Clinical trial NCT06590428: Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
Official title: Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Rifampin-resistant Tuberculosis
Drug-resistant Tuberculosis
Keywords: HIV Status
Therapeutic Drug Monitoring
anti-Tuberculosis activity
Linezolid
Lead sponsor: Albert Einstein College of Medicine
Sponsor class: OTHER
Collaborators: name: University of Cape Town
name: St George's, University of London
name: Emory University
name: National Department of Health, South Africa
name: Columbia University
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2024-09-19
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization.

Participants will receive 600mg daily dose of oral LZD for Rifampicin-resistant tuberculosis (RR-TB) as part of standard of care for both arms. This dosage may be reduced to 300mg daily based on the plasma trough concentration obtained from the first pharmacokinetic (PK) specimen.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: Inclusion Criteria:

* Adult male or female patient \> 18 years of age
* Microbiological confirmation of rifampicin-resistant tuberculosis (e.g., phenotypic 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 RR-TB treatment regimen containing linezolid, no more than 14 days prior to enrollment
* HIV status is known

  * Both HIV-positive and HIV-negative individuals are eligible
  * If an individual reports unknown HIV results, 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
  * If an individual declines to share his or her HIV status, they are not eligible for the study. Patients reporting unknown HIV status will be required to have had confirmatory testing within 6 months of study screening

Exclusion Criteria:

* Current unstable or uncontrolled major medical comorbidity that would interfere with subject's ability to participate in the study
* Pregnant at time of screening
* Initial linezolid dose \< 600mg daily

Primary outcomes:
measure: Discontinuation of Linezolid or non-TDM guided dose reduction
timeFrame: Within 6 months after initiation of LZD therapy
Secondary outcomes:
measure: Evidence of Linezolid Toxicity
timeFrame: Within 6 months after initiation of LZD therapy
measure: Unsuccessful final Tuberculosis (TB) end-of-treatment outcome
timeFrame: After 6 months, and up to 12 months after initiation of LZD therapy
measure: Emergence of new phenotypic resistance to Linezolid
timeFrame: Within 6 months after initiation of LZD therapy
Other outcomes:
Locations:
city: East London
country: South Africa
facility: Nkqubela TB Specialist Hospital
state: Eastern Cape
Study officials:
affiliation: Albert Einstein College of Medicine
name: James CM Brust, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cape Town
name: Gary Maartens, MBChB
role: PRINCIPAL_INVESTIGATOR
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