Treatment of Latent Tuberculosis Infection With Isoniazid

Study Overview
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Brief Summary
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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
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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).

Official Title
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Drugs for Treatment of Latent Tuberculosis Infection Objective 4: Identify Biomarkers for Clinical Trials of Drugs Active Against Latent TB

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Isoniazid
* Drug: isoniazid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Recently converted contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) immediately after recruitment. | Drug: Isoniazid<br>* Isoniazid (5mg per kg up to 300 mg daily for 6 months)<br>* Other names: treatment of latent tuberculosis infection;Drug: isoniazid<br>* isoniazid (5mg per kg up to 300 mg daily for 6 months<br>* Other names: Treatment of latent tuberculosis infection;|
| Active Comparator: B<br>B. Recently converted contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) three months after recruitment. | Drug: Isoniazid<br>* Isoniazid (5mg per kg up to 300 mg daily for 6 months)<br>* Other names: treatment of latent tuberculosis infection;Drug: isoniazid<br>* isoniazid (5mg per kg up to 300 mg daily for 6 months<br>* Other names: Treatment of latent tuberculosis infection;|
| Experimental: C<br>C. Remote contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) immediately after recruitment | Drug: Isoniazid<br>* Isoniazid (5mg per kg up to 300 mg daily for 6 months)<br>* Other names: treatment of latent tuberculosis infection;Drug: isoniazid<br>* isoniazid (5mg per kg up to 300 mg daily for 6 months<br>* Other names: Treatment of latent tuberculosis infection;|
| Active Comparator: D<br>D. Remote contacts receiving isoniazid (5mg per kg up to 300 mg daily for 6 months) three months after recruitment. | Drug: Isoniazid<br>* Isoniazid (5mg per kg up to 300 mg daily for 6 months)<br>* Other names: treatment of latent tuberculosis infection;Drug: isoniazid<br>* isoniazid (5mg per kg up to 300 mg daily for 6 months<br>* Other names: Treatment of latent tuberculosis infection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Mtb antigen-specific IFNγ-producing T cells measured by ELISPOT assay |  | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene expression profiling |  | 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Latent tuberculosis, biomarkers, isoniazid, ELISPOT, PPD positive individuals