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

NCT02503839 | Completed Phase 1 DMC

• 2 other identifiers: 2015/6922014-004986-26
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 2

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. 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. 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. 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.
4. 4.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.
5. 5.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.

Conditions

Tuberculosis

Keywords

Host-modulating therapy; Vaccine; Cyclooxygenase inhibitors

Outcome Measures

Primary Outcomes (6)

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

  Number and % of study patients with AE or SAE

  From day 0 until day 238 (14 weeks after the last dose of etoricoxib)

• 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

  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).

• 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

  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).

• Immunogenicity of etoricoxib (arm#1)

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

  Day 0 (baseline) to day 84

• Immunogenicity of H56:IC31 vaccine (arm#2)

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

  From before first immunisation (day 84) to 14 days after second immunisation (day 154).

• 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.

  From before first immunisation (day 84) to 14 days after second immunisation (day 154).

Secondary Outcomes (1)

• 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 Arms (4)

Arm#1

EXPERIMENTAL

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

Arm#2

EXPERIMENTAL

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

Biological: H56:IC31

Arm#3

NO INTERVENTION

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

EXPERIMENTAL

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; Biological: H56:IC31

Interventions

etoricoxib DRUG

cyclooxygenase-2 inhibitor. Anti-inflammatory

Also known as: Arcoxia®

Arm#1; Arm#4

H56:IC31 BIOLOGICAL

Therapeutic and prophylactic TB vaccine

Arm#2; Arm#4

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• (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.

Sponsors & Collaborators

• Anne Margarita Dyrhol Riise: lead
• University of Oslo: collaborator
• Statens Serum Institut: collaborator
• Haukeland University Hospital: collaborator

Study Sites (2)

Haukeland University Hospital

Bergen, 5020, Norway

Location

Oslo University Hospital

Oslo, 0424, Norway

Location

Related Publications (3)

• Nore KG, Louet C, Bugge M, Gidon A, Jorgensen MJ, Jenum S, Dyrhol-Riise AM, Tonby K, Flo TH. The Cyclooxygenase 2 Inhibitor Etoricoxib as Adjunctive Therapy in Tuberculosis Impairs Macrophage Control of Mycobacterial Growth. J Infect Dis. 2024 Mar 14;229(3):888-897. doi: 10.1093/infdis/jiad390.

  PMID: 37721470 DERIVED

• 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.

  PMID: 34811370 DERIVED

• 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.

  PMID: 30888024 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Etoricoxib

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Sulfones; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Anne Margarita Dyrhol-Riise, PhD

  Oslo University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 10, 2015
• First Posted: July 21, 2015
• Study Start: November 1, 2015
• Primary Completion: September 1, 2019
• Study Completion: March 23, 2020
• Last Updated: April 8, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Data available as supplementary information in the published manuscript.
• 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)

Locations

NO (2)