Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06590428
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-09
Brief Title:
Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ToxZid
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 DRrifampicin-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 25 mgL 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
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 DRrifampicin-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 25 mgL 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None