Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

Study Overview
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Brief Summary
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The purpose of the study is to generate receiver-operating-characteristic (ROC) curves for urine colorimetry to identify tuberculosis (TB) patients (children and adults) with low drug anti-TB drug exposures, which will define the diagnostic accuracy. Our central hypothesis is that urine colorimetry will successfully identify patients with low anti-TB serum drug levels, and do so with diagnostic characteristics similar to other widely used tests in TB management.

Detailed Description
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TB remains a leading infectious disease cause-of-death worldwide, with an estimated 1.5 million TB deaths each year. There is wide variability in absorption and metabolism of the anti-TB drugs, and low drug concentrations in blood are associated with inferior TB treatment outcomes, including treatment failure, relapse, and the emergence of drug-resistant infections. According to the most recent CDC/ATS/IDSA guidelines for TB treatment, therapeutic drug monitoring should be routinely considered for use among patients in high-risk groups, including adults with co-morbid type 2 diabetes mellitus (DM) and children. However, therapeutic drug monitoring requires sophisticated laboratory techniques unavailable for millions of patients receiving TB therapy in resource-limited settings where the vast majority of TB cases are treated. A new approach to measuring anti-TB drug exposures, based on technology easily adapted to resource-limited settings, is vitally needed and would be in line the World Health Organization's goal of the optimization of anti-TB drug regimens as a key component of the End TB Strategy. A simple, inexpensive test to identify pediatric and adult TB patients with low drug exposures, available at the point-of-care at the time of the patient encounter, would support clinical decision-making. The performance of therapeutic drug monitoring requires specialty laboratory capabilities, such as high-performance liquid chromatography or gas chromatography. Technical expertise is also required to collect, process, and ship samples to the specialty laboratory. In many high-burden settings, the complexity and cost of these laboratory methods preclude the use of therapeutic drug monitoring in the clinical care of tuberculosis patients. These complexities also foster a dependence of TB endemic sites on laboratories in resource-rich environments. Consequently, patients with inadequate drug exposures cannot be identified early in anti-TB therapy, at the critical time when dosing adjustments could be expected to improve treatment outcomes. Urine colorimetry provides a low-technology approach for measuring anti-TB drug exposures, suitable for point-of-care testing. Colorimetry is the measurement of intensity of signal at a specific wavelength in the visible region of the spectrum. Urine colorimetry was evaluated as a method to assess the relative bioavailability of different fixed-dose combinations of anti-TB drugs administered to healthy volunteers. Our proposal is based on the scientific premise that more detailed anti-TB drug exposure information can be obtained from urine sampling during TB treatment, not only to determine the presence or absence of drugs or metabolites, but to determine whether the presence of drugs or metabolites has surpassed a critical exposure threshold, informing drug dosing decision-making at the point-of-care. Potential advantages of urine colorimetric methods include a non-invasive sampling approach, improved patient acceptability, and the low cost and stability of chemical reagents. Colorimetry is particularly suited for point-of-care diagnostics, possibly with battery-operated or smartphone-based tools. With a simple diagnostic test available at the point-of-care, with results provided at the time of the clinical encounter, the TB clinician will be able to adjust drug doses and optimize regimens.

Official Title
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Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

Conditions
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Tuberculosis

Intervention / Treatment
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* Diagnostic Test: urine colorimetric assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: We will include patients of both genders meeting all of these criteria: Those 4 years and older; Diagnosed with active TB and initiation of combination anti-TB therapy with isoniazid, rifampin, and pyrazinamide, with or without DM; Able to provide informed consent and assent for those 7-17 years old. Exclusion Criteria: Anuric (i.e. not capable of producing urine due to chronic renal disease); Pregnancy or breastfeeding; Prisoners

Ages Eligible for Study
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Minimum Age: 4 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adults and children, U.S.<br>We will conduct a prospective, observational study of the pharmacokinetics of first-line anti-TB drugs (isoniazid, rifampin, and pyrazinamide) among TB patients (i.e. patients with active TB disease). | Diagnostic Test: urine colorimetric assay<br>* Colorimetric assays will be performed for urine drug concentrations of rifampin, isoniazid and pyrazinamide from urine collected throughout one dosing interval. Assay results will experimental only and not used to change patient care.<br>|
| Tanzanian children<br>We will conduct a prospective, observational study of the pharmacokinetics of first-line anti-TB drugs (isoniazid, rifampin, and pyrazinamide) among TB patients (i.e. patients with active TB disease). | Diagnostic Test: urine colorimetric assay<br>* Colorimetric assays will be performed for urine drug concentrations of rifampin, isoniazid and pyrazinamide from urine collected throughout one dosing interval. Assay results will experimental only and not used to change patient care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine Cmax | Urine peak concentration (Cmax) of rifampin as determined by urine colorimetry | Day 1 | 
| Urine rifampin AUC | Urine total rifampin area under the concentration time curve (AUC) as determined by urine colorimetry | Day 1 | 
| Urine isoniazid Cmax | Urine peak concentration (Cmax) of isoniazid as determined by urine colorimetry | Day 1 | 
| Urine isoniazid AUC | Urine total isoniazid area under the concentration time curve as determined by urine colorimetry | Day 1 | 
| Urine pyrazinamide Cmax | Urine peak concentration (Cmax) of pyrazinamide as determined by urine colorimetry | Day 1 | 
| Urine pyrazinamide AUC | Urine total pyrazinamide area under the concentration time curve as determined by urine colorimetry | Day 1 |