A Study of an Oral Short-course Regimen Including Bedaquiline for the Treatment of Participants With Multidrug-resistant Tuberculosis in China

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy and safety of an oral bedaquiline-containing multidrug-resistant tuberculosis (MDR-TB) short-course regimen (SCR) compared to an oral SCR not including bedaquiline at the end of treatment in participants with pulmonary MDR-TB in China.

Official Title
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A Pragmatic Randomized Controlled Trial to Evaluate the Efficacy and Safety of an Oral Short-course Regimen Including Bedaquiline for the Treatment of Patients With Multidrug-resistant Tuberculosis in China

Conditions
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Tuberculosis, Multidrug-Resistant

Intervention / Treatment
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* Drug: Bedaquiline
* Drug: Levofloxacin
* Drug: Linezolid
* Drug: Cycloserine
* Drug: Clofazimine
* Drug: Pyrazinamide
* Drug: Protionamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a positive sputum Mycobacterium tuberculosis culture from a test performed at screening Has microbiological confirmation of rifampicin resistance by GeneXpert and to isoniazid (INH) via molecular drug-susceptibility testing (DST) showing katG mutation Has a chest imaging result compatible with a diagnosis of pulmonary Tuberculosis (TB) Agrees to use effective contraception during the 40-week study treatment phase. A female participant must be: of nonchildbearing potential; of childbearing potential and practicing effective methods of contraception during the 40-week study treatment phase Is willing to undergo human immunodeficiency virus (HIV) testing Exclusion Criteria: Has received prior treatment with bedaquiline Has prior exposure to at least 1 second-line drug in the regimen for at least 4 weeks Has any grade 3 or 4 laboratory abnormality as confirmed by a clinical expert Has a known allergy or intolerance to bedaquiline or other drugs in the regimen Is infected with a strain of nontuberculous mycobacteria Is HIV-positive

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bedaquiline-containing Short-course Regimen (SCR)<br>Participants will receive an oral dose of bedaquiline 400 milligrams (mg) once daily for first 2 weeks followed by bedaquiline 200 mg thrice a week for 22 weeks (with at least 48 hours between doses) in combination with oral doses of levofloxacin (LFX) up to 1000 mg (weight-based), cycloserine (CS) up to 750 mg (weight-based), clofazimine (CFZ) 100 mg daily for 40 weeks and linezolid [LZD] 600 mg daily for at least 24 weeks . If a participant is still sputum culture-positive for Mycobacterium tuberculosis by Week 16, bedaquiline treatment will be extended from Week 24 to Week 40. | Drug: Bedaquiline<br>* Bedaquiline uncoated tablets will be administered orally.<br>* Other names: SIRTURO;Drug: Levofloxacin<br>* Levofloxacin filmcoated will be administered orally<br>Drug: Linezolid<br>* Linezolid tablets will be administered orally<br>Drug: Cycloserine<br>* Cycloserine capsules will be administered orally.<br>Drug: Clofazimine<br>* Clofazimine capsules will be administered orally.<br>|
| Experimental: Non-bedaquiline-containing Short-course Regimen (SCR)<br>Participants will receive oral doses of LFX up to 1000 mg (weight-based), CS up to 750 mg (weight-based), CFZ 100 mg, Pyrazinamide (PZA) up to 2000 mg (weight-based), Protionamide (PTO) up to 800 mg (weight-based) daily for first 16 weeks and LZD 600 mg daily for at least 24 weeks. | Drug: Levofloxacin<br>* Levofloxacin filmcoated will be administered orally<br>Drug: Linezolid<br>* Linezolid tablets will be administered orally<br>Drug: Cycloserine<br>* Cycloserine capsules will be administered orally.<br>Drug: Clofazimine<br>* Clofazimine capsules will be administered orally.<br>Drug: Pyrazinamide<br>* Pyrazinamide tablets will be administered orally.<br>Drug: Protionamide<br>* Protionamide enteric-coated tablets will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with a Favorable Treatment Outcome at the End of Treatment | Percentage of participants with a favorable treatment outcome at the end of treatment will be reported. A participant's outcome will be classified as favorable if their last 3 culture results by the end of treatment are negative unless they have previously been classified as unfavorable. These 3 cultures must be taken on separate visits; the latest of which being no more than 8 weeks prior to the end of treatment. | At the end of treatment (Week 40) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with a Favorable Treatment Outcome at 48 Weeks Post the End of Treatment | Percentage of participants with a favorable treatment outcome at 48 weeks post the end of treatment will be reported. A participant's outcome will be classified as favorable if their last 3 culture results by the end of treatment are negative unless they have previously been classified as unfavorable. These 3 cultures must be taken on separate visits; the latest of which being no more than 8 weeks prior to the end of treatment. | At 48 weeks post the end of treatment (Week 88) | 
| Percentage of Participants Achieving Treatment Success at the end of Treatment | Percentage of participants achieving treatment success at the end of treatment will be reported. Treatment success is achieved if participants completed their prescribed tuberculosis (TB) treatment; or if their last 3 culture results are negative by the end of treatment, these 3 cultures must be taken on separate visits and should be after the initial 6-month treatment period. | At the end of treatment (Week 40) | 
| Percentage of Participants with a Modified Favorable Treatment Outcome at the end of Treatment and at 48 Weeks Post end of Treatment | Percentage of participants with a modified favorable treatment outcome at the end of treatment and at 48 weeks post end of treatment will be reported. A participant's treatment outcome will be classified as modified favorable if their last 2 culture results by the end of treatment are negative unless they have previously been classified as unfavorable. These 2 cultures must be taken on separate visits; the latest of which being no more than 8 weeks prior to the end of treatment. | At the end of treatment (Week 40) and at 48 weeks post end of treatment (Week 88) | 
| Percentage of Participants Experiencing All-cause Mortality | Percentage of participants experiencing all-cause mortality will be reported. | Up to Week 88 | 
| Percentage of Participants Experiencing Grade 3 or Greater Treatment-emergent Adverse Events (TEAEs) During Study Treatment and Follow-up | Percentage of participants experiencing grade 3 or greater TEAEs during study treatment and follow-up will be reported. An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as any event that begins or worsens in severity after initiation of study drug through to the end of study. An assessment of severity grade will be made using the following 5 general categorical descriptors based on division of acquired immunodeficiency syndrome (AIDS) grading for AE severity assessment. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening, and Grade 5= Death. | During study treatment and follow-up (From Week 1 up to Week 88) | 
| Percentage of Participants Experiencing TEAEs | Percentage of participants experiencing TEAEs will be reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as any event that begins or worsens in severity after initiation of study drug through to the end of study. | From Week 1 up to Week 88 | 
| Percentage of Participants with TB Relapses and Re-infections During the Treatment-free Follow-up Phase | Percentage of participants with TB relapses and re-infections during the treatment-free follow-up phase will be reported. | During the treatment-free follow-up phase (Up to 48 weeks) | 
| Percentage of Participants Whose Isolates Develop Resistance to Bedaquiline and Other Drugs Used in the Regimen | Percentage of participants whose isolates develop resistance to bedaquiline and other drugs used in the regimen will be reported. | Up to Week 88 |