Rifampin-resistant TuberculosisTHERMOLNCT06590428
Therapeutic Drug Monitoring for Linezolid in the Treatment of Rifampin-resistant Tuberculosis
A study testing Therapeutic Drug Monitoring for Linezolid in people with Rifampin-resistant Tuberculosis and Drug-resistant Tuberculosis, run by Albert Einstein College of Medicine at 1 site in South Africa.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rifampin-resistant Tuberculosis, Drug-resistant Tuberculosis
- What is being tested?
- Therapeutic Drug Monitoring for Linezolid
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 280 participants
- Where
- 1 siteSouth Africa
- Study dates
- 7 Apr 2026to Dec 2029
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
South Africa1 site, 1 recruiting
- Recruiting
Nkqubela TB Specialist Hospital
East London, Eastern Cape, 5206
Gary Maartens, MBChB
Gary Maartens, MBChB
About this study
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.
Read the 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.
- Being tested
- Therapeutic Drug Monitoring for Linezolid
- Keywords
- HIV Status, Therapeutic Drug Monitoring, anti-Tuberculosis activity, Linezolid
- Medical subject headings
- Tuberculosis, Multidrug-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Therapeutic Drug Monitoring for LinezolidOther
TDM with dose adjustment for trough concentration >2.5 mg/L LZD
| Study group | Role | What they receive |
|---|---|---|
| Therapeutic Drug Monitoring (TDM) | Other | Participants in the TDM arm will have their linezolid dose reduced if their trough concentration is greater than 2.5 mg/L Receives: Other: Therapeutic Drug Monitoring for Linezolid |
| Standard of Care (SOC) | No intervention | Participants in the SOC arm will have their linezolid adjusted or held if they develop clinical adverse events. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Discontinuation of Linezolid or non-TDM guided dose reduction
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.
Measured: Within 6 months after initiation of LZD therapy
Secondary outcomes (5)
Evidence of Linezolid Toxicity
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.
Measured: Within 6 months after initiation of LZD therapy
Unsuccessful final Tuberculosis (TB) end-of-treatment outcome
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
Measured: After 6 months, and up to 12 months after initiation of LZD therapy
Emergence of new phenotypic resistance to Linezolid
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
Measured: Within 6 months after initiation of LZD therapy
TB-free survival
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.
Measured: 12 months after initiation of LZD therapy
Non-TDM-guided dose reduction of linezolid
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.
Measured: Within 6 months after initiation of LZD therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Sep 2024
- Study start7 Apr 2026
- Primary completionJun 2029 (estimated)
- Study completionDec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (71)Papers the sponsor has linked to this study.
- Other trials for Rifampin-resistant TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 280 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Albert Einstein College of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- University of Cape Town, St George's, University of London, Emory University, National Department of Health, South Africa, Columbia University, National Institute of Allergy and Infectious Diseases (NIAID)
- Responsible party
- Sponsor
- Investigators
- James CM Brust, MD, Principal investigator, Albert Einstein College of MedicineGary Maartens, MBChB, Principal investigator, University of Cape Town
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06590428
- Sponsor's protocol ID
- 2024-16182
- Other IDs
- R01AI184416
- Acronym
- THERMOL
- Status last verified
- Apr 2026
- First submitted
- 9 Sep 2024
- Last updated
- 4 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
World Health Organization. Global Tuberculosis Report 2022. Geneva.
Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martin-Casabona N, Drobniewski F, Gilpin C, Havelkova M, Lepe R, Lumb R, Metchock B, Portaels F, Rodrigues MF, Rusch-Gerdes S, Van Deun A, Vincent V, Laserson K, Wells C, Cegielski JP. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis. 2007 Mar;13(3):380-7. doi: 10.3201/eid1303.061400.
PubMed 17552090Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, Palmero D, Perez-Guzman C, Vargas MH, D'Ambrosio L, Spanevello A, Bauer M, Chan ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D; "The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB". Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J. 2013 Jul;42(1):169-179. doi: 10.1183/09031936.00136312. Epub 2012 Oct 11.
PubMed 23060633Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep. 2006 Mar 24;55(11):301-5.
PubMed 16557213Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, Weissman D, Marra C, Lalloo UG, Friedland GH; Tugela Ferry Care and Research (TF CARES) Collaboration. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010 Jan 1;181(1):80-6. doi: 10.1164/rccm.200907-0989OC. Epub 2009 Oct 15.
PubMed 19833824Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova OS, Ferrara G, Cirillo DM, Gori A, Matteelli A, Spanevello A, Codecasa LR, Raviglione MC; SMIRA/TBNET Study Group. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J. 2007 Oct;30(4):623-6. doi: 10.1183/09031936.00077307. Epub 2007 Aug 9.
PubMed 17690121Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP. Extensively drug-resistant tuberculosis in the United States, 1993-2007. JAMA. 2008 Nov 12;300(18):2153-60. doi: 10.1001/jama.300.18.2153.
PubMed 19001626Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006 Nov 4;368(9547):1575-80. doi: 10.1016/S0140-6736(06)69573-1.
PubMed 17084757Pietersen E, Ignatius E, Streicher EM, Mastrapa B, Padanilam X, Pooran A, Badri M, Lesosky M, van Helden P, Sirgel FA, Warren R, Dheda K. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet. 2014 Apr 5;383(9924):1230-9. doi: 10.1016/S0140-6736(13)62675-6. Epub 2014 Jan 17.
PubMed 24439237Schnippel K, Ndjeka N, Maartens G, Meintjes G, Master I, Ismail N, Hughes J, Ferreira H, Padanilam X, Romero R, Te Riele J, Conradie F. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. Lancet Respir Med. 2018 Sep;6(9):699-706. doi: 10.1016/S2213-2600(18)30235-2. Epub 2018 Jul 11.
PubMed 30001994Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment-2017; Ahmad N, Ahuja SD, Akkerman OW, Alffenaar JC, Anderson LF, Baghaei P, Bang D, Barry PM, Bastos ML, Behera D, Benedetti A, Bisson GP, Boeree MJ, Bonnet M, Brode SK, Brust JCM, Cai Y, Caumes E, Cegielski JP, Centis R, Chan PC, Chan ED, Chang KC, Charles M, Cirule A, Dalcolmo MP, D'Ambrosio L, de Vries G, Dheda K, Esmail A, Flood J, Fox GJ, Frechet-Jachym M, Fregona G, Gayoso R, Gegia M, Gler MT, Gu S, Guglielmetti L, Holtz TH, Hughes J, Isaakidis P, Jarlsberg L, Kempker RR, Keshavjee S, Khan FA, Kipiani M, Koenig SP, Koh WJ, Kritski A, Kuksa L, Kvasnovsky CL, Kwak N, Lan Z, Lange C, Laniado-Laborin R, Lee M, Leimane V, Leung CC, Leung EC, Li PZ, Lowenthal P, Maciel EL, Marks SM, Mase S, Mbuagbaw L, Migliori GB, Milanov V, Miller AC, Mitnick CD, Modongo C, Mohr E, Monedero I, Nahid P, Ndjeka N, O'Donnell MR, Padayatchi N, Palmero D, Pape JW, Podewils LJ, Reynolds I, Riekstina V, Robert J, Rodriguez M, Seaworth B, Seung KJ, Schnippel K, Shim TS, Singla R, Smith SE, Sotgiu G, Sukhbaatar G, Tabarsi P, Tiberi S, Trajman A, Trieu L, Udwadia ZF, van der Werf TS, Veziris N, Viiklepp P, Vilbrun SC, Walsh K, Westenhouse J, Yew WW, Yim JJ, Zetola NM, Zignol M, Menzies D. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018 Sep 8;392(10150):821-834. doi: 10.1016/S0140-6736(18)31644-1.
PubMed 30215381Conradie F, Diacon A, Howell P, et al. Sustained high rate of successful treatment outcomes: Interim results of 75 patients in the Nix-TB clinical study of pretomanid, bedaquiline and linezolid. 49th Union World Conference on Lung Health The Hague, Netherlands 24-27 October 2018 Abstract OA03-213-25.
Diacon AH, De Jager VR, Dawson R, Narunsky K, Vanker N, Burger DA, Everitt D, Pappas F, Nedelman J, Mendel CM. Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2020 Mar 24;64(4):e02012-19. doi: 10.1128/AAC.02012-19. Print 2020 Mar 24.
PubMed 31988102Zurenko GE, Yagi BH, Schaadt RD, Allison JW, Kilburn JO, Glickman SE, Hutchinson DK, Barbachyn MR, Brickner SJ. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother. 1996 Apr;40(4):839-45. doi: 10.1128/AAC.40.4.839.
PubMed 8849237Cynamon MH, Klemens SP, Sharpe CA, Chase S. Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother. 1999 May;43(5):1189-91. doi: 10.1128/AAC.43.5.1189.
PubMed 10223934