Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
- Conditions
- Rifampin-resistant TuberculosisDrug-resistant Tuberculosis
- Interventions
- Other: Therapeutic Drug Monitoring for Linezolid
- Registration Number
- NCT06590428
- Lead Sponsor
- Albert Einstein College of Medicine
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 280
-
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Therapeutic Drug Monitoring (TDM) Therapeutic Drug Monitoring for Linezolid Participants in the TDM arm will have their linezolid dose reduced if their trough concentration is greater than 2.5 mg/L
- Primary Outcome Measures
Name Time Method Discontinuation of Linezolid or non-TDM guided dose reduction 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.
- Secondary Outcome Measures
Name Time Method Evidence of Linezolid Toxicity 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 or neurologic 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.
Unsuccessful final Tuberculosis (TB) end-of-treatment outcome 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 diedEmergence of new phenotypic resistance to Linezolid 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
Trial Locations
- Locations (1)
Nkqubela TB Specialist Hospital
🇿🇦East London, Eastern Cape, South Africa