Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis (THERMOL)

April 28, 2026 updated by: Albert Einstein College of Medicine
This study is a two-arm, pragmatic, open-label, randomized clinical trial to determine the efficacy of Therapeutic Drug Monitoring (TDM) in preventing premature discontinuation of Linezolid (LZD) in participants with Rifampicin-resistant tuberculosis (RR-TB). Following the initiation of treatment, participants will be monitored throughout the approximate 6-month duration of RR-TB therapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Drug-resistant tuberculosis (TB) is a major global epidemic and poses a particular threat to HIV-infected individuals. With limited effective drugs available for treatment, multidrug-, and extensively drug-resistant TB carry a high mortality rate and threaten global TB and HIV control efforts.

New and repurposed medications have recently been found to improve survival and cure rates. Linezolid-a drug initially developed for the treatment of Gram-positive infections-has considerable anti-TB activity and has been at the center of this treatment revolution. Since 2018, WHO has recommended that all multi DR/rifampicin-resistant (MDR) and extensively drug-resistant tuberculosis (XDR) tuberculosis treatment regimens include linezolid. When given long-term, however, linezolid-associated toxicity-particularly myelosuppression and peripheral neuropathy-is very common, affecting 50-80% of patients and often requiring a temporary or permanent discontinuation of therapy. Such interruptions put patients at risk of treatment failure and the emergence of additional resistance to linezolid or one of the other drugs in the regimen. As linezolid use continues to increase worldwide, such resistance could become widespread, squandering a valuable medication. Previously conducted research has shown that linezolid toxicities are associated with trough plasma concentration and that the drug has considerable inter-individual variability. The investigator team, therefore, hypothesize that therapeutic drug monitoring (TDM) could identify those with higher linezolid concentrations and permit pre-emptive dose reductions that could avert drug toxicity and premature discontinuation.

This study will take place at the Nkqubela TB Specialist Hospital in East London, South Africa. TB diagnosis and initial treatment regimen will be determined by the hospital clinical team, per local guidelines. Following enrollment, participants will be randomized after enrollment to either undergo a therapeutic drug monitoring (TDM) strategy for LZD, or standard of care (SOC). Participants in both arms will have a trough plasma linezolid concentration drawn approximately one week after enrollment (within one month of TB treatment initiation). The PK specimens collected from TDM arm participants will be analyzed by University of Cape Town lab staff. The PK specimens collected from SOC participants will be stored for future analysis.

Standard treatment for RR-TB in South Africa includes 6 months of therapy, including linezolid 600 mg daily for duration of treatment. Those in the TDM arm whose concentration is above a set threshold (2.5 mg/L) will have their LZD dose reduced to 300mg daily, while those in the SOC arm will receive routine monitoring alone. All participants will be screened monthly for hematologic and neurologic toxicity. Hospital and clinic providers will manage all treatment other than the TDM-guided linezolid dose reduction. If participants in either the SOC or TDM arm experience linezolid toxicity, hospital and clinic providers may choose to temporarily or permanently discontinue linezolid, regardless of any prior TDM-guided dose reduction, in accordance with South African national guidelines.

Aim 1 (Primary Outcome Measure of this study) and Aim 2 (the first Secondary Outcome Measure) are described in the Outcome Measures section. For Aim 3, population PK modeling will be used to explore the complex relationship between linezolid pharmacokinetic parameters and the trajectory of toxicities over time. It will also be determined as to whether those whose dose is lowered still meet exposure targets for drug efficacy. South Africa has among the highest global burden of drug-resistant TB and HIV and has led the world in the rollout of new RR-TB drugs and regimens. The aims of this study will answer fundamental questions about LZD pharmacology that will directly inform its use in South Africa and worldwide.

Study Type

Interventional

Enrollment (Estimated)

280

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • South Africa
    • Eastern Cape
      • East London, Eastern Cape, South Africa, 5206
        • Recruiting
        • Nkqubela TB Specialist Hospital
        • Contact:
          • Gary Maartens, MBChB
        • Principal Investigator:
          • Gary Maartens, MBChB

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adult male or female patient > 18 years of age
  • Microbiological confirmation of rifampicin-resistant tuberculosis (e.g., phenotypic or genotypic drug susceptibility testing, GeneXpert MTB/RIF™). Participants may have resistance to additional medications as well - i.e., MDR and XDR TB - but must have resistance to at least rifampin
  • Initiated on a rifampicin-resistant tuberculosis (RR-TB) treatment regimen containing linezolid, no more than 14 days prior to randomization

  • HIV status is known and confirmed

    • Both HIV-positive and HIV-negative individuals are eligible
    • If an individual reports unknown HIV status, they must consent to HIV testing at time of enrollment to confirm status. If they decline to be tested, they are not eligible for the study

Exclusion Criteria:

  • Severe medical condition with expected death in the next 7 days
  • Pregnant at time of screening
  • Initial linezolid dose < 600mg daily
  • Severe form of extrapulmonary TB (i.e., meningitis, pericarditis, or osteomyelitis)
  • Unlikely to follow-up at Nkqubela Hospital based on location of residence

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Therapeutic Drug Monitoring (TDM)
Participants in the TDM arm will have their linezolid dose reduced if their trough concentration is greater than 2.5 mg/L
Other: Therapeutic Drug Monitoring for Linezolid
TDM with dose adjustment for trough concentration >2.5 mg/L LZD
No Intervention: Standard of Care (SOC)
Participants in the SOC arm will have their linezolid adjusted or held if they develop clinical adverse events.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Discontinuation of Linezolid or non-TDM guided dose reduction
Time Frame: Within 6 months after initiation of LZD therapy
Linezolid (LZD) discontinuation for any cause along with non-TDM-guided LZD dose reduction will be assessed. The number of participants who discontinue LZD (defined as an interruption > 2 weeks in duration), including self-discontinuation by the patient or a decision by the provider to temporarily or permanently discontinue LZD, OR have a non-TDM-guided dose-reduction in response to an adverse event, will be summarized by study arm using basic descriptive statistics.
Within 6 months after initiation of LZD therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Unsuccessful final Tuberculosis (TB) end-of-treatment outcome
Time Frame: After 6 months, and up to 12 months after initiation of LZD therapy

Unsuccessful final TB treatment outcome is defined as either treatment failure, death, or participant lost to follow-up, as per World Health Organization (WHO) definitions, defined below. End-of-treatment TB outcomes will be captured for all study participants. The number of participants with unsuccessful final TB treatment outcomes will be summarized by study arm using basic descriptive statistics. TB treatment outcomes will be assessed at the end of 6 months of treatment; however, if treatment is extended for any reason, medical records will be reviewed 12 months after treatment initiation to capture a final TB treatment outcome.

Treatment failure: The patient's treatment was terminated or they needed to permanently change their regimen due to a lack of response to treatment, adverse drug reaction, or increased drug resistance.

Lost to follow-up: The patient stopped taking their medication for two or more months in a row after registering.

Death: The patient died
After 6 months, and up to 12 months after initiation of LZD therapy
Emergence of new phenotypic resistance to Linezolid
Time Frame: Within 6 months after initiation of LZD therapy
The percentage of participants in each arm who develop phenotypic Linezolid (LZD) resistance will be assessed. Participants who experience treatment failure and remain sputum culture-positive after 4 months, will have a sputum sample collected for additional drug-resistance testing. Results of any isolates which undergo such resistance testing will be reviewed to identify anyone with treatment-emergent linezolid resistance. Additionally, during follow-up visits, participants will be directly assessed for development of LZD resistance. The percentage of participants who develop phenotypic resistance to LZD, as determined by either of these methods, will be summarized by study arm using basic descriptive statistics
Within 6 months after initiation of LZD therapy
Evidence of Linezolid Toxicity
Time Frame: Within 6 months after initiation of LZD therapy
Evidence of Linezolid (LZD) toxicity will be evaluated by the number of participants who experience Grade 3 or Grade 4 hematologic (e.g., anemia, thrombocytopenia, neutropenia) or neurologic (e.g., peripheral neuropathy or optic neuritis) adverse events associated with LZD toxicity. LZD-associated Grade 3 or Grade 4 events, documented at any time point up to 6 months, will be summarized by adverse event type and frequency for each study arm.
Within 6 months after initiation of LZD therapy
TB-free survival
Time Frame: 12 months after initiation of LZD therapy
TB-free survival will be assessed by review of each participant's medical record as well as EDRWeb, a South African registry of patients with drug-resistant tuberculosis, to determine whether or not the participant is still alive and free of TB disease. The number/percentage of participants who are alive and free of TB disease will be summarized by study arm.
12 months after initiation of LZD therapy
Non-TDM-guided dose reduction of linezolid
Time Frame: Within 6 months after initiation of LZD therapy
At each study visit, the participant's medical and pharmacy records will be reviewed to determine if the hospital or clinical provider has decreased the dose of linezolid for any reason other than study-related therapeutic drug-monitoring. The number/percentage of participants who had dosage of linezolid decreased will be summarized by study arm.
Within 6 months after initiation of LZD therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Albert Einstein College of Medicine

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Columbia University
Emory University
University of Cape Town
St George's, University of London
National Department of Health, South Africa

Investigators

  • Principal Investigator: James CM Brust, MD, Albert Einstein College Of Medicine
  • Principal Investigator: Gary Maartens, MBChB, University of Cape Town

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 7, 2026

Primary Completion (Estimated)

June 1, 2029

Study Completion (Estimated)

December 1, 2029

Study Registration Dates

First Submitted

September 9, 2024

First Submitted That Met QC Criteria

September 9, 2024

First Posted (Actual)

September 19, 2024

Study Record Updates

Last Update Posted (Actual)

May 4, 2026

Last Update Submitted That Met QC Criteria

April 28, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024-16182
  • R01AI184416 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The study will generate a range of data types from structured participant interviews to linezolid trough plasma concentrations. The investigators aim to widely share the knowledge generated by this proposal to advance knowledge in the field of TB research and avoid duplication of relevant work. Participant-level clinical and laboratory data will be preserved through deposition of the data in a controlled access public repository.

IPD Sharing Time Frame

Scientific data included in published manuscripts will be available at the time of publication or the end of the award, whichever comes first; all other generated scientific data will be shared no later than the end of the award. Data will be made available for an indefinite period or until Emory University requests that it be withdrawn.

IPD Sharing Access Criteria

All de-identified study data not designated as restricted use will be made available to the research community upon request and approval by study MPIs. Code used to perform statistical analysis will be deposited in a publicly available repository or may be requested from the investigators to ensure others can seek to reproduce the results, if desired. Public use and restricted access study data and associated documentation will be made available to the research community free of charge through the Emory Dataverse, an open data repository intended for the preservation, discoverability and accessibility of data produced by the Emory University research community, or other appropriate data repository.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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