Diagnostics and Pharmacotherapy for Severe Forms of TB (DMID 15-0100)

Diagnostics and Pharmacotherapy for Severe Forms of TB

Major Research Aim: To study novel molecular diagnostics and the pharmacokinetic variability among a spectrum of TB disease states, including severe forms of TB like disseminated TB, TB meningitis and drug resistant TB, among adults and children from multiple international sites.

Study Overview

• Status: Completed
• Conditions: Tuberculosis

Detailed Description

Aim 1. Measure pharmacokinetics to anti-tuberculosis (TB) medications in severe TB syndromes (including multidrug-resistant TB, pediatric TB, TB sepsis and TB meningitis) from diverse geographies (including Tanzania, Uganda, Bangladesh, and Siberia) and correlate these findings to TB treatment outcome (TB treatment failure: death/ default/ relapse/ further acquired drug resistance).

Aim 2. Decipher mechanisms of pharmacokinetic variability to TB drugs, particularly malabsorption due to concurrent gastrointestinal disease.

Aim 3. Deployment of quantitative susceptibility testing (minimum inhibitory concentration-MIC) and rapid MIC-informed molecular methods (e.g., TaqMan Array Card-TAC) for M. tuberculosis.

In addition to the stated aims, the primary elements of capacity building requisite for this project include the training in and deployment of the fieldable molecular diagnostic platforms, onsite pharmacokinetic monitoring, and a broad strengthening of longitudinal cohort management for clinical research.

• Study Type: Observational
• Enrollment (Actual): 478

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects will be recruited by medical officer review of new admissions to the TB hospitals at the study sites- Kibong'oto National TB Hospital (Tanzania), Haydom Lutheran Hospital (Tanzania), Irkutsk Regional Clinical Tuberculosis Hospital (Siberia/Russian Federation), National Institute of Diseases of the Chest Hospital (Bangladesh), ICDDRB Hospital (Bangladesh), Mbarara Regional Referral Hospital (Uganda).

Description

Inclusion Criteria:

Patients admitted to one of the study site hospitals with at least ONE of the following:

1. Clinical suspicion for TB in a child, as defined by NIH Consensus Case Definitions for TB research in children, and started on TB treatment
2. Clinical suspicion for TB meningitis, as defined by the International TB Meningitis Workshop Consensus Case Definitions for TB Meningitis
3. Clinical suspicion for TB sepsis, as defined by the Uganda/PRISM-U definitions
4. Microbiologic evidence of MDR-TB from a respiratory specimen within the past 6 months

Exclusion Criteria:

1. Pregnant women-self reported
2. Patient unable per treating physician discretion to undergo sample collection
3. Patient or representative/guardian unable to sign written informed consent
4. Patient unable to return for follow-up or be contacted by phone for follow-up

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure area under the concentration curve (AUC) to anti-tuberculosis (TB) medications relative to TB treatment outcome in severe TB syndromes	Severe TB syndromes include multidrug-resistant TB, pediatric TB, TB sepsis and TB meningitis from diverse geographies (including Tanzania, Uganda, Bangladesh, and Siberia). The parameter of most importance to cidal activity of anti-TB medications among the cohort is AUC. TB treatment outcome will be defined as death, microbiological failure, relapse or acquired drug resistance, and machine learning algorithms such as classification and regression tree analyses will be used to define AUC threshold for each anti-TB medication predictive of poor TB treatment outcome. Conventional logistic regression will then be used to determine the additive odds for a patient with one of more medications below an algorithm derived threshold being significantly more likely to have a poor TB treatment outcome.	December 2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Collect stool in patients undergoing pharmacokinetic testing to measure the environmental enteropathy index	Stool will be collected in patients with severe TB syndromes undergoing pharmacokinetic testing and assayed for stool biomarkers of malabsorption (environmental enteropathy index) and modeled as a determinant of those with AUC values of one or more anti-TB medications below thresholds predictive of TB treatment outcome.	December 2019
Collect stool in patients undergoing pharmacokinetic testing to measure the quantitative burden and species distribution of enteric pathogens by the enteric TAC assay- 35 bacterial, viral, parasitic species)	Stool will be collected in patients with severe TB syndromes undergoing pharmacokinetic testing and assayed for detection of molecular targets of enteric pathogens by TaqMan Array Card (TAC) platform. Enteric pathogen burden (including the effect of multiple pathogens in a single sample) will be modeled as a determinant of those with AUC values of one or more anti-TB medications below thresholds predictive of TB treatment outcome.	December 2019

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); University of Florida; International Centre for Diarrhoeal Disease Research, Bangladesh; Mbarara University of Science and Technology; Kilimanjaro Christian Medical Centre, Tanzania; Haydom Lutheran Hospital; Scientific Center for Family Health and Human Reproduction Problems, Russia
• Investigators: Principal Investigator: Scott K Heysell, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2016
• Primary Completion (Actual): July 31, 2020
• Study Completion (Actual): January 31, 2021

Study Registration Dates

• First Submitted: February 22, 2018
• First Submitted That Met QC Criteria: June 5, 2018
• First Posted (Actual): June 18, 2018

Study Record Updates

• Last Update Posted (Actual): March 9, 2022
• Last Update Submitted That Met QC Criteria: March 8, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: 18452; U01AI115594 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No