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
Phase: PHASE4
Conditions: Linezolid, Tuberculosis Multi Drug Resistant Active, Therapeutic Drug Monitoring (TDM)
Sponsor: Marco Schiuma

 
1 
 
 
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
Linezolid tolerance during the BPaL regimen  
with dosage personalization based on Therapeutic 
Drug Monitoring (TDM) during  
Multidrug-Resistant tuberculosis treatment 
 
 
 
 
 
February 2025 

 
2 
 
 
 
 
 
 
REPUBLIC OF GUINEA 
=========== 
WORK – JUSTICE – SOLIDARITY 
 
National Ethics Committee for Health Research (CNERS) 
 
 
Application form for ethical review of a health research project/protocol 
 
 
Title of the health research protocol: 
Linezolid tolerance during the BPaL regimen with dosage personalization based on Therapeutic 
Drug Monitoring (TDM) during Multidrug-Resistant tuberculosis. 
Personalized dosage and Linezolid Optimization with TDM in MDR-TB: the PLOT-TB study 
 
 
Principal investigator: 
Name and surname: HASSANE HAROUNA 
Profession: Doctor 
Academic rank: Doctor 
 
Phone: 620717593 WhatsApp: +22796970075 Email: hassoul20@yahoo.fr 
 
Affiliation institution: Action Damien 
Address of the affiliated institution: Action Damien Guinée, Camayenne, Commune of Dixinn 
Post Office Box: 1893 
City: Conakry Country: Guinea 
 
Research collaborators/team 
1. Co-Principal Investigator: Prof. Andrea Gori 
Professor Andrea Gori is an expert in infectious diseases, a professor at the University of 
Milan, and head of the infectious diseases department at Sacco Hospital in Milan. His research 
focuses on HIV, tuberculosis, and infections in immunocompromised patients. Since 1992, he 
has led clinical research projects centered on the immunopathogenesis of viral and bacterial 
infections. 
 
 
2. Other collaborators 
 
 
 
 
 

 
3 
 
 
 
Name 
Title 
Function in the 
project 
Affiliation 
Email 
Phone 
Dr. Adama 
Marie 
Bangoura 
Medical 
Doctor 
Coordination 
of 
activities in 
Guinea 
 
National 
Tuberculosis 
Program - 
Guinea 
adabangou@yahoo.fr 
 
620520667 
Prof. Andrea 
Gori 
Infectious 
Diseases 
Professor at 
Biochemical 
Sciences 
Département 
Protocol 
editing, article 
writing, data 
analysis, 
search for 
funding 
 
University of 
Milan 
andrea.gori@unimi.it 
+39 
0234042454 
Dr. 
Aboubacar 
Sidiki 
Magassouba 
Medical 
Doctor 
Article writing 
data analysis 
National 
Tuberculosis 
Program - 
Guinea 
magasbakary01@gmail.com 
 
622396910 
Dr. Alberto 
Roggi 
Medical 
Doctor 
Protocol 
editing, 
article writing 
data analysis 
Action 
Damien 
Brussels 
 
alberto.roggi@damienfoundation.be 
 
+39 
3396492133 
Dr. Cherif 
Gba- 
Foromo 
Doctor of 
medicine, 
Master's 
Public health 
Recruitment of 
participants, 
collection of 
data 
 
Action 
Damien 
Guinea 
 
cheriflola83@gmail.com 
 
62259432 
 
Professor 
Djelo 
Boubacar 
Diallo 
 
Professor of 
pulmonology, 
responsible 
for 
TB-MR 
 
Review of 
literature, 
article writing 
 
Service of 
Pulmonology 
of the 
Ignace 
University 
Hospital 
Deen 
 
diallodjelo@yahoo.fr 
 
628584005 
 
Dr. Moussa 
Condé 
 
Dr. 
Pharmacist- 
biologist, 
Head 
Service 
 
Samples 
analysis, data 
analysis 
Referent 
National 
Mycobacteria 
Laboratory 
condmous82@gmail.com 
628466141 
 
Dr. Marco 
Schiuma 
Medical 
Doctor, 
Infectious 
Diseases 
Specialist 
Protocol 
editing, article 
writing, data 
analysis 
Sacco 
hospital, 
Milan 
schiuma.marco@asst-fbf-sacco.it 
+39 
3284931986 

 
4 
 
 
Partner institution(s): 
 
 
Name 
Address 
Role in the project 
Email 
Phone 
PNLT 
Dixinn, 
Camayenne/Rési 
Micheline dence; 
BP:634. 
Coordination of 
activities 
adabangou@yahoo.fr 
620520667 
University 
from Milan 
Department of 
Biomedical Sciences 
and "L. Sacco" 
Clinics 
Via GB Grassi 74, 
20157, Milan, Italy. 
Protocol drafting, 
analysis of the 
results and 
article writing 
andrea.gori@unimi.it 
+39 0234042454 
Sacco Hospital, 
Milan 
Department of 
infectious diseases 
Protocol drafting, 
analysis of the 
results and 
article writing 
schiuma.marco@asst- 
fbf-sacco.it 
+39 3284931986 
Action 
Damien 
Brussels 
263 Boulevard 
Leopold II, 1081 
Koekelberg, 
Brussels, 
Belgium. 
Protocol drafting 
data analysis, 
article writing 
alberto.roggi@damienfo 
undation.be 
+39 3396492133 
Ignace Deen 
University Hospital 
Pulmonology 
Department, 
Conakry, Guinea. 
Literature review, 
article writing 
diallodjelo@yahoo.fr 
628584005 

 
5 
 
 
TABLE OF CONTENTS 
 
Table of Contents 
TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 
 
LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 
1 CONTEXT AND JUSTIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 
2 OBJECTIVE OF THE STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 
2.1 
2.2 
General objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 
Specific objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 
3 METHODOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 
3.1 STUDY PLAN AND SITE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 
3.2 POPULATION AND DURATION OF THE STUDY. . . . . . . . . . . . . . . . . . . . . . . . . .8 
3.3 INCLUSION CRITERIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8  
3.4 EXCLUSION CRITERIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8  
3.5 SAMPLE SIZE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 9 
3.6 PROCEDURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 
3.6.1 Group A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9  
3.6.2 Group B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9  
3.7 LINEZOLIDE TOXICITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10  
3.8 DATA COLLECTION AND ANALYSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10  
3.9 ETHICAL CONSIDERATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10  
3.10 DISSEMINATION OF RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 
4 CHRONOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 
5 BUDGET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  12 
6 BIBLIOGRAPHY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  13 
7 APPENDICES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 
 
 
 
 
 
 
 
 
 
 
 
 

 
6 
AD 
BPaLM 
LNRM 
Lzd 
WHO 
NGO 
PNLT 
TB 
TB-MR 
TDM 
Action Damien 
Bedaquiline-Pretomanid-Linezolid-Moxifloxacin 
National Reference Laboratory for Mycobacteria 
Linezolid 
World Health Organization 
Non-Governmental Organization 
National Tuberculosis Control Program 
Tuberculosis 
Multidrug-resistant tuberculosis 
Therapeutic drug monitoring 
 
 
 
 
LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
7 
 
 
 
 
1. CONTEXT AND JUSTIFICATION 
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%1. 
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 regimen1. 
 
Since 2022, the WHO has recommended the use of the 6-month short course of BPaL/BPaL-M for 
national tuberculosis control programs2 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 mg3. 
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 efficacy4. 
 
 
2. OBJECTIVE OF THE STUDY 
2.1 General objective 
The main objective of this study is to determine 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 
2.2 Specific Objectives 
The specific objectives aim to evaluate: 
 

 
8 
 
 
 
 
- the role of TDM in the optimization of linezolid dosage in TB-MDR patients treated with the 
BPaL/BPaL-M regimen 
- 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. 
3 METHODOLOGY 
3.1 STUDY PLAN AND SITE 
 
This is a prospective, interventional, randomized, controlled clinical trial. It will be conducted at the Tombolia 
TB-MDR treatment clinic, one of the four sites of the city of Conakry which annually notifies approximately 
70 patients out of a national total of approximately 300 MDR-TB cases. 
The study will be conducted in collaboration with the University of Milan, the Sacco Hospital of Milan, the 
the national tuberculosis control program in Guinea and the NGO Action Damien, which works on the operational 
level and conducts several studies in numerous countries, including Guinea, among patients with MDR-TB. In 
particular, the University of Milan will supply the entire technical equipment to analize linezolid blood 
concentrations thanks to the INFACT project. 
 
3.2 POPULATION AND DURATION OF THE STUDY 
The study will be conducted on MDR-TB patients receiving linezolid as part of the BPaL/BPaL-M regimen 
(April 2025 to April 2028). 
3.3 INCLUSION CRITERIA 
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. 
3.4 EXCLUSION CRITERIA 
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 
 
 
 

 
9 
 
 
 
 
 
 
3.5 SAMPLE SIZE 
The sample size was determined based on the reported prevalence in the literature of peripheral 
neuropathy in patients with MDR-TB3, given a precision of 7% for the study and a confidence level of 
95%5,6. The defined sample size includes 150 participants. 
3.6 PROCEDURE 
The study will include two groups of patients, all of whom will receive linezolid as part of  
BPaL/BPaL-M, in accordance with current WHO guidelines: 
3.6.1 Group A 
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. 
 
3.6.2 Group B 
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). 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, in accordance with the figure 1. 
The blood sample will be collected in a single 4 mL serum tube at the Tombolia care site by the 
responsible nurse, then all samples transported to the National Reference Laboratory for 
Mycobacteria (LNRM) by the MDR-TB recovery agent. At the LNRM, the samples will be centrifuged 
and stored up to one week at 2 to 8 °C before being processed.

 
10 
 
 
 
 
If the analysis is delayed by more than a week, the samples must be kept frozen (-20 °C) for up to 
four weeks before being submitted for analysis. 
The “CDX90” device produced by “Furuno” and supplied by “TEMA Ricerche” will be used to 
measure the plasma concentration of linezolid by using "ARKTM Linezolid” kit from “ARK 
Diagnostics Inc. (Fremont, CA)”, supplied by "TEMA Ricerche". 
The reference concentration of linezolid will be between 0.6 and 2 mg/l. 
Note: The total concentration of linezolid (24 hours after the last dose of the medication) will be 
obtained for each patient, as it allows the AUC7 value to be estimated. 
3.7 LINEZOLIDE TOXICITY 
The toxicity of linezolid will be defined as follows: 
- Onset or worsening of peripheral or optic neuropathy 
- Drop in hemoglobin below 8 g/dl 
- Platelet count below 50,000/mcl 
- Neutrophil count below 750/mcl 
- Lactate acidosis (Lactate > 3, clinical signs or symptoms consistent with lactate acidosis). 
3.8 DATA COLLECTION AND ANALYSIS 
 
The data will be collected through individual forms containing the demographic and clinical 
characteristics of each patient, later uploaded on REDCap softwere.  
Statistical methods, including descriptive statistics and regression analysis will be used to analyze the 
relationship between plasma concentrations of linezolid and treatment outcomes. Subgroup analyses 
may be performed based on factors such as age, sex and comorbidities. 
 
3.9 ETHICAL CONSIDERATIONS 
1. The study will be conducted in accordance with the principles of the Declaration of Helsinki and the 
good clinical practices. 
2. An information form (Appendix 1) will be read/explained to the participants, as well as an informed 
consent/assent form (Appendix 2) will be offered to all participants and/or their guarantors for 
signature before the start of treatment. 
3. The confidentiality of participant information will be maintained. 
 
3.10 DISSEMINATION OF RESULTS 
The results of the study will be published in journals and at conferences. 
Participants will be informed of the overall results of the study. 
 
 

 
11 
 
 
 
4 CHRONOLOGY 
The study should be conducted over a period of 3 years (3 months for preparation, 24 months 
For patient recruitment, 6 months to complete treatment, 3 months for analysis of 
data). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
12 
 
 
 
 
 
5 BUDGET 
 
 
CATEGORY 
 
 
Equipment 
costs 
 
 
 
 
 
CDX90 Analyzer 
 
 
 
 
Linezolid TDM kit 
 
2025 
 
 
 
€6,000 
 
 
 
 
€21,120 
 
2026 
 
2027 
UNIMI BUDGET 
 
University of 
Milan, thanks to 
INFACT project 
 
University of 
Milan, thanks to 
 
Total PLOT-TB 
 
€6,000 
(excluding VAT) 
€7,320 
(VAT included) 
€21,120 
(excluding VAT) 
Cost in GNF 
 
 
 
65,880,000 
 
 
 
 
231,930,000 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFACT project 
€25,770 
(VAT included) 
 
Equipment Consumables 
 
 
 
University of 
 
 
Shipping 
€1,700 
 
 
Milan, thanks to 
€1,500 
13,500,000 
 
 
 
 
INFACT project 
 
 
 
 
 
 
University of 
 
 
 
Customs 
€2,800 
 
 
Milan, thanks to 
€12,240 
110,160,000 
 
 
 
 
INFACT project 
 
 
 
Incentive for patients 
 
 
 
University of 
 
 
 
 
 
 
Milan 
 
 
 
Compensation for 
 
 
 
University of 
 
 
Local costs 
nurses 
€3,000 
€4,000 
€3,000 
Milan 
€10,000 
90,000,000 
 
Transport of 
 
 
 
University of 
 
 
 
samples 
 
 
 
Milan 
 
 
 
Other 
 
 
 
University of 
Milan 
 
 
 
Ethics Committee 
Protocol submission fee 
€555 
 
 
University of 
Milan 
€555 
4,995,000 
Total 
 
 
 
 
€57,385 
 
516,465,000 

 
13 
 
 
6 BIBLIOGRAPHY 
 
1. Global tuberculosis report 2024. Geneva: World Health Organization; 2024. Licence: CC 
BY-NC-SA 3.0 IGO 
 
2. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant 
tuberculosis treatment, 2022 update. Geneva: World Health Organization; 2022. Licence: 
CC BY-NC-SA 3.0 IGO. 
 
3. Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-Pretomanid-Linezolid 
Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022;387(9):810-823. 
doi:10.1056/NEJMoa2119430 
 
4. Abdelwahab MT, Wasserman S, Brust JCM, et al. Linezolid Population Pharmacokinetics 
in South African Adults with Drug-Resistant Tuberculosis. Antimicrob Agents Chemother. 
2021;65(12). doi:10.1128/AAC.01381-21 
 
5. Daniel, Wayne W. Biostatistics: a foundation for analysis in the health sciences. Vol. 129. 
Wiley, 1978. 
 
6. Pourhoseingholi MA, Vahedi M, Rahimzadeh M. Sample size calculation in medical 
studies. Gastroenterol Hepatol Bed Bench. 2013 Winter;6(1):14-7. PMID: 24834239; 
PMCID: PMC4017493. 
 
7. Alffenaar JWC, Kosterink JGW, Altena R van, van der Werf TS, Uges DRA, Proost JH. 
Limited Sampling Strategies for Therapeutic Drug Monitoring of Linezolid in Patients With 
Multidrug-Resistant Tuberculosis. Ther Drug Monit. 2010;32(1):97-101. 
doi:10.1097/FTD.0b013e3181cc6d6f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
14 
 
 
 
 
 
 
Figure 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Linezolid TDM 
0.6 – 2 mg/l 
Continue regular 
sampling 
< 0.6 mg/l 
Increase the dosage 
by 300 mg (max 
1200 mg) 
New sample after 1 
week 
> 2 mg/l 
Reduce the  
dosage by 300 mg 
(min 300 mg every 
second day) 
New sample after 1 
week