NexGen EBA Radiologic and Immunologic Biomarkers of Sterilizing Drug Activity in Tuberculosis

Study Overview
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Brief Summary
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Background: - Tuberculosis (TB) is a lung infection caused by bacteria. When people with TB cough, they may spread these bacteria. Researchers are looking for new TB medicines. They want to find a faster way to tell if a drug might combat TB. Objective: - To learn the effect of different anti-TB drugs on microbiological, radiographic and immunologic markers in people with TB. Eligibility: - Adults age 18-65 who weigh 30-90 kg and have common TB bacteria that can be treated with common TB medicines. Design: Participants will be admitted to the hospital for screening. They will have medical history, physical exam, and chest radiograph. They will give blood, urine, and sputum samples. Participants will be put in 1 of 8 groups. Participants will get one or a combination of TB medicines daily for about 14 days. Each day, participants: Will discuss side effects. May have a physical exam. Will spit mucus into a cup. They may breathe in saline water through a nebulizer to make them cough. Participants will have blood taken 3-4 times during the study Participants will have 2-3 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) scans. FDG is a radioactive sugar molecule which helps measure TB disease in the lungs. It will be injected into a vein. Participants will lie in a scanner that takes pictures. Around study day 14, participants will leave the hospital. They will be referred to a local TB clinic. There they will get the standard 4 TB medicines. Those in group 8 will already be on these medicines and will have another FDG-PET/CT on day 28. Participants will be in the study for up to 28 days.

Detailed Description
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Early bactericidal activity (EBA), which measures decline in serial sputum colony forming unit (CFU) counts over the first 2-14 days of treatment, has been used extensively as a means of initially evaluating the potency of individual or combinations of antituberculous agents. This approach is endorsed by the Global Alliance for TB Drug Development and the US FDA. However, EBA seems to correlate poorly with the relative ability of an agent to prevent relapse and produce a durable cure (often referred to as sterilizing activity ). The reasons for this discrepancy may have to do with a limitation of sputum measurements to capture populations that persist beyond airway surfaces in discrete lesions such as granulomas, nodules, or cavities. The elimination of these persistent populations depend on the pharmacodynamic properties of a regimen and may be better captured by biologic and functional markers that can reflect dynamic treatment effects within these relevant host environments. Recent studies of the response to TB chemotherapy have identified promising new biomarkers of sterilization in 2 areas. First, immunologic changes appear to have potential in small subject cohorts to predict sterilizing cure within 1 month after commencing treatment. Second, 18F-FDG PET/CT has been used in tuberculosis as a qualitative means of assessing drug response in small case series at multiple time points, starting as early as 1 month. PET activity reflects uptake and phosphorylation of FDG by neutrophils and macrophages, and CT provides structural information on disease pathology. Hence, PET/CT data may offer additional insights into lesion-specific sterilizing activity. This study will add 18F-FDG PET/CT scans and immunological assays at 0, 2, and (in the HRZE arm) 4 weeks to standard EBA methodology using regimens containing isoniazid (INH [H]), rifampin (RIF [R]), pyrazinamide (PZA [Z]), moxifloxacin (MXF [M]), and ethambutol (EMB [E]). We hypothesize that drug regimens associated with higher sterilizing activity (e.g., containing rifampin or pyrazinamide) will show distinctive early cytokine and chemokine patterns and discrete, quantifiable changes on PET/CT in certain lesion types during the 2-week period, compared to drug regimens with poor sterilizing activity (e.g., containing isoniazid or moxifloxacin). Demonstration of such an association would provide rationale for including radiologic and immunologic analysis, alongside conventional EBA, in early phase clinical studies of novel drugs, and would also provide important new insights into the biology of human and bacterial responses to TB drugs.

Official Title
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NexGen EBA Radiologic and Immunologic Biomarkers of Sterilizing Drug Activity in Tuberculosis

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: Treatment
* Radiation: PET/CT Scan
* Procedure: Sample Collection


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age 18 to 65 years with body weight from 30 kg to 90 kg Sputum acid-fast bacilli (AFB) smear positive (at least 1+ on the WHO International Union Against Tuberculosis and Lung Disease scale) Likely able to produce approximately 10 mL of sputum per day Xpert MTB/RIF-confirmed M.tb Rifampin-sensitive pulmonary tuberculosis as indicated by Xpert MTB/RIF ALT <3X upper limit of normal, creatinine <2X upper limit of normal Willingness to have samples stored EXCLUSION CRITERIA: Clinically suspected disseminated TB or acuity of illness too much as deemed by clinicians Has been treated for tuberculosis within the past 3 years Treatment with agents known to have anti-tuberculosis activity (e.g., fluoroquinolones, linezolid) for any indications during the current episode of clinical illness or within 2 months prior to screening, whichever is longer Cirrhosis or chronic kidney disease Disease complications or concomitant illness that might compromise safety or the interpretation of trial endpoints, such as known diagnosis of chronic inflammatory condition (e.g., sarcoidosis, rheumatoid arthritis, and connective tissue disorder) Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within 2 weeks prior to screening Subjects with diabetes, point of care HbA1c above 6.5, or random glucose over 200 mg/dL Conditions which compromise the subject s ability to take or absorb oral drugs Normal PA-Chest radiograph, determined during screening Total lung (left or right) collapse on PA-Chest radiograph HIV positive Pregnant or breastfeeding Any other condition that, in the responsible clinician s judgment, renders a subject too sick to safely tolerate 2 weeks study therapy Any condition that constitutes a contraindication to any of the drugs to be used on any study arms

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>TB drugs | Drug: Treatment<br>* Different Drug combinations<br>Radiation: PET/CT Scan<br>* PET/CT Scans<br>Procedure: Sample Collection<br>* Sample Collection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize, in the context of a standard EBA study, the effect of various antituberculosis drugs on radiographic and immunologic markers as measured by PET/CT and immunologic assays, in subjects with drug sensitive pulmonary tuberculosis wh... | A description of the individual markers that change over time is of interest to better understand both the markers and the effects of each treatment. A second analysis will focus on classification of whether a treatment arm includes: 1) only one agent ( singlet ), 2) only two agents (a doublet ), or 3) four agents (a quadruplet ). | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PET/CT Changes | Correlation of PET/CT changes with treatment response, microbiologic and immunologic outcomes | 14 days | 
| Rank order of drugs | Comparison of the rank order of drugs based upon bacteriologic, radiologic and immunologic features. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment-Response, Radiological Imaging, Biomarkers, Antitubercular Agents, Log-CFU Reduction