Tuberculosis
Conditions
Keywords
Host-modulating therapy, Vaccine, Cyclooxygenase inhibitors
Brief 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.
Interventions
DRUGetoricoxib
cyclooxygenase-2 inhibitor. Anti-inflammatory
BIOLOGICALH56:IC31
Therapeutic and prophylactic TB vaccine
Sponsors
University of Oslo
Statens Serum Institut
Haukeland University Hospital
Anne Margarita Dyrhol Riise
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 18 to 70 years at the time of randomization. 2. Microbiologically confirmed pulmonary TB (culture and/or PCR + susceptibility testing) and/or microbiologically confirmed extra-pulmonary TB (culture and/or PCR + susceptibility testing). 3. Drug sensitive Mtb strains (except single resistance where fully adequate anti-TB chemotherapy regimen could be provided). 4. Is willing and likely to comply with the trial procedures and is prepared to grant authorized persons access to their medical record. 5. Has completed the written informed consent process prior to the start of screening evaluations. 6. Females: Ability to avoid pregnancy during the trial. Subjects may receive H56:IC31 vaccination (arm#2 and #4) if they meet the following criteria: 1. Sputum obtained prior to 1th immunization (day 84) must be Mtb negative evaluated by at least two consecutive AFS or GeneXpert/PCR at least 7 days apart. 2. Documented reduction in the extent of TB disease at the infectious site(s) within day 84 evaluated by physical and/or radiological examination. 3. Clinical improvement with normal vital signs (blood pressure, temperature and pulse), improvement of any TB related symptoms to Grade 1-3, stable or increased body-weight and reduced inflammatory blood parameters (CRP, ESR and WBC counts) compared to baseline.
Exclusion criteria
Main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of combined etoricoxib and H56:IC31 vaccine (arm#4) assessed by the number of participants with adverse events | 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). | Number and % of study patients with AE or SAE |
| Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events | From day 0 until day 238 (14 weeks after the last dose of etoricoxib) | Number and % of study patients with AE or SAE |
| Safety of H56:IC31 vaccine (arm#2) assessed by the number of participants with adverse events | 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). | Number and % of study patients with AE or SAE |
| Immunogenicity of combined etoricoxib and H56:IC31 vaccine (arm#4) | From before first immunisation (day 84) to 14 days after second immunisation (day 154). | Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides. |
| Immunogenicity of etoricoxib (arm#1) | Day 0 (baseline) to day 84 | Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides. |
| Immunogenicity of H56:IC31 vaccine (arm#2) | From before first immunisation (day 84) to 14 days after second immunisation (day 154). | Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exploratory immune studies | 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). | 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. |
Countries
Norway
Outcome results
None listed