunteers, aged 18-40 years. The study
      will be conducted in Worcester, South Africa. Subjects will be assigned by chance to 1 of 2
      possible treatment groups. Group 1 will receive 6 months of oral INH treatment followed by
      intradermal (administered into the skin) BCG revaccination and one year of follow-up. Group 2
      will be observed for 7 months which will be followed by intradermal BCG revaccination and
      another 6 months of follow-up. Then 6 months of INH treatment will be given. Participants
      will be involved in study procedures for about to 22 months.
    

Detailed description: 
      This study is a phase I, single-center, open label, randomized controlled clinical trial
      assessing the effect of pre-clearance of latent Mycobacterium tuberculosis (MTB) by
      Isoniazid, isonicotinic acid hydrazine (INH) treatment before Bacillus Calmette-Guérin (BCG)
      revaccination versus BCG revaccination alone on mycobacterial-specific immune responses in
      tuberculin skin test (TST) positive adults. Subjects initially assigned to observation prior
      to BCG revaccination will receive INH treatment of latent tuberculosis infection (LTBI)
      beginning six months after revaccination. Volunteers will include 82 healthy, TST positive
      human immunodeficiency virus (HIV)-uninfected, male and female persons aged 18-40 years. The
      primary objectives of the study are to: determine the effect of INH preclearance on the
      kinetics and characteristics of the specific immune response following BCG revaccination in
      adults with latent MTB infection (TST positive); and determine the safety and reactogenicity
      of BCG revaccination in TST positive adults. The secondary objectives of the study are to:
      determine the effect of INH preclearance and BCG revaccination on MTB-specific Th1 effector
      and central memory cell function; determine the effect of INH preclearance and BCG
      revaccination on MTB-specific Treg cell function; and determine the effect of INH
      preclearance and BCG revaccination on innate immune responses as measured by T cell mediated
      inhibition of intracellular mycobacterial growth and inflammatory cytokine production. All
      subjects are expected to be enrolled over 12 months. The duration of screening, enrollment,
      and follow-up for subjects is up to 22 months. Subjects will be randomly assigned to receive
      either: 6 months of INH treatment for LTBI (completed within no more than 7 months) followed
      by intradermal BCG revaccination or 7 months of observation (run in period) followed by
      intradermal BCG revaccination followed after 6 months of observation by 6 months of INH
      treatment for LTBI. Both groups will receive their BCG vaccinations during the same time
      period. Volunteers will be evaluated at 7 and 14 days and 1, 3, 6 and/or 12 months after BCG
      revaccination and each month of INH therapy and the end of study for safety, reactogenicity
      and immunogenicity. Blood for immunologic studies will be drawn at study enrollment for
      subjects, just prior to BCG revaccination, and 1, 2 weeks and 1, 3 and either 6 or 12 months
      (depending on which study arm) after BCG vaccination, and months 1, 3, 6 of INH therapy and
      the end of study for measurement of MTB specific T cell responses. Both treatment arms will
      be followed for safety and immunogenicity endpoints for 12 months after BCG revaccination.
      Immunologic outcomes have been chosen with the goal of measuring the characteristics and
      kinetics of human immune responses following BCG vaccination to support the ultimate aim of
      developing methods to determine the biological relevance of immune responses induced by BCG
      revaccination and their relevance to protection from tuberculosis (TB). Overall, this study
      may provide key information on the characteristics and kinetics of immune responses following
      BCG revaccination in adults and whether these are affected by preclearance with INH treatment
      of LTBI.
    

Intervention name(s): BCG strain Danish; Isoniazid
Intervention type(s): Biological; Drug
Intervention description(s): Intradermal Bacillus Calmette-Guerin (BCG) live-attenuated vaccine prepared using the Danish 1331 BCG substrain; adult dose contains 2 to 8 x 10^5 colony forming units (CFU) BCG.; United States Pharmacopeia 100 mg or 300 mg oral tablets [5 mg/kilogram/day (rounded up to nearest 100 mg; maximum dose 300 mg/day)].
Intervention MeSH terms: Isoniazid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: South Africa,tuberculosis,vaccine