Innovating Shorter, All- Oral, Precised, Individualized Treatment Regimen for Rifampicin Resistant Tuberculosis：Contezolid, Delamanid and Bedaquiline Cohort

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare the efficacy and safety of a Contezolid and Delamanid-Containing short regimen to standard longer regimen in Rifampicin-resistant pulmonary tuberculosis (RR-TB). The main questions it aims to answer are: Is the efficacy of short regimen non-inferior to standard regimen? Is the short regimen safe enough to replace the standard regimen? Participants will: Be given with either short or standard regimen for RR-TB treatment Be asked to complete the scheduled visit as planned.

Official Title
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A Multicenter, Randomized, Open-Label Study To Evaluate The Efficacy And Safety Of A Contezolid, Delamanid and Bedaquiline-Containing Short Regimen For The Treatment Of Rifampicin-Resistant Pulmonary Tuberculosis

Conditions
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Pulmonary Tuberculosis, Rifampicin-resistant Tuberculosis

Intervention / Treatment
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* Drug: Bedaquiline
* Drug: Delamanid
* Drug: Contezolid
* Drug: Levofloxacin
* Drug: Moxifloxacin
* Drug: Clofazimine
* Drug: Linezolid
* Drug: Cycloserine
* Drug: Prothionamide
* Drug: Pyrazinamide
* Drug: Para-Aminosalicylic Acid
* Drug: Ethambutol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age ≥18y and <70y when signing informed consent; Initial or re-treatment for pulmonary tuberculosis with: 1) MTB positive in sputum or bronchoalveolar lavage fluid culture at or within 3 months before screening, or MTB positive in molecular test at or within 3 months before screening, and; 2) recorded Rifampicin-resistance at or before screening; 3. Imaging (Chest X-ray or CT scan) proved pulmonary tuberculosis within 1 year before screening; 4. Never used BDQ, DLM or CZD, or the accumulative duration of any of the treatment is not more than 2 weeks 5. For women in childbearing age, negative in pregnancy test and effective contraceptive measures throughout study is required; 6. For men, effective contraceptive measures is required; 7. Willing to participate the study and sign informed consent. Exclusion criteria: The participant will be excluded by investigator based on the medical history or concomitant diseases such as serious metabolic disease, cardiovascular disease, hepatobiliary disease, renal disease, autoimmune disease, neuropsychiatric disorders, hematological disease, malignant neoplastic disease and so on; or the study will have negative impact on the well-being of the participant, or the participant is considered unable to complete the evaluation by investigator; History of alcohol or drug abuse that the study is considered have negative impact on the well-being of the participant by investigator; HIV positive; Chronic hepatitis with HBsAg, HBeAg and anti-HBC antibody positive, or HBV-DNA>1000 CPs/mL with rising ALT/AST; Allergic to or known hypersensitive to any of study drugs; Extensive (or advanced) pulmonary TB disease: presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography; Hematogenous disseminated pulmonary tuberculosis and serious extrapulmonary tuberculosis (such as tuberculosis in digestive system, urogenital system, osteoarticular tuberculosis, tuberculous meningitis); With any of following risk factors for cardiovascular disease: 1) history of arrhythmia and on consequential treatment; 2) QTcF>500ms on ECG; 3) history of ventricular arrhythmia; 4) torsade de pointe with heart failure, hypokalemia or familial long Q-T syndrome; 5) other possible risk factor for arrythmia; Previous or current optic nerve disorder that may progress or deteriorate during the study by investigator's consideration; Was enrolled within 2 months before screening, or currently in other studies; except for those who participating observational study or in the post-treatment period; Being considered unlikely to survive for more than 6 months by investigator; BMI < 17kg/m2 May need surgical procedures based on the evaluation of pulmonary lesions; May continuous use prohibited concomitant medications that is considered not suitable for the study by investigator; Positive in pregnancy test or known pregnancy, breastfeeding, or plan to become pregnant during or within 6 months after the study treatment; Abnormal laboratory test results: 1) Plasma potassium lower than lower limit of normal (LLN); 2) Hb < 8.0 g/dL； 3) platelet count <75,000/mm3； 4) WBC count<3000/mm3； 5）AST/ALT >3×ULN； 6）creatinine>2×ULN；7）total bilirubin>2×ULN, or >1.5×ULN，with abnormal AST or ALT; 8) Albumin < 30g/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Short-Term Regimen<br>Intervention will be determined based on Fluoroquinolones(FQs) resistance. For those sensitive to FQs: BDQ DLM CZD LFX(MFX) for 6 months For those resistant to FQs: BDQ DLM CZD CFZ for 6 months | Drug: Bedaquiline<br>* Oral, 400mg qd for 2 weeks, then 200 mg 3 times per week<br>* Other names: BDQ;Drug: Delamanid<br>* Oral, 100mg bid<br>* Other names: DLM;Drug: Contezolid<br>* Oral, 800mg bid<br>* Other names: CZD;Drug: Levofloxacin<br>* Oral, 400mg qd for weight <50kg, 600-750mg qd for weight ≥50kg<br>* Other names: LFX;Drug: Moxifloxacin<br>* Oral, 400mg qd<br>* Other names: MFX;Drug: Clofazimine<br>* Oral, 100mg qd<br>* Other names: CFZ;|
| Active Comparator: Standard Regimen<br>Intervention will be determined based on Fluoroquinolones(FQs) resistance. For those sensitive to FQs: BDQ LZD LFX(MFX) CS CFZ regimen for 6 months, then LFX(MFX) CS CFZ for 12 months For those resistant to FQs: LFX(MFX) will be replaced by Pto, PZA, PAS or EMB | Drug: Bedaquiline<br>* Oral, 400mg qd for 2 weeks, then 200 mg 3 times per week<br>* Other names: BDQ;Drug: Levofloxacin<br>* Oral, 400mg qd for weight <50kg, 600-750mg qd for weight ≥50kg<br>* Other names: LFX;Drug: Moxifloxacin<br>* Oral, 400mg qd<br>* Other names: MFX;Drug: Clofazimine<br>* Oral, 100mg qd<br>* Other names: CFZ;Drug: Linezolid<br>* Oral, 600mg qd<br>* Other names: LZD;Drug: Cycloserine<br>* Oral, 250mg bid<br>* Other names: CS;Drug: Prothionamide<br>* Oral, 600mg qd for weight <50kg, 600-800mg qd for weight ≥50kg<br>* Other names: Pto;Drug: Pyrazinamide<br>* Oral, 1500mg qd for weight <50kg, 1750mg qd for weight ≥50kg<br>* Other names: PZA;Drug: Para-Aminosalicylic Acid<br>* 8000mg qd for weight <50kg, 10000mg qd for weight ≥50kg<br>* Other names: PAS;Drug: Ethambutol<br>* 750mg qd for weight <50kg, 1000mg qd for weight ≥50kg<br>* Other names: EMB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Favourable outcome rate at 24 months after randomization | The proportion of participants with a favourable outcome. A participant's outcome will be classified as favourable if their last two sputum culture results are negative unless they have previously been classified as unfavourable. These two cultures must be taken on separate visits (with ≥28d interval); the latest of which not being earlier than month 23 from randomization. | from randomization to 24 months after | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unfavourable outcome rate at 24 months after randomization | Including Death; Treatment failure Lost-to-follow-up Treatment Discontinuation Ttreatment prolonging Still on treatment at the end of follow up Recurrence | from randomization to 24 months after | 
| Time to culture conversion | Time from treatment initiation to first negative result in sputum culture confirmed by two consecutive cultures with an interval of ≥28d | from randomization to 24 months after | 
| Grade 3 or higher adverse event rate | Proportion of participants experiencing at least one grade 3 or higher adverse event, or serious adverse event defined by the Division of AIDS severity criteria for adverse events | from randomization to 24 months after | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tuberculosis, Rifampicin-resistant, short regimen, contezolid, delamanid