Immunological Biomarkers in Tuberculosis Management (OPTI-4TB)

Optimization of Tuberculosis Diagnosis and Management Using Four Immunological Biomarkers

Tuberculosis (TB) is the leading cause of death by infectious disease in the world, responsible for 1.6 million deaths in 2017. The treatment of active TB requires at least a 6-month combined antibiotic regimen and can cause heavy side effects. As a consequence, treatment adherence is not optimal, particularly in primary care settings. Rapid and reliable monitoring of anti-TB treatment adherence and efficacy is critical to provide adequate patient care and curb relapse episodes and acquired drug resistance.

Investigators propose to evaluate the performance in terms of diagnosis accuracy and outcome prediction of four new biomarkers of active TB: 1) a double IGRA (Interferon Gamma Release Assay) including QuantiFERON-Gold Plus® and HBHA; 2) a whole blood transcriptomic analysis of mRNA (messenger Ribonucleic acid) expression of a panel of 150 genes; 3) a whole blood proteomic analysis; 4) an ex vivo immunophenotyping using flow and mass cytometry to characterize the lymphocyte populations.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis; Tuberculosis Infection
• Intervention / Treatment: Other: Multiple blood samples; Other: Single blood sample

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Florence ADER, M.D., Ph.D; Phone Number: +33 04 72 07 11 07; Email: florence.ader@chu-lyon.fr
• Study Contact Backup: Name: Oana DUMITRESCU, M.D., PhD; Phone Number: +33 04 72 07 11 07; Email: oana.dumitrescu@chu-lyon.fr

Study Locations

• France
  • Lyon, France, 69004
    • Recruiting
    • Service des Maladies Infectieuses - Hôpital de la Croix Rousse - Hospices Civils de Lyon
    • Contact: Oana DUMITRESCU, M.D., PhD; Phone Number: +33 04 72 07 11 07; Email: oana.dumitrescu@chu-lyon.fr
    • Contact: Florence ADER, M.D., Ph.D.; Phone Number: +33 04 72 07 11 07; Email: florence.ader@chu-lyon.fr
    • Principal Investigator: Florence ADER, M.D., Ph.D.
    • Sub-Investigator: Anne CONRAD, CCU-AH
    • Sub-Investigator: Thomas PERPOINT, PH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adult ≥ 18 year-old

• Patients having given written consent
• Patients accepting a follow up ≥ 6 months
• Proven active tuberculosis (positive direct examination and/or PCR)
• Latent tuberculosis infection assessed by positive IGRA

Exclusion Criteria:

• Malignant solid tumor
• Malignant hemopathy
• Solid organ transplantation or hematopoietic stem cell transplantation
• Immunosuppressive treatments (i.e. biologics, calcineurin inhibitors, corticosteroids)
• Auto-inflammatory disease
• Chronic liver diseases
• Chronic infection with HIV, HCV (hepatitis C virus) or HBV (hepatitis B virus)
• Antimycobacterial treatment initiated > 7 days
• Pregnancy or breastfeeding
• Refusal to participate to the study
• Persons deprived of their liberty by judicial or administrative decision
• Protected adults
• Patients not affiliated to health-care social security
• The homeless

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Active tuberculosis	Other: Multiple blood samples; Patients with active tuberculosis will have 5 research-specific blood samples: V1, (baseline) immediately before initiating anti-tuberculosis treatment, then 4 samples during anti-tuberculosis treatment and follow-up, i.e. at 48 hours (V2), 15 days (V3), 2 months (V4) and 6 months (V5) after initiation of treatment. The total volume of each sample will be 20 mL for a total of 100 mL.
Other: Latent tuberculosis infection	Other: Single blood sample; Patients with Latent tuberculosis infection will have a single specific sample of 14 mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concordance of the kinetics of biomarkers with the evolution of the disease	It is a composite outcome. Evolution of the disease is defined by clinical status, radiological computed tomography evolution and negation of the mycobacterial culture of routine respiratory samples. The biomarkers assessed are: 1) a combination of IGRAs test (QuantiFERON-Gold Plus and HBHA); 2) a transcriptomic signature; 3) a protein signature; 4) a phenotypic signature (by implementing an immunomonitoring approach).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analytical characteristics of a combination of 2 IGRAs (QuantiFERON-TB Gold Plus (QFT-P) and HBHA) in the diagnosis / prognosis of tuberculosis disease.	Measurement of gamma interferon responses induced by different conditions of ex-vivo stimulation of the blood sample by specific Mtb peptides. This biomarker will be confronted with the evolution of the evolution of the disease as defined in the primary outcome measure.	6 months
Performance of an immunomonitoring test by mass or flow cytometry in the diagnosis / prognosis of tuberculosis by measuring the dynamics of the blood population of T lymphocytes over time.	Qualitative and quantitative monitoring of the different subpopulations of immune cells (CD4 + T cells, CD8 +(cluster of differentiation 8) T cells, MAIT, Th1, Th2, Th1, Tfh, Treg, naive, effector and memory cells) during anti-tuberculosis treatment will be carried out. The analytical characteristics (sensitivity, specificity, VPN and VPP) of this immunomonitoring tool will be determined by comparing the abundance of different cellular phenotypes with the evolution of the disease as defined in the primary outcome measure.	6 months
Evaluate the performance of a test based on the interpretation of a transcriptomic signature in plasma in the diagnosis / prognosis of TB.	A transcriptomic signature in plasma is a set of genes involved in the immune response specifically deregulated during the different stages of infection and disease progression. This assessment will be made from blood samples. The transcriptomic signature composed of 16 genes will be evaluated during the anti-tuberculosis treatment and confronted with the evolution of the disease as defined in the primary outcome measure.	6 months
Assess the performance of a test based on the interpretation of a protein signature in the diagnosis / prognosis of tuberculosis.	A protein signature is composed of cytokines and chemokines, also deregulated during the various stages of infection and progression of the disease. This assessment will be made from blood samples. The protein signature composed of cytokines / chemokines of interest (ie IP-10, TNF-a (tumor necrosis factor - a), IL-1(interleukin - 1), IL-18, IL-12, CCL4, IL-2, IFN-g (interferon - g),…) will be evaluated during the anti-tuberculosis treatment and confronted with the evolution of the disease as defined in the primary outcome measure.	6 months
Determine the achievement of target concentrations of rifampicin	To determine the achievement of target concentrations of rifampicin the pharmacokinetic profile of rifampicin will be evaluate by a combination of parameters such as the area under the curve, maximum and minimum concentration, clearance, volume of distribution, modeled from three concentration measurements at each visit. (V2, V3 and V4).	6 months
Establish the rate of metabolic self-induction of rifampicin	To establish the rate of metabolic self-induction of rifampicin the pharmacokinetic profile of rifampicin will be evaluate by a combination of parameters such as the area under the curve, maximum and minimum concentration, clearance, volume of distribution, modeled from three concentration measurements at each visit. (V2, V3 and V4).	6 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

General Publications

• Bahuaud O, Genestet C, Hoffmann J, Dumitrescu O, Ader F. Opti-4TB: A protocol for a prospective cohort study evaluating the performance of new biomarkers for active tuberculosis outcome prediction. Front Med (Lausanne). 2022 Sep 14;9:998972. doi: 10.3389/fmed.2022.998972. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2019
• Primary Completion (Estimated): September 10, 2026
• Study Completion (Estimated): October 10, 2026

Study Registration Dates

• First Submitted: December 23, 2019
• First Submitted That Met QC Criteria: February 12, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Actual): August 12, 2024
• Last Update Submitted That Met QC Criteria: August 9, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis
• Other Study ID Numbers: 69HCL18_0757

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No