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

• ClinicalTrials.gov Identifier: NCT02371681
• Recruitment Status: Completed
• First Posted: February 26, 2015
• Last Update Posted: May 7, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Tuberculosis	Drug: Treatment; Radiation: PET/CT Scan; Procedure: Sample Collection	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 262 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: NexGen EBA Radiologic and Immunologic Biomarkers to Enhance Early Bactericidal Activity Measurements of Sterilizing Drug Activity in Tuberculosis
• Study Start Date: February 25, 2015
• Actual Primary Completion Date: September 1, 2017
• Actual Study Completion Date: November 14, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; TB drugs	Drug: Treatment; Different Drug combinations; Radiation: PET/CT Scan; PET/CT Scans; Procedure: Sample Collection; Sample Collection

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 14 days ]
   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 who have not received anti-TB treatment within the last 3 years.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.

Secondary Outcome Measures :

1. PET/CT Changes [ Time Frame: 14 days ]
   Correlation of PET/CT changes with treatment response, microbiologic and immunologic outcomes
2. Rank order of drugs [ Time Frame: 14 days ]
   Comparison of the rank order of drugs based upon bacteriologic, radiologic and immunologic features.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older 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

Locations

South Africa

Stellenbosch University, Faculty of Medicine and Health Sciences

Cape Town, 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

Publications:

Dartois V, Barry CE. Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Curr Clin Pharmacol. 2010 May;5(2):96-114. Review.

Goo JM, Im JG, Do KH, Yeo JS, Seo JB, Kim HY, Chung JK. Pulmonary tuberculoma evaluated by means of FDG PET: findings in 10 cases. Radiology. 2000 Jul;216(1):117-21.

Jindani A, Doré CJ, Mitchison DA. Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days. Am J Respir Crit Care Med. 2003 May 15;167(10):1348-54. Epub 2003 Jan 6.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02371681
• Other Study ID Numbers: 999915070; 15-I-N070
• First Posted: February 26, 2015
• Last Update Posted: May 7, 2021
• Last Verified: July 20, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Treatment-Response; Radiological Imaging; Biomarkers; Antitubercular Agents; Log-CFU Reduction

Additional relevant MeSH terms:

Tuberculosis; Tuberculosis, Pulmonary; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections