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

NCT02371681 | Completed Phase 2

• 2 other identifiers: 99991507015-I-N070
• Study Type: interventional
• Target: 262
• Locations: 1 country
• Sites: 2

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.

Conditions

Pulmonary Tuberculosis

Keywords

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

Outcome Measures

Primary Outcomes (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, 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 Outcomes (2)

• PET/CT Changes

  14 days

• Rank order of drugs

  14 days

Study Arms (1)

1

EXPERIMENTAL

TB drugs

Drug: Treatment; Radiation: PET/CT Scan; Procedure: Sample Collection

Interventions

Treatment DRUG

Different Drug combinations

1

PET/CT Scan RADIATION

PET/CT Scans

1

Sample Collection PROCEDURE

Sample Collection

1

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

Stellenbosch University, Faculty of Medicine and Health Sciences

Cape Town, South Africa

Location

TASK Applied Sciences

Cape Town, South Africa

Location

Related Publications (4)

• 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. doi: 10.2174/157488410791110797.

  PMID: 20156156 BACKGROUND

• 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. doi: 10.1148/radiology.216.1.r00jl19117.

  PMID: 10887236 BACKGROUND

• Jindani A, Dore 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. doi: 10.1164/rccm.200210-1125OC. Epub 2003 Jan 6.

  PMID: 12519740 BACKGROUND

• Jones A, Saini J, Kriel B, Via LE, Cai Y, Allies D, Hanna D, Hermann D, Loxton AG, Walzl G, Diacon AH, Romero K, Higashiyama R, Liu Y, Berg A. Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts. BMC Infect Dis. 2022 Apr 2;22(1):327. doi: 10.1186/s12879-022-07308-3.

  PMID: 35366820 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Therapeutics; Specimen Handling

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Clifton E Barry, Ph.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2015
• First Posted: February 26, 2015
• Study Start: February 25, 2015
• Primary Completion: September 1, 2017
• Study Completion: November 14, 2017
• Last Updated: June 18, 2023

Record last verified: 2023-06

Locations

ZA (2)