Clinical trial NCT00293228: Treatment of Latent Tuberculosis Infection With Isoniazid
Official title: Drugs for Treatment of Latent Tuberculosis Infection Objective 4: Identify Biomarkers for Clinical Trials of Drugs Active Against Latent TB
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Tuberculosis
Keywords: Latent tuberculosis
biomarkers
isoniazid
ELISPOT
PPD positive individuals
Lead sponsor: Instituto Nacional de Salud Publica, Mexico
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: Wellcome Trust
First posted: 2006-02-17
Enrollment: 200
Sex: ALL
Minimum age (years): 10
Maximum age (years): 85
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to study the effect that treatment of dormant tuberculosis infection has on the immunological system.

We expect to observe an impact over the production of cytokines by peripheral white blood cells which may be useful to know if treatment has been effective.

Detailed description: As part of on-going studies conducted in the Orizaba Health Jurisdiction in southeastern Mexico, household contacts of pulmonary TB patients who recently converted their tuberculin test and TST+ve contacts from randomly selected control households with no history of TB within the last 2 years (remote contacts) will be enrolled. We assume that these individuals are infected with Mycobacterium tuberculosis. Additional confidence that all subjects enrolled are latently infected will come from ELISPOT analysis of the response to ESAT-6 and CFP-10. We propose to administer INH to 100 TST+ve recent and 100 TST+ve remote contacts for 6 months. To control for spontaneous fluctuations of biomarker levels, we propose to defer therapy by 3 months to half the subjects in each group. Thus, four groups will be defined:

A. Recently converted contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) immediately after recruitment.

B. Recently converted contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) three months after recruitment.

C. Remote contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) immediately after recruitment.

D. Remote contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) three months after recruitment.

All contacts will undergo clinical evaluation at enrolment and review. The development of active TB will trigger withdrawal and full treatment. Fortnightly clinical review of group B during the deferred phase will be undertaken. ELISPOT analysis will be performed on all subjects at 0, 1, 4, 13, 26 and 40 weeks in groups A and C, and at 0, 13, 14, 17, 26, 40 and 54 weeks in groups B and D. A subset of 10 patients per group will be sampled for expression analysis at 0, 4, 26 and 40 weeks (groups A and C) and at 0, 13, 17 and 40 weeks in groups B and D (160 hybridizations in total).

Eligibility criteria: Inclusion criteria:

* Informed consent
* Age 10-45
* Either sex
* Resident in study area
* Documented TST+ve (\>10mm, Mantoux method, 2TU, PPD Statens Serum Institute)
* Normal chest radiograph
* HIV negative test

Exclusion criteria:

* Active tuberculosis
* Previous diagnosis of tuberculosis
* Treatment for active or latent tuberculosis
* Contact with TB patients harboring MDR or INH resistant isolates of Mtb
* Diseases or therapies associated with immunosuppression
* Diabetes mellitus
* Abnormal liver enzyme levels.
* HB below 8gr/dl
* Pregnancy (ascertained by urinary β-HCG)
* Allergy or intolerance to isoniazid
* Peripheral neuropathy
* Ingestion of drugs interacting with isoniazid

Primary outcomes:
measure: Frequency of Mtb antigen-specific IFNγ-producing T cells measured by ELISPOT assay
timeFrame: 9 months
Secondary outcomes:
measure: Gene expression profiling
timeFrame: 9 months
Other outcomes:
Locations:
city: Cuernavaca
country: Mexico
facility: Instituto Nacional de Salud Pública
state: Morelos
Study officials:
affiliation: Instituto Nacional de Salud Pública
name: Lourdes Garcia-Garcia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Jose Sifuentes-Osornio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Alfredo Ponce-de-Leon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Enfermedades Respiratorias
name: Eduardo Sada-Diaz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Enfermedades Respiratorias
name: Martha Torres-Rojas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wilkinson KA, Kon OM, Newton SM, Meintjes G, Davidson RN, Pasvol G, Wilkinson RJ. Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens. J Infect Dis. 2006 Feb 1;193(3):354-9. doi: 10.1086/499311. Epub 2005 Dec 29.
citation: DeRiemer K, Garcia-Garcia L, Bobadilla-del-Valle M, Palacios-Martinez M, Martinez-Gamboa A, Small PM, Sifuentes-Osornio J, Ponce-de-Leon A. Does DOTS work in populations with drug-resistant tuberculosis? Lancet. 2005 Apr 2-8;365(9466):1239-45. doi: 10.1016/S0140-6736(05)74812-1.
citation: Torres M, Garcia-Garcia L, Cruz-Hervert P, Guio H, Carranza C, Ferreyra-Reyes L, Canizales S, Molina S, Ferreira-Guerrero E, Tellez N, Montero-Campos R, Delgado-Sanchez G, Mongua-Rodriguez N, Sifuentes-Osornio J, Ponce-de Leon A, Sada E, Young DB, Wilkinson RJ. Effect of isoniazid on antigen-specific interferon-gamma secretion in latent tuberculosis. Eur Respir J. 2015 Feb;45(2):473-82. doi: 10.1183/09031936.00123314. Epub 2014 Oct 30.