Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the MDR Tuberculosis Pandemic

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.

Inclusion criteria

• Age between 18 to 70 years at the time of randomization.
• Microbiologically confirmed pulmonary TB (culture and/or PCR + susceptibility testing) and/or microbiologically confirmed extra-pulmonary TB (culture and/or PCR + susceptibility testing).
• Drug sensitive Mtb strains (except single resistance where fully adequate anti-TB chemotherapy regimen could be provided).
• Is willing and likely to comply with the trial procedures and is prepared to grant authorized persons access to their medical record.
• Has completed the written informed consent process prior to the start of screening evaluations.
• Females: Ability to avoid pregnancy during the trial.

Subjects may receive H56:IC31 vaccination (arm#2 and #4) if they meet the following criteria:

• 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.
• Documented reduction in the extent of TB disease at the infectious site(s) within day 84 evaluated by physical and/or radiological examination.
• 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 exclusion criteria:

(i) Study-specific: Disseminated TB. Evidence of a new acute illness that may compromise the safety of the subject in the trial on study day 0. History of autoimmune disease or immunosuppression. History or laboratory evidence of any possible immunodeficiency state. Anemia (<9 g/100 ml). HIV sero-positivity. Chronic hepatitis B (HBs antigen positive) with increased liver transaminases (ASAT, ALAT) or chronic hepatitis C (HCV RNA positive). Concomitant or sporadic use of NSAID or corticosteroids (>2 times per week). Other immune modulating therapies including DMARDS. Total cholesterol > 7 mmol/L. Hypertension >140/90 mm Hg (treated or untreated) or treated with >1 antihypertensive drug at any blood pressure. Cardiovascular events or stroke in parents, siblings or off-springs occurring < 55 years of age. Serum creatinine above reference levels (females > 90 µmol/L; males > 105 µmol/L). Known diabetes mellitus type I or diabetes mellitus type II with HbA1c >7%. Pregnancy (S-hCG >5 IU/l for females at childbearing age). Breastfeeding.

• Exclusion criteria for etoricoxib according to SPC: Known hypersensitivity for etoricoxib or etoricoxib tablet substances. Known hypersensitivity for sulphonamides. Active peptic ulcer or gastrointestinal haemorrhage. History of asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic reactions after taking acetyl salicylic acid or NSAID including COX-2 inhibitors. Moderate/severe deranged liver function (Child-Pugh >7). Serum-creatinine clearance < 30 ml/min. Inflammatory bowel disease. Heart failure (NYHA II-IV). Established ischaemic heart disease, peripheral arteriosclerosis and/or cerebrovascular disease, including previous myocardial infarction, angina pectoris, unstable angina, PCI or coronary bypass, previous transitory ischemic attack or apoplexia/stroke.

• Exclusion criteria for H56:IC31: Known hypersensitivity for vaccines or vaccine adjuvants.