Latency in Pulmonary Tuberculosis

NCT01154959 | Completed Phase 3

• 1 other identifier: LTB01
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

The immune responses in latent tuberculosis are poorly understood. While it is difficult to define the onset of latency during natural infection, patients undergoing treatment for tuberculosis are driven into a state of latency or cure. The present study on the effect of 3 and 4 month regimens containing moxifloxacin in sputum smear and culture positive pulmonary tuberculosis (TRC Study number 24) offers us the opportunity to study definitive immune responses pre and post treatment. We will evaluate a variety of innate and adaptive immune responses in patients before and after treatment and our study will compare the differences in immuno-phenotype (eg. Markers of T, B and NK cell activation, proliferation and regulatory phenotype) and function (eg. Production of cytokines, proliferative responses to TB antigens) at different time points following treatment. In addition, since a small percentage of patients will undergo relapse following treatment, the kinetics of immune responses in these patients will used to assess immunological predictors of relapse in tuberculosis.

Conditions

Pulmonary Tuberculosis

Keywords

Pulmonary TB; Immune response; ATT; Immune responses in pulmonary tuberculosis; Predictors for relapse

Outcome Measures

Primary Outcomes (1)

• 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.

  2 years

Secondary Outcomes (1)

• Determining the correlation of increase in regulatory factors with the development of relapse in treated TB patients.

  2 years

Study Arms (5)

Regimen 1

EXPERIMENTAL

Rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin daily for 3 months (3RHZEM)

Drug: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol

Regimen 2

EXPERIMENTAL

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)

Drug: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol

Regimen 3

EXPERIMENTAL

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)

Drug: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol

Regimen 4

EXPERIMENTAL

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)

Drug: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol

Control Regimen

ACTIVE COMPARATOR

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)

Drug: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol

Interventions

Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol DRUG

Moxifloxacin (400mg), Isoniazid (300mg daily, 600mg thrice weekly), Rifampicin (450mg, and 600mg for patients weighing 60kg or more), Pyrazinamide (1500mg), Ethambutol (800mg)

Control Regimen; Regimen 1; Regimen 2; Regimen 3; Regimen 4

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Tuberculosis Research Centre, India: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Tuberculosis Research Centre

Chennai, Tamil Nadu, 600031, India

Location

Related Publications (20)

• 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.

  PMID: 4810628 BACKGROUND

• 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.

  PMID: 11807725 BACKGROUND

• Wayne LG, Sohaskey CD. Nonreplicating persistence of mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139-63. doi: 10.1146/annurev.micro.55.1.139.

  PMID: 11544352 BACKGROUND

• 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.

  PMID: 13819440 BACKGROUND

• Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol. 2001 Oct;1(1):20-30. doi: 10.1038/35095558.

  PMID: 11905811 BACKGROUND

• 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.

  PMID: 18953716 BACKGROUND

• 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.

  PMID: 16362982 BACKGROUND

• 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.

  PMID: 18218322 BACKGROUND

• North RJ, Jung YJ. Immunity to tuberculosis. Annu Rev Immunol. 2004;22:599-623. doi: 10.1146/annurev.immunol.22.012703.104635.

  PMID: 15032590 BACKGROUND

• 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.

  PMID: 17961090 BACKGROUND

• Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002 Dec;2(12):933-44. doi: 10.1038/nri954.

  PMID: 12461566 BACKGROUND

• 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.

  PMID: 18408735 BACKGROUND

• 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.

  PMID: 18400187 BACKGROUND

• 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.

  PMID: 17201677 BACKGROUND

• 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.

  PMID: 15036230 BACKGROUND

• 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.

  PMID: 15032588 BACKGROUND

• 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.

  PMID: 15771580 BACKGROUND

• 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.

  PMID: 18400189 BACKGROUND

• 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.

  PMID: 26095067 DERIVED

• 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.

  PMID: 25363329 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Moxifloxacin; Isoniazid; Ethambutol

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Subash Babu, MBBS, PhD

  Tuberculosis Research Centre, India

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Scientific Director, NIH-NIRT-ICER

Study Record Dates

• First Submitted: June 30, 2010
• First Posted: July 1, 2010
• Study Start: February 1, 2010
• Primary Completion: December 1, 2015
• Study Completion: July 1, 2016
• Last Updated: April 19, 2021

Record last verified: 2021-04

Locations

IN (1)