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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

39 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-11-30

Study Completion Date

2020-03-23

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Tuberculosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm#1

arm#1 (n=10) receiving etoricoxib from inclusion day 0 and in 140 days.

Step-wise inclusion starting with arm#1,arm#2 and arm#3 (first group) randomized (2:2:1) and if safety data are satisfactory proceeding with arm #4 and the rest of arm#3 randomized (2:2:1).

Group Type EXPERIMENTAL

etoricoxib

Intervention Type DRUG

cyclooxygenase-2 inhibitor. Anti-inflammatory

Arm#2

arm#2 (n=10) receiving H56:IC31 vaccine at day 84 and 140 and no etoricoxib.

Group Type EXPERIMENTAL

H56:IC31

Intervention Type BIOLOGICAL

Therapeutic and prophylactic TB vaccine

Arm#3

arm#3 (n=10), the first group (n=5) serving as control to arm#1 and arm#2, the next group (n=5) serving as control to arm#4.

Group Type NO_INTERVENTION

No interventions assigned to this group

Arm#4

arm#4 (n=10) receiving etoricoxib from inclusion day 0 and in 140 days and H56:IC31 vaccine at day 84 and 140.

Group Type EXPERIMENTAL

etoricoxib

Intervention Type DRUG

cyclooxygenase-2 inhibitor. Anti-inflammatory

H56:IC31

Intervention Type BIOLOGICAL

Therapeutic and prophylactic TB vaccine

Interventions

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etoricoxib

cyclooxygenase-2 inhibitor. Anti-inflammatory

Intervention Type DRUG

H56:IC31

Therapeutic and prophylactic TB vaccine

Intervention Type BIOLOGICAL

Other Intervention Names

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Arcoxia®

Eligibility Criteria

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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

(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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No