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

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ClinicalTrials.gov Identifier: NCT02371681
Recruitment Status : Completed
First Posted : February 26, 2015
Last Update Posted : June 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information
First Submitted Date  ICMJE February 25, 2015
First Posted Date  ICMJE February 26, 2015
Last Update Posted Date June 24, 2020
Study Start Date  ICMJE February 25, 2015
Actual Primary Completion Date September 1, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 5, 2019)
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 w... [ Time Frame: 14 days ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 25, 2015)
Changes from baseline to 14 days in microbiologic, radiographic, and immunologic markers within mono- and combination-therapy arms as outlined. Additional analysis will test whether there are measureable interactions of effects of drug (on marke... [ Time Frame: 14 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2019)
  • PET/CT Changes [ Time Frame: 14 days ]
    Correlation of PET/CT changes with treatment response, microbiologic and immunologic outcomes
  • Rank order of drugs [ Time Frame: 14 days ]
    Comparison of the rank order of drugs based upon bacteriologic, radiologic and immunologic features.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2015)
  • Correlation of change in PET characteristics and change in immunological markers [ Time Frame: 14 days ]
  • Correlation of changes of PET characteristics and CFU changes [ Time Frame: 14 days ]
  • Correlation of time to Positivity (TTP) of liquid culture and CFU changes [ Time Frame: 14 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NexGen EBA Radiologic and Immunologic Biomarkers of Sterilizing Drug Activity in Tuberculosis
Official Title  ICMJE NexGen EBA Radiologic and Immunologic Biomarkers to Enhance Early Bactericidal Activity Measurements of Sterilizing Drug Activity in Tuberculosis
Brief Summary

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

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 depends 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, F-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), rifampin (RIF), pyrazinamide (PZA), moxifloxacin (MXF), and ethambutol (EM). 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.

PRIMARY OBJECTIVE:

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 treatment-na(SqrRoot) ve subjects with pulmonary drug sensitive tuberculosis.

SECONDARY OBJECTIVES:

  1. To describe the nature and magnitude of drug/regimen-specific PET/CT changes over the initial 14 days of therapy in pulmonary drug sensitive tuberculosis subjects.
  2. To describe the change in PET/CT signals after 2 and 4 weeks of standard therapy with HRZE.
  3. To describe the correspondence between change in PET/CT and standard EBA measures among following chemotherapeutic regimens: isoniazid (INH [H]), rifampin (RIF [R]), pyrazinamide (PZA [Z]), HZ, RZ, M (MXF [M]), MRZE, and HRZE.
  4. To compare the qualitative changes in PET/CT among H, R, Z, HZ, RZ, M, and MRZE with that of HRZE.
  5. To characterize EBA using time to liquid culture positivity (TTP).
  6. To compare absolute and dynamic profiles of immunological assays composed of specific chemokines and cytokines, at 0, 2, and (in HRZE arm) 4 weeks for each treatment regimen.
  7. Comparison of specific changes in PET/CT characteristics between combination regimens and their components
  8. Comparison of specific changes in immunologic markers between combination regimens and their components
  9. To compare drug and drug metabolite levels to changes in PET/CT signals

Design:

This is a prospective, randomized study of drug-na(SqrRoot) ve subjects in South Africa with smear-positive, drug-sensitive pulmonary tuberculosis.

Population:

N=160 drug-na(SqrRoot) ve, smear positive subjects with tuberculosis from Cape Town, Republic of South Africa

Subject Participation Duration:

2-6 weeks

Estimated Time to Complete Enrollment:

12 months

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Tuberculosis
Intervention  ICMJE
  • Drug: Treatment
    Different Drug combinations
  • Radiation: PET/CT Scan
    PET/CT Scans
  • Procedure: Sample Collection
    Sample Collection
Study Arms  ICMJE Experimental: 1
TB drugs
Interventions:
  • Drug: Treatment
  • Radiation: PET/CT Scan
  • Procedure: Sample Collection
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 4, 2018)
262
Original Estimated Enrollment  ICMJE
 (submitted: February 25, 2015)
350
Actual Study Completion Date  ICMJE November 14, 2017
Actual Primary Completion Date September 1, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. Age 18 to 65 years with body weight from 30 kg to 90 kg
    2. Sputum acid-fast bacilli (AFB) smear positive (at least 1+ on the WHO International Union Against Tuberculosis and Lung Disease scale)
    3. Likely able to produce approximately 10 mL of sputum per day
    4. Xpert MTB/RIF-confirmed M.tb
    5. Rifampin-sensitive pulmonary tuberculosis as indicated by Xpert MTB/RIF
    6. ALT <3X upper limit of normal, creatinine <2X upper limit of normal
    7. Willingness to have samples stored

EXCLUSION CRITERIA:

  1. Clinically suspected disseminated TB or acuity of illness too much as deemed by clinicians
  2. Has been treated for tuberculosis within the past 3 years
  3. 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
  4. Cirrhosis or chronic kidney disease
  5. 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)
  6. Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within 2 weeks prior to screening
  7. Subjects with diabetes, point of care HbA1c above 6.5, or random glucose over 200 mg/dL
  8. Conditions which compromise the subject s ability to take or absorb oral drugs
  9. Normal PA-Chest radiograph, determined during screening
  10. Total lung (left or right) collapse on PA-Chest radiograph
  11. HIV positive
  12. Pregnant or breastfeeding
  13. Any other condition that, in the responsible clinician s judgment, renders a subject too sick to safely tolerate 2 weeks study therapy
  14. Any condition that constitutes a contraindication to any of the drugs to be used on any study arms
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02371681
Other Study ID Numbers  ICMJE 999915070
15-I-N070
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Clifton E Barry, Ph.D. National Institute of Allergy and Infectious Diseases (NIAID)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 4, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP