Linezolid Tolerance During the BPaL Regimen With Dosage Personalization Based on Therapeutic Drug Monitoring (TDM) During Multidrug-Resistant Tuberculosis Treatment

Официальное название

Tolérance du Linézolide Pendant le Régime BPaL Avec Personnalisation de la Posologie Basée Sur la Surveillance Thérapeutique Des Médicaments (TDM) au Cours du Traitement de la Tuberculose Multirésistante

Обзор

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: * the variation in the occurrence of adverse events between patients who undergo a modification of the linezolid dose based on the TDM and patients taking linezolid standard dose * the treatment outcome in patients who undergo a modification of the linezolid dose based on TDM and patients taking linezolid standard dose * variations in the distribution of TDM throughout treatment in order to identify potential common trends.

Вмешательства

• Препарат Linezolid dose personalization based on TDM
  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)

Первичные конечные точки

• Rate of linezolid related side effects. [Срок оценки: From enrollment to the end of treatment at 6 months]

Вторичные конечные точки (3)

• Feasibility of linezolid dosage personalization based on TDM in low resources setting [Срок оценки: From enrollment to the end of treatment at 6 months]
• Treatment outcome [Срок оценки: From the enrollment to the end of the treatment at 6 months]
• Linezolid TDM trends [Срок оценки: From enrollment to the end of treatment at 6 months]

Критерии участия

Критерии включения

• 1\. Confirmed diagnosis of MDR-TB
• 2\. Linezolid prescribed as part of the BPaL/BPaL-M regimen
• 3\. Age 15 years or older
• 4\. Informed consent obtained from the participant or assent from the parent/legal guardian for participants under 18 years of age.

Критерии исключения

• 1\. Pregnancy or breastfeeding
• 2\. Severe liver or kidney failure
• 3\. Known hypersensitivity to linezolid
• 4\. Concomitant use of medications with drug interactions potential with linezolid

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Guinea · 1 центр

• Centre de Santé de Tombolia — Conakry

Публикации

• 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. PMID 34543098
• 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 PMID 36053506
• 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/ PMID 36630546
• Global tuberculosis report 2024. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO
• 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. PMID 20042919
• Pourhoseingholi MA, Vahedi M, Rahimzadeh M. Sample size calculation in medical studies. Gastroenterol Hepatol Bed Bench. 2013 Winter;6(1):14-7. PMID 24834239
• Daniel, Wayne W. Biostatistics: a foundation for analysis in the health sciences. Vol. 129. Wiley, 1978.

Идентификаторы

NCT: NCT07477119 · 079/CNERS/25

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗