BPaL Regimen in FQ Resistant MDR-TB

Study Overview
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Brief Summary
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The objective of this study is to analyze the efficacy of a new regimen using Bedaquiline, Pretomanid, and Linezolid for 26 weeks (6 months) for the treatment of FQ-resistant MDR-TB through the clinical trial. The recently completed Zenix trial observed that lower doses and/or shorter durations of linezolid than 1200mg for 6 months appear to have high efficacy and improved safety. Therefore, the primary objective of this study is to analyze the effectiveness and safety of the BPaL regimen including modified dosing of linezolid for the patients with fluoroquinolone-resistant MDR-TB.

Official Title
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The 6-month BPaL Regimen for the Treatment of Patients With Fluoroquinolone Resistant MDR-TB: Multicenter, Single-arm, Operational Research, Clinical Trial

Conditions
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Pre-XDR-TB

Intervention / Treatment
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* Drug: BPaL regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 19 years old at enrolment Bodyweight over 35Kg If culture positive in sputum or bronchoscopy specimen within 3 months of screening and confirmed as MDR-TB in the rapid or conventional DST. Confirmed as resistance to fluoroquinolones in rapid and/or genotypic DST If tuberculosis is confirmed by chest radiologic imaging Exclusion Criteria: Uncontrolled DM Extrapulmonary TB that would require treatment longer than would be usual for pulmonary TB Less than 30 Karnofsky score at enrolment BMI less than 17 Known severe allergy to any of the BPaL component drugs Medical history of Glucose-galactose malabsorption, galactose intolerance, and Lapp lactase deficiency HIV-positive When the QTcF interval exceeds 500 msec on the electrocardiogram at baseline Patients who are at risk of Torsade de Pointes due to underlying heart diseases such as heart failure or arrhythmia For women of childbearing potential if the pregnancy test is positive, women who are breastfeeding or planning to become pregnant within 6 months of discontinuation/termination of treatment during the study, or who do not want contraception (i.e., oral and subcutaneous hormonal contraceptives, condoms, diaphragms, intrauterine device, or use of appropriate contraceptive methods including abstinence) *Note: Double contraception (e.g., when a male uses a barrier contraceptive method such as a condom, a female partner uses a hormonal contraceptive or an additional contraceptive method such as an intrauterine device) is required while taking the study drug and up to 6 months after stopping/terminating the study drug. In particular, taking the study drug may affect the efficacy of hormonal contraceptives, and even if you are using only barrier contraception at the same time with your partner, you cannot be sure of preventing pregnancy, so it is necessary to maintain double contraception. Men who plan to become pregnant during the study period or within 6 months of discontinuation/termination of treatment, or who do not wish to use double contraception or abstinence during this period. Patients who have Grade 3 or 4 or higher peripheral neuritis, or Grade 1 or 2 with a high probability of progression to peripheral neuritis, Current use of monoamine oxidase Inhibitor or used 2 weeks before treatment Use of serotonergic antidepressant within 3 days of treatment Any contraindication that may affect QTc interval (amiodarone, chloroquine, chlorpromazine, clarithromycin, haloperidol, etc.) Any contraindication that may cause myelosuppression Taking drugs that affect the cytochrome P450 enzyme within 30 days (quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan, etc.) Previously treated with Bedaquiline or Linezolid for more than 4 weeks Abnormal value of a blood test at baseline: Hypokalemia, Hemoglobin < 8.0 g/dL, Platelet < 75,000/mm3, ANC < 1000/mm3 AST or ALT > 3 X ULN, Total bilirubin >2.0 X ULN, Albumin < 3.2 mg/dL Serum creatinine > 2 X ULN, Serum calcium < LLN, Serum magnesium < LLN

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm (investigational arm)<br>BPaL | Drug: BPaL regimen<br>* The regimen consists of only oral medication using bedaquiline, linezolid, and pretomanid for 26 weeks. Bedaquiline (400 mg/day for the 2 weeks, 200mg/TIW afterward). Pretomanid 200mg/day. Linezolid 600mg/day for the 9 weeks, 300mg/day afterward.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A microbiological failure or clinical failure or relapse | A microbiological failure or clinical failure or relapse during the treatment period and the 12-month follow-up period after end of treatment | until 12 months after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sputum culture conversion during the treatment period | Analyze the time to liquid and solid culture conversion and estimate the median value using the Kaplan-Meier Method | 26 weeks | 
| Proportion of culture-negative patients at specific times (weeks 4, 8, 12, 16, and 26) | Frequency analysis of liquid and solid culture conversion at a specific time point | 26 weeks | 
| Prescribed dose of Linezolid | Analyze the actual dose of linezolid prescribed | 26 weeks | 
| All-cause mortality | Analyze the frequency and fraction of deaths and estimate the median using the Kaplan-Meier Method | 26 weeks |