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

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 1

Locations

Norway

Study Type

Interventional

Intervention

etoricoxib

H56:IC31

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Host-modulating therapy, Vaccine, Cyclooxygenase inhibitors

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

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.

Sites / Locations

Haukeland University Hospital
Oslo University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

No Intervention

Experimental

Arm Label

Arm#1

Arm#2

Arm#3

Arm#4

Arm Description

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).

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

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.

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

Outcomes

Primary Outcome Measures

Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events

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

Number and % of study patients with AE or SAE

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

Immunogenicity of etoricoxib (arm#1)

Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.

Immunogenicity of H56:IC31 vaccine (arm#2)

Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT02503839

First Posted

July 10, 2015

Last Updated

April 7, 2022

Sponsor

Anne Margarita Dyrhol Riise

Collaborators

University of Oslo, Statens Serum Institut, Haukeland University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02503839

Brief Title

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

Acronym

TBCOX2

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Completed

Study Start Date

November 2015 (Actual)

Primary Completion Date

September 2019 (Actual)

Study Completion Date

March 23, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Anne Margarita Dyrhol Riise

Collaborators

University of Oslo, Statens Serum Institut, Haukeland University Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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 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. 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. 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 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

Keywords

Host-modulating therapy, Vaccine, Cyclooxygenase inhibitors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm#1

Arm Type

Experimental

Arm Description

Arm Title

Arm#2

Arm Type

Experimental

Arm Description

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

Arm Title

Arm#3

Arm Type

No Intervention

Arm Description

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.

Arm Title

Arm#4

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

etoricoxib

Other Intervention Name(s)

Arcoxia®

Intervention Description

cyclooxygenase-2 inhibitor. Anti-inflammatory

Intervention Type

Biological

Intervention Name(s)

H56:IC31

Intervention Description

Therapeutic and prophylactic TB vaccine

Primary Outcome Measure Information:

Title

Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events

Description

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)

Title

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

Description

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).

Title

Safety of combined etoricoxib and H56:IC31 vaccine (arm#4) assessed by the number of participants with adverse events

Description

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).

Title

Immunogenicity of etoricoxib (arm#1)

Description

Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.

Time Frame

Day 0 (baseline) to day 84

Title

Immunogenicity of H56:IC31 vaccine (arm#2)

Description

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).

Title

Immunogenicity of combined etoricoxib and H56:IC31 vaccine (arm#4)

Description

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).

Secondary Outcome Measure Information:

Title

Exploratory immune studies

Description

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).

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anne Margarita Dyrhol-Riise, PhD

Organizational Affiliation

Oslo University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Haukeland University Hospital

City

Bergen

ZIP/Postal Code

5020

Country

Norway

Facility Name

Oslo University Hospital

City

Oslo

ZIP/Postal Code

0424

Country

Norway

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The study is published. https://doi.org/10.1038/s41467-021-27029-6

IPD Sharing Time Frame

Data available as supplementary information in the published manuscript.

IPD Sharing Access Criteria

The full source datasets generated during and/or analyzed during the current study are available in the repository of the open science framework (https://osf.io/khvf4)

IPD Sharing URL

https://doi.org/10.1038/s41467-021-27029-6

Citations:

PubMed Identifier

34811370

Citation

Jenum S, Tonby K, Rueegg CS, Ruhwald M, Kristiansen MP, Bang P, Olsen IC, Sellaeg K, Rostad K, Mustafa T, Tasken K, Kvale D, Mortensen R, Dyrhol-Riise AM. A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients. Nat Commun. 2021 Nov 22;12(1):6774. doi: 10.1038/s41467-021-27029-6.

Results Reference

derived

PubMed Identifier

30888024

Citation

Tonby K, Mortensen R, Ruhwald M, Dyrhol-Riise AM, Jenum S. KLRG1-Expressing CD4 T Cells Are Reduced in Tuberculosis Patients Compared to Healthy Mycobacterium tuberculosis-Infected Subjects, but Increase With Treatment. J Infect Dis. 2019 Jun 5;220(1):174-176. doi: 10.1093/infdis/jiz056. No abstract available.

Results Reference

derived

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

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