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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02371681
First Posted: February 26, 2015
Last Update Posted: November 16, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
  Purpose

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.

Condition Intervention Phase
Tuberculosis Drug: Moxifloxacin Drug: Pyrazindamide Drug: Rifampicin Drug: Isonizaid Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: NexGen EBA Radiologic and Immunologic Biomarkers to Enhance Early Bactericidal Activity Measurements of Sterilizing Drug Activity in Tuberculosis

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 350
Study Start Date: February 25, 2015
Study Completion Date: November 14, 2017
Primary Completion Date: September 1, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
TB drugs
Drug: Moxifloxacin
TB drug
Drug: Pyrazindamide
TB drug
Drug: Rifampicin
TB drug
Drug: Isonizaid
TB drug

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 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, 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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02371681


Locations
South Africa
TASK Applied Sciences
Cape Town, South Africa
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Clifton E Barry, Ph.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02371681     History of Changes
Other Study ID Numbers: 999915070
15-I-N070
First Submitted: February 25, 2015
First Posted: February 26, 2015
Last Update Posted: November 16, 2017
Last Verified: August 18, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
HR2E/RIPE
South Africa
Time to Positivity/TTP
FDG-PET/CT

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Moxifloxacin
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers