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| Name | Class |
|---|---|
| ASST Fatebenefratelli Sacco | OTHER |
| University of Milan | OTHER |
| Damien Foundation | OTHER |
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Multidrug-resistant tuberculosis (MDR-TB) poses a significant challenge to global public health.
Globally, the World Health Organization (WHO) estimates the number at 400,000 patients with MDR-TB for 2023. Only 44% were diagnosed and put on treatment, the therapeutic success rate of the 2021 cohort is only 68%.
In Guinea, the number of patients with MDR-TB is estimated at 450, and the treatment success rate is 74% for the 2021 cohort, primarily with the 9-months short oral regimen.
Since 2022, the WHO has recommended the use of the 6-month short course of BPaL/BPaL-M for national tuberculosis control programs and Guinea began implementing this new regime within the programmatic framework starting in January 2025.
Linezolid, a key component of new therapeutic regimens such as BPaL/BPaL-M, shows high bactericidal activity, although it is associated with serious adverse effects in a high percentage of patients, including myelosuppression, neuropathy and, in some cases, fatal lactic acidosis. In particular, peripheral neuropathy, an adverse event often irreversible that may lead to linezolid and the BPaL/BPaL-M regimen discontinuation, is reported in approximately 24% of patients receiving linezolid at 600 mg.
A linezolid blood trough level of above 2 mg/l is associated with side effects, but its pharmacokinetics varies considerably between individuals and over time.
There is little data on the role of therapeutic drug monitoring (TDM) in guiding its administration, some studies showing how the standard dose of 600 mg could exceed the toxicity target and the reduced dose of 300 mg might not achieve the target efficacy.
The main objective of this study is to determine the role of TDM in the optimization of linezolid dosage in TB-MDR patients treated with the BPaL/BPaL-M regimen.
The specific objectives aim to evaluate:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A: linezolid 600 mg standard dose. Only TDM monitoring | No Intervention | Linezolid will be administered at the recommended dose of 600 mg. The linezolid level will be measured for each patient once a week during the first month (4 blood samples), then once a month for the following 5 months (5 blood samples) to complete the 6-month regimen (at least 9 blood samples for each patient). One additional sample will be taken if linezolid-related side effects appear. No changes to the linezolid dosage will be made except as directed in accordance with the national guidelines for the management of MDR-TB. | |
| Group B: linezolid dose personalization based on TDM | Experimental | Linezolid will be initially administered at the recommended dose of 600 mg. The linezolid level will be measured for each patient once a week during the first month (4 blood samples), then once a month for the following 5 months (5 blood samples) to complete the 6-month regimen (at least 9 blood samples for each patient). Additional samples will be taken if linezolid-related side effects appear or if the trough linezolid concentration in the blood does not reach the reference range of 0.6-2 mg/l. The dosage of linezolid will be modified according to the TDM |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Linezolid dose personalization based on TDM | Drug | The dosage of linezolid will be modified according to the TDM as follows: if > 2 mg/l the dosage will be decreased by 300 mg (minimum 300 mg every second day, TDM repeated after one week); if < 0.6 mg/l the dosage will be increased by 300 mg (maximum 1200 mg, TDM repeated after one week); if between 0.6 and 2 mg/l the dosage will not be changed (regular TDM timepoints) |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of linezolid related side effects. | The primary objective is to evaluate the variation in the rate of occurrence of adverse events between patients who undergo a modification of the linezolid dose based on the TDM and patients taking linezolid standard dose. We hypothesize that patients who under go linezolid dose personalization based on TDM will maintain linezolid blood levels within the therapeutic range (0.6-2 mg/l). This could result in a different rate in linezolid related side effects between the two groups | From enrollment to the end of treatment at 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Feasibility of linezolid dosage personalization based on TDM in low resources setting | The objective is to determine if TDM has a role in the optimization of linezolid dosage in TB-MDR patients in a setting similar to Guinea. The feasibility and implementability of the method will be assessed by comparing the number of blood samples actually collected from each participant with the number of samples scheduled according to the predefined theoretical sampling time set for each participant. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marco Schiuma | Contact | +393284931986 | schiuma.marco@asst-fbf-sacco.it | |
| Souleymane Hassane Harouna | Contact | +224620717593 | hassoul20@yahoo.fr |
| Name | Affiliation | Role |
|---|---|---|
| Marco Schiuma | ASST Fatebenefratelli Sacco, Luigi Sacco University Hospital, Milan, Italy | Study Director |
| Souleymane Hassane Harouna | Action Daminen Guinée | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de Santé de Tombolia | Recruiting | Conakry | Guinea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34543098 | Background | Abdelwahab MT, Wasserman S, Brust JCM, Dheda K, Wiesner L, Gandhi NR, Warren RM, Sirgel FA, Meintjes G, Maartens G, Denti P. Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0138121. doi: 10.1128/AAC.01381-21. Epub 2021 Sep 20. | |
| 36053506 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 1, 2025 | Mar 9, 2026 |
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| From enrollment to the end of treatment at 6 months |
| Treatment outcome | The objective is to evaluate the treatment outcome (defined by WHO as: treatment failed, cured, treatment completed, died, lost to follow up, treatment success, sustained treatment success) in patients who undergo a modification of the linezolid dose based on TDM and patients taking linezolid standard dose. | From the enrollment to the end of the treatment at 6 months |
| Linezolid TDM trends | The objective is to describe the TDM values during the treatment, define variations in the distribution of TDM throughout treatment in order to identify potential common trends (for example median lower values at the beginning of the treatment for all the patients, linked to higher inflammation, increased values at the end of the treatment for linezolid accumulation) | From enrollment to the end of treatment at 6 months |
| Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430. |
| 36630546 | Background | WHO consolidated guidelines on tuberculosis: Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update [Internet]. Geneva: World Health Organization; 2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK588564/ |
| Background | Global tuberculosis report 2024. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO |
| 20042919 | Background | Alffenaar JW, Kosterink JG, van Altena R, van der Werf TS, Uges DR, Proost JH. Limited sampling strategies for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Ther Drug Monit. 2010 Feb;32(1):97-101. doi: 10.1097/FTD.0b013e3181cc6d6f. |
| 24834239 | Background | Pourhoseingholi MA, Vahedi M, Rahimzadeh M. Sample size calculation in medical studies. Gastroenterol Hepatol Bed Bench. 2013 Winter;6(1):14-7. |
| Background | Daniel, Wayne W. Biostatistics: a foundation for analysis in the health sciences. Vol. 129. Wiley, 1978. |
| Prot_000.pdf |
| ID | Term |
|---|---|
| D018088 | Tuberculosis, Multidrug-Resistant |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| D010523 | Peripheral Nervous System Diseases |
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D064419 | Chemically-Induced Disorders |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
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