Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the MDR Tuberculosis Pandemic
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      Tuberculosis (TB) is a global challenge and for the increasing epidemic of multi-drug
      resistant (MDR)-TB there is restricted treatment options. This calls for research of new
      immune-modulating treatment strategies that can strengthen the patients immune system to
      better fight the TB bacteria. The pro-inflammatory, but still immunosuppressive mediator
      prostaglandin E2 (PGE2) is produced by cyclooxygenase-2 (COX-2) in inflamed infected tissue.
      Studies from both human and animal models show that COX-2 inhibitors (COX-2i) can improve the
      immune system and strengthen vaccines responses.

      Hypothesis

        1. A hyperactive COX-2/PGE2 signal system in active TB causes down-regulated immune
           responses that favour TB survival, but this can be abrogated by COX-2i.

        2. TB-specific immunisation with targeted antigens presented as a therapeutic TB vaccine
           and enhanced by COX-2i will improve immune-mediated host clearance of TB.

        3. Combinations of COX-2i and a therapeutic TB vaccine to conventional anti-TB chemotherapy
           offer new treatment modalities for TB, including MDR/XDR-TB.

      Approach to test the hypothesis

        1. Study design: 4-arm, open and randomized clinical intervention trial of patients
           starting treatment for active TB in specialized Norwegian TB centres and where two arms
           will receive the COX-2i etoricoxib with and without a TB vaccine, one arm vaccine only
           and the last arm serve as control receiving only standard anti-TB therapy. For safety
           precautions, only patients bearing sensitive TB strains are included and study arms will
           be sequentially introduced.

        2. In a mouse model examine in more detail the effects of reversion of chronic inflammation
           with COX-2i locally in tissue and the interplay with TB vaccine responses, immune
           regulation, correlates of protection and survival in a well-characterized model for
           TB-exposed mice.
    

Detailed description: 
      The hypothesis is that treating TB patients with a therapeutic TB vaccine and COX-2
      inhibiting drugs in addition to standard antibiotic TB therapy will improve the patients
      immune system and boost TB vaccine responses.

      The project will provide safety and immunogenicity data from a Norwegian phase 1 clinical
      trial of the therapeutic TB vaccine candidate H56:IC31 and the COX-2i etoricoxib given to TB
      patients together with standard TB antibiotics.

      The investigators will also perform exploratory in-depth studies of immune regulatory
      mechanisms and try to identify biomarkers for efficacy of treatment both in humans and in a
      parallel mouse model. These results may further optimize the therapeutic strategy and prepare
      for larger clinical trials and finally contribute to new treatment options for MDR-TB.

      Objectives:

        -  Study the safety and tolerability of etoricoxib given for 20 weeks (day 0-140) alone and
           in combination with the therapeutic TB vaccine H56:IC31 given as two immunizations at
           day 84 and day 140 in patients with active TB disease treated with conventional 26-week
           anti-TB chemotherapy.

        -  Study the immune effects of etoricoxib given for 20 weeks (day 0-140) on immune
           regulation and TB vaccine (H56:IC31) immunogenicity in patients with active TB disease
           treated with conventional 26-week anti-TB chemotherapy.
    

Intervention name(s): etoricoxib; H56:IC31
Intervention type(s): Drug; Biological
Intervention description(s): cyclooxygenase-2 inhibitor. Anti-inflammatory; Therapeutic and prophylactic TB vaccine
Other intervention name(s): Arcoxia®
Intervention MeSH terms: Etoricoxib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Host-modulating therapy; Vaccine; Cyclooxygenase inhibitors