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

NCT07477119 | Recruiting Phase 4

• 1 other identifier: 079/CNERS/25
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Linezolid; Tuberculosis Multi Drug Resistant Active; Therapeutic Drug Monitoring (TDM)

Keywords

linezolid; TDM; Therapeutic Drug Monitoring; MDR-TB; Guinea; Adverse Drug Reaction; Peripheral Neuropathy; Myelosuppression; Tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (3)

• Feasibility of linezolid dosage personalization based on TDM in low resources setting

  From enrollment to the end of treatment at 6 months

• Treatment outcome

  From the enrollment to the end of the treatment at 6 months

• Linezolid TDM trends

  From enrollment to the end of treatment at 6 months

Study Arms (2)

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

Drug: Linezolid dose personalization based on TDM

Interventions

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)

Group B: linezolid dose personalization based on TDM

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Marco Schiuma: lead
• ASST Fatebenefratelli Sacco: collaborator
• University of Milan: collaborator
• Damien Foundation: collaborator

Study Sites (1)

Centre de Santé de Tombolia

Conakry, Guinea

RECRUITING

Related Publications (7)

• 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 BACKGROUND

• 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.

  PMID: 36053506 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/

  PMID: 36630546 BACKGROUND

• Global tuberculosis report 2024. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO

  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.

  PMID: 20042919 BACKGROUND

• Pourhoseingholi MA, Vahedi M, Rahimzadeh M. Sample size calculation in medical studies. Gastroenterol Hepatol Bed Bench. 2013 Winter;6(1):14-7.

  PMID: 24834239 BACKGROUND

• Daniel, Wayne W. Biostatistics: a foundation for analysis in the health sciences. Vol. 129. Wiley, 1978.

  BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Drug-Related Side Effects and Adverse Reactions; Peripheral Nervous System Diseases; Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Chemically-Induced Disorders; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Marco Schiuma

  ASST Fatebenefratelli Sacco, Luigi Sacco University Hospital, Milan, Italy

  STUDY DIRECTOR

• Souleymane Hassane Harouna

  Action Daminen Guinée

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marco Schiuma

CONTACT

+393284931986; schiuma.marco@asst-fbf-sacco.it

Souleymane Hassane Harouna

CONTACT

+224620717593; hassoul20@yahoo.fr

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Doctor, Infectious Diseases Specialist

Study Record Dates

• First Submitted: March 10, 2026
• First Posted: March 17, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): April 1, 2028
• Last Updated: May 13, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

GU (1)