Immunological Biomarkers in Tuberculosis Management (OPTI-4TB)
Primary Purpose
Tuberculosis, Tuberculosis Infection
Status
Unknown status
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Multiple blood samples
Single blood sample
Sponsored by
About this trial
This is an interventional diagnostic trial for Tuberculosis
Eligibility Criteria
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
Sites / Locations
- Service des Maladies Infectieuses - Hôpital de la Croix Rousse - Hospices Civils de LyonRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Other
Other
Arm Label
Active tuberculosis
Latent tuberculosis infection
Arm Description
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
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.
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.
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.
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.
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).
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).
Full Information
NCT ID
NCT04271397
First Posted
December 23, 2019
Last Updated
February 12, 2020
Sponsor
Hospices Civils de Lyon
1. Study Identification
Unique Protocol Identification Number
NCT04271397
Brief Title
Immunological Biomarkers in Tuberculosis Management
Acronym
OPTI-4TB
Official Title
Optimization of Tuberculosis Diagnosis and Management Using Four Immunological Biomarkers
Study Type
Interventional
2. Study Status
Record Verification Date
February 2020
Overall Recruitment Status
Unknown status
Study Start Date
September 30, 2019 (Actual)
Primary Completion Date
April 9, 2023 (Anticipated)
Study Completion Date
April 9, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Tuberculosis Infection
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Active tuberculosis
Arm Type
Other
Arm Title
Latent tuberculosis infection
Arm Type
Other
Intervention Type
Other
Intervention Name(s)
Multiple blood samples
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Single blood sample
Intervention Description
Patients with Latent tuberculosis infection will have a single specific sample of 14 mL.
Primary Outcome Measure Information:
Title
Concordance of the kinetics of biomarkers with the evolution of the disease
Description
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).
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Analytical characteristics of a combination of 2 IGRAs (QuantiFERON-TB Gold Plus (QFT-P) and HBHA) in the diagnosis / prognosis of tuberculosis disease.
Description
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.
Time Frame
6 months
Title
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.
Description
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.
Time Frame
6 months
Title
Evaluate the performance of a test based on the interpretation of a transcriptomic signature in plasma in the diagnosis / prognosis of TB.
Description
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.
Time Frame
6 months
Title
Assess the performance of a test based on the interpretation of a protein signature in the diagnosis / prognosis of tuberculosis.
Description
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.
Time Frame
6 months
Title
Determine the achievement of target concentrations of rifampicin
Description
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).
Time Frame
6 months
Title
Establish the rate of metabolic self-induction of rifampicin
Description
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).
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Florence ADER, M.D., Ph.D
Phone
04 72 07 11 07
Ext
+33
Email
florence.ader@chu-lyon.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Oana DUMITRESCU, M.D., PhD
Phone
04 72 07 11 07
Ext
+33
Email
oana.dumitrescu@chu-lyon.fr
Facility Information:
Facility Name
Service des Maladies Infectieuses - Hôpital de la Croix Rousse - Hospices Civils de Lyon
City
Lyon
ZIP/Postal Code
69004
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florence ADER, M.D., Ph.D.
Phone
04 72 07 11 07
Ext
+33
Email
florence.ader@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Oana DUMITRESCU, M.D., PhD
Phone
04 72 07 11 07
Ext
+33
Email
oana.dumitrescu@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Florence ADER, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Anne CONRAD, CCU-AH
First Name & Middle Initial & Last Name & Degree
Thomas PERPOINT, PH
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
36186786
Citation
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.
Results Reference
derived
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Immunological Biomarkers in Tuberculosis Management
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