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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
39
cyclooxygenase-2 inhibitor. Anti-inflammatory
Therapeutic and prophylactic TB vaccine
Haukeland University Hospital
Bergen, Norway
Oslo University Hospital
Oslo, Norway
Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events
Number and % of study patients with AE or SAE
Time frame: From day 0 until day 238 (14 weeks after the last dose of etoricoxib)
Safety of H56:IC31 vaccine (arm#2) assessed by the number of participants with adverse events
Number and % of study patients with AE or SAE
Time frame: From day 0 until day 238. For vaccine related adverse events; immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Safety of combined etoricoxib and H56:IC31 vaccine (arm#4) assessed by the number of participants with adverse events
Number and % of study patients with AE or SAE
Time frame: From day 0 until day 238 (14 weeks after the last dose of etoricoxib). For vaccine related adverse events; from immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Immunogenicity of etoricoxib (arm#1)
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
Time frame: Day 0 (baseline) to day 84
Immunogenicity of H56:IC31 vaccine (arm#2)
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
Time frame: From before first immunisation (day 84) to 14 days after second immunisation (day 154).
Immunogenicity of combined etoricoxib and H56:IC31 vaccine (arm#4)
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
Time frame: From before first immunisation (day 84) to 14 days after second immunisation (day 154).
Exploratory immune studies
Study in depth the effect of etoricoxib on immune activation, regulation and TB vaccine immunogenicity measured by the percentage of innate cells (monocytes/MDSC) and CD4+ and CD8+ T cells expressing various activation, supression and regulation markers in response to stimulation with TB antigenic peptide pools (Ag85B, ESAT-6, Rv2660c). Serologi to H56 and gene signature analyses.
Time frame: From day 0 (baseline) until day 238 (study end); 14, 28, 56, 84, 98, 140, 154, 182, 210, 238 days from baseline (selected timepoints for various analysis).
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