Point-of-care Pharmacogenomic Testing to Optimize Isoniazid Dosing for Tuberculosis Prevention

Study Overview
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Brief Summary
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This trial is designed to determine whether modifying the dose of isoniazid for individuals according to their n-acetyltransferase 2 (NAT2) genotype could increase the probability of achieving equivalence of area-under-the-curve.

Official Title
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Point-of-care Pharmacogenomic Testing to Optimize Isoniazid Dosing for Tuberculosis Prevention

Conditions
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Tuberculosis Infection, Isoniazid Adverse Reaction

Intervention / Treatment
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* Drug: Low-dose isoniazid
* Drug: Standard dose of isoniazid
* Drug: High-dose isoniazid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible for latent tuberculosis treatment by Brazil's national guidelines* provides written informed consent to participate in the study Exclusion Criteria: Evidence of active tuberculosis or currently under evaluation for active tuberculosis Receiving drugs that interact with Rifapentine (e.g. methadone, warfarin) Known intolerance or hypersensitivity to isoniazid or rifapentine Prior treatment for active or latent tuberculosis > 14 days Close contact to isoniazid- or rifampicin-resistant tuberculosis (TB) case Neutropenia (absolute neutrophil count <1000 cells/mm3) Clinical diagnosis of active liver disease or alcohol dependence alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapid acetylator<br>Participants will receive 1 standard dose (Day 0), followed by 1 higher dose (Day 7), follow by 2 standard doses (Days 14 and 21). | Drug: Standard dose of isoniazid<br>* 15 mg/kg oral tablet (up to 900 mg)<br>Drug: High-dose isoniazid<br>* Pharmacogenomic-modified dose of isoniazid - 25 mg/kg oral tablet (maximum 1500 mg)<br>|
| Active Comparator: Intermediate acetylator<br>Participants will receive 4 standard doses (Days 0, 7, 14 and 21). | Drug: Standard dose of isoniazid<br>* 15 mg/kg oral tablet (up to 900 mg)<br>|
| Experimental: Slow acetylator<br>Participants will receive 2 standard doses (Days 0 and 7), followed by 1 lower dose (Day 21), follow by 1 standard dose (Day 21). | Drug: Low-dose isoniazid<br>* Pharmacogenomic-modified dose of isoniazid - 5 mg/kg oral tablet (maximum 300 mg)<br>Drug: Standard dose of isoniazid<br>* 15 mg/kg oral tablet (up to 900 mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Isoniazid plasma area-under-the-curve |  | 1, 2, 8, and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum isoniazid concentration (Cmax) |  | 1, 2, 8, and 24 hours post-dose | 
| Isoniazid concentration at 24 hours |  | 24 hours post-dose |