- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01154959
Latency in Pulmonary Tuberculosis
Characterization of Immune Responses in Treatment-induced Latency in Pulmonary Tuberculosis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Although Mycobacterium tuberculosis (Mtb) infects approximately 2 billion people worldwide, 90% of Mtb infected individuals are able to resist overt disease (active tuberculosis) development and manifest only latent infection. Latent tuberculosis (TB) is defined as the persistent presence of live Mtb within an infected host without causing disease. It is characterized by a delayed type hypersensitivity response to purified protein derivative (PPD) mediated by mycobacteria specific T cells. During latency, Mtb is contained in localized granulomas where the mycobacteria reside in macrophages and in which growth and replication appears to be constrained. Maintenance of the granulomatous lesion is mediated by CD4+ and CD8+ T cells. Based on murine models, immunity to Mtb requires Th1 responses and (to a lesser extent) Th17 responses. Thus, IL 12, IFN gamma, and TNF alpha (and IL 17 and IL 23) all play important roles in induction and maintenance of protective immune responses against tuberculous disease. Although CD4+ T lymphocytes of Th1 type are critical for protective immunity, evidence exists that CD8+ T cells as well as unconventional T cells (gamma-delta T cells and CD 1 restricted T cells) contribute to optimum protection in susceptible animal models. Aside from producing cytokines that activate macrophages and initiate granuloma formation, T cells also have direct mycobactericidal activities through the concerted actions of perforins and granulysins.
T cell differentiation into Th1 and Th2 lineages based on their cytokine profile and transcription factor expression has served as the basis of our understanding the pathogenesis of a variety of infectious and allergic diseases. With the advent of newer techniques, T cell differentiation has expanded into several subsets, including Tregs, Th17 cells, and polyfunctional T cells, among others. Th1 cells are absolutely essential for resistance to TB both in mice and humans. Deficiencies in the IL 12 IFN gamma Stat1 pathway leads to disseminated mycobacterial infection in humans and to abrogation of resistance in mice. In addition, TNF alpha, another Th1 cytokine, is of almost equal importance, as treatment with biologics (e.g., anti TNF alpha antibodies) for inflammatory disorders such as rheumatoid arthritis has caused reactivation of TB in some individuals.
Latent TB can be maintained for the lifetime of the individual unless the immunological balance between the host and the pathogen is perturbed, resulting in reactivation of Mtb and active disease. The host and environmental factors involved in compromising the ability to contain latent infection are human immunodeficiency virus co infection, malnutrition, aging, stress, Type 2 diabetes, use of immunosuppressive agents, and other genetic factors. On the pathogen side, latency is thought to reflect a transition from replicating to nonreplicating dormant bacilli, with this transition being influenced by a variety of factors including oxygen deprivation and nitric oxide. The use of in vitro and in vivo models of latency combined with genome wide transcriptome profiling has led to the identification of Mtb genes highly expressed during latency called dosR or devR (dormancy) genes; however, each of the host and pathogen related factors controlling resistance and/or susceptibility to TB awaits complete elucidation.
The subsets of CD4+ T cells constitute an ever expanding repertoire, classified by their discrete cytokine profiles and often by expression of prototypical transcription factors and/or cell surface molecules. Two relatively newly emerging CD4+ T cell subsets of importance are Th17 cells, characterized by production of IL 17 family of cytokines, and regulatory T cells (Tregs), characterized by surface expression of CD25 and the transcription factor FoxP3. Little is known about the role of these two subsets in latent TB. The mechanism by which Mtb subverts immune responses to establish chronic, latent infection is also not well understood. Recently, a number of regulatory factors, including Tregs, IL 10, TGF-beta, CTLA 4, and PD 1, have been implicated in the establishment of chronic viral, bacterial, and parasitic infections.
The role of T, B and NK cells in the evolution of the immune response following therapy in Mycobacterium tuberculosis infection has to be elucidated. The development of cellular immune responses in TB-infected patients post-chemotherapy to delineate the cellular arms of immunity in response to crude and defined TB antigens in treated patients needs to be studied.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Tamilnadu
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Chennai, Tamilnadu, India, 600031
- Tuberculosis Research Centre
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age 18 years and above
- Residing in or around Chennai or Madurai
- No anti-TB treatment in the past or should have had less than one month of treatment (but less than one week in the preceding one month before enrollment in the study)
- At least two sputum smears should be positive for tubercle bacilli by fluorescent microscopy
- Express willingness to attend the treatment centre for supervised treatment
- Express willingness for home visits by the staff of the centre
- Express willingness to give written informed consent
Exclusion Criteria:
- Body weight less than 30 kg
- Hepatic or renal disease as evidenced by clinical or biochemical abnormalities
- Diabetes mellitus
- A history of seizure or loss of consciousness
- Psychiatric illness
- An abnormal electrocardiogram or anti-arrhythmic medication
- Those in a moribund state
- Sero-positive for HIV antibodies
- Pregnancy or lactation
- Visual disorders other than refractory error
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Regimen 1
Rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin daily for 3 months (3RHZEM)
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Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)
|
EXPERIMENTAL: Regimen 2
Rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin daily for 2 months followed by rifampicin, isoniazid, and moxifloxacin daily for 2 months (2 RHZEM daily / 2 RHM daily)
|
Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)
|
EXPERIMENTAL: Regimen 3
Rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin daily for 2 months followed by rifampicin, isoniazid, and moxifloxacin thrice weekly for 2 months (2 RHZEM daily / 2RHM thrice weekly)
|
Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)
|
EXPERIMENTAL: Regimen 4
Rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin daily for 2 months followed by rifampicin, isoniazid, ethambutol and moxifloxacin thrice weekly for 2 months (2 RHZEM daily / 2 RHEM thrice weekly)
|
Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)
|
ACTIVE_COMPARATOR: Control Regimen
Rifampicin, isoniazid, pyrazinamide and ethambutol thrice weekly for 2 months followed by rifampicin and isoniazid thrice weekly for 4 months (2 RHZE thrice weekly / 4 RH thrice weekly)
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Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The immune response to crude antigens - PPD and CFA and defined antigens - ESAT-6 and CFP-10 as well as positive controls- SEB and anti-CD3.
Time Frame: 2 years
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2 years
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Determining the correlation of increase in regulatory factors with the development of relapse in treated TB patients.
Time Frame: 2 years
|
2 years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Subash Babu, MBBS, PhD, Tuberculosis Research Centre, India
Publications and helpful links
General Publications
- Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-48. doi: 10.1146/annurev.immunol.23.021704.115611.
- Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974 Feb;99(2):131-8. doi: 10.1093/oxfordjournals.aje.a121593. No abstract available.
- Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen VO, Andersen AB. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J Infect Dis. 2002 Feb 1;185(3):401-4. doi: 10.1086/338342. Epub 2002 Jan 17.
- Wayne LG, Sohaskey CD. Nonreplicating persistence of mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139-63. doi: 10.1146/annurev.micro.55.1.139.
- EDWARDS PQ, EDWADS LB. Story of the tuberculin test from an epidemiologic viewpoint. Am Rev Respir Dis. 1960 Jan;81(1)Pt 2:1-47. No abstract available.
- Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol. 2001 Oct;1(1):20-30. doi: 10.1038/35095558.
- Lin MY, Ottenhoff TH. Not to wake a sleeping giant: new insights into host-pathogen interactions identify new targets for vaccination against latent Mycobacterium tuberculosis infection. Biol Chem. 2008 May;389(5):497-511. doi: 10.1515/bc.2008.057.
- Ulrichs T, Kaufmann SH. New insights into the function of granulomas in human tuberculosis. J Pathol. 2006 Jan;208(2):261-9. doi: 10.1002/path.1906.
- Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine. 2008 Feb;41(2):79-83. doi: 10.1016/j.cyto.2007.11.022. Epub 2008 Jan 22.
- North RJ, Jung YJ. Immunity to tuberculosis. Annu Rev Immunol. 2004;22:599-623. doi: 10.1146/annurev.immunol.22.012703.104635.
- Locht C, Rouanet C, Hougardy JM, Mascart F. How a different look at latency can help to develop novel diagnostics and vaccines against tuberculosis. Expert Opin Biol Ther. 2007 Nov;7(11):1665-77. doi: 10.1517/14712598.7.11.1665.
- Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002 Dec;2(12):933-44. doi: 10.1038/nri954.
- Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008 May;8(5):337-48. doi: 10.1038/nri2295.
- McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008 Apr;28(4):445-53. doi: 10.1016/j.immuni.2008.03.001.
- Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821-52. doi: 10.1146/annurev.immunol.25.022106.141557.
- Fontenot JD, Rudensky AY. Molecular aspects of regulatory T cell development. Semin Immunol. 2004 Apr;16(2):73-80. doi: 10.1016/j.smim.2003.12.002.
- Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62. doi: 10.1146/annurev.immunol.21.120601.141122.
- Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008 Apr;28(4):468-76. doi: 10.1016/j.immuni.2008.03.003.
- Kumar NP, Moideen K, Dhakshinraj SD, Banurekha VV, Nair D, Dolla C, Kumaran P, Babu S. Profiling leucocyte subsets in tuberculosis-diabetes co-morbidity. Immunology. 2015 Oct;146(2):243-50. doi: 10.1111/imm.12496. Epub 2015 Jul 6.
- Kumar NP, Sridhar R, Nair D, Banurekha VV, Nutman TB, Babu S. Type 2 diabetes mellitus is associated with altered CD8(+) T and natural killer cell function in pulmonary tuberculosis. Immunology. 2015 Apr;144(4):677-86. doi: 10.1111/imm.12421.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Lung Diseases
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Tuberculosis, Pulmonary
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antimetabolites
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Hypolipidemic Agents
- Lipid Regulating Agents
- Anti-Bacterial Agents
- Leprostatic Agents
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Antitubercular Agents
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Fatty Acid Synthesis Inhibitors
- Moxifloxacin
- Rifampin
- Isoniazid
- Pyrazinamide
- Ethambutol
Other Study ID Numbers
- LTB01
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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