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Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the MDR Tuberculosis Pandemic (TBCOX2)

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ClinicalTrials.gov Identifier: NCT02503839
Recruitment Status : Recruiting
First Posted : July 21, 2015
Last Update Posted : October 17, 2017
Sponsor:
Collaborators:
University of Oslo
Statens Serum Institut
Haukeland University Hospital
Information provided by (Responsible Party):
Anne Margarita Dyrhol Riise, Oslo University Hospital

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: etoricoxib Biological: H56:IC31 Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the Multidrug-resistant Tuberculosis Pandemic; an Open Label Phase I Clinical Trial of the Therapeutic TB H56:IC31 Vaccine and Cyclooxygenase-inhibitors
Actual Study Start Date : November 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: 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).

Drug: etoricoxib
cyclooxygenase-2 inhibitor. Anti-inflammatory
Other Name: Arcoxia®

Experimental: Arm#2
arm#2 (n=10) receiving H56:IC31 vaccine at day 84 and 140 and no etoricoxib.
Biological: H56:IC31
Therapeutic and prophylactic TB vaccine

No Intervention: 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.
Experimental: 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.
Drug: etoricoxib
cyclooxygenase-2 inhibitor. Anti-inflammatory
Other Name: Arcoxia®

Biological: H56:IC31
Therapeutic and prophylactic TB vaccine




Primary Outcome Measures :
  1. Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events [ Time Frame: From day 0 until day 238 (14 weeks after the last dose of etoricoxib) ]
    Number and % of study patients with AE or SAE

  2. Safety of H56:IC31 vaccine (arm#2) assessed by the number of participants with adverse events [ Time Frame: 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

  3. Safety of combined etoricoxib and H56:IC31 vaccine (arm#4) assessed by the number of participants with adverse events [ 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). ]
    Number and % of study patients with AE or SAE

  4. Immunogenicity of etoricoxib (arm#1) [ Time Frame: Day 0 (baseline) to day 140 ]
    Percentage of polyfunctional (IFN-γ, IL-2, TNF-α) CD4+ T cells: Change between day 0 and day 140.

  5. Immunogenicity of H56:IC31 vaccine (arm#2) [ Time Frame: From immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154). ]
    Percentage of polyfunctional (IFN-γ, IL-2, TNF-α) CD4+ T cells: change between day 84 and day 98 and day 140 and day 154, respectively (14 days post-immunisation response)

  6. Immunogenicity of combined etoricoxib and H56:IC31 vaccine (arm#4) [ Time Frame: From immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154). ]
    Percentage of polyfunctional (IFN-γ, IL-2, TNF-α) CD4+ T cells: change between day 84 and day 98 and day 140 and day 154, respectively (14 days post-immunisation response)


Secondary Outcome Measures :
  1. Exploratory immune studies [ 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). ]
    Study in depth the effect of etoricoxib on immune activation, regulation and TB vaccine immunogenicity measured by the percentage of CD4+ and CD8+ T cells expressing the proliferation marker cfse, various activation markers (HLA-DR) and regulation markers (FOXP3, CD25) in response to stimulation with TB antigenic peptide pools (Ag85B, ESAT-6, Rv2660c).



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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.

2. 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.

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02503839


Contacts
Contact: Kristian Tonby, PhD +47 41550565 KRITONBY@ous-hf.no
Contact: Jenum Synne, PhD +47 92249736 synne.jenum@ous-hf.no

Locations
Norway
Haukeland University Hospital Recruiting
Bergen, Norway, 5020
Contact: Tehmina Mustafa, PhD, MD    +47 97633677    tehmina.mustafa@uib.no   
Oslo University Hospital Recruiting
Oslo, Norway, 0424
Contact: Anne M Dyrhol-Riise, PhD, MD    +4792857261    a.m.d.riise@medisin.uio.no   
Sponsors and Collaborators
Anne Margarita Dyrhol Riise
University of Oslo
Statens Serum Institut
Haukeland University Hospital
Investigators
Principal Investigator: Anne Margarita Dyrhol-Riise, PhD Oslo University Hospital

Responsible Party: Anne Margarita Dyrhol Riise, Professor, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT02503839     History of Changes
Other Study ID Numbers: 2015/692
2014-004986-26 ( EudraCT Number )
First Posted: July 21, 2015    Key Record Dates
Last Update Posted: October 17, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Anne Margarita Dyrhol Riise, Oslo University Hospital:
Host-modulating therapy
Vaccine
Cyclooxygenase inhibitors

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Vaccines
Etoricoxib
Cyclooxygenase Inhibitors
Immunologic Factors
Physiological Effects of Drugs
Cyclooxygenase 2 Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents