The Effect of 18-month Regimen Containing 6 Anti-tuberculosis Drugs for Patients With MDR-TB

Study Overview
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Brief Summary
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WHO has recommended that multidrug-resistant tuberculosis (MDR-TB, defined as resistance to at least isoniazid (H) and rifampicin (R) be addressed as a public health crisis and enhance capacity to deliver effective treatment and care. According to the 2018 WHO TB Report, the overall treatment success rate of MDR-TB is 55% while much lower in China at just only 41% with the 24-month regimen. In order to further verify the safety and efficiency of optimizing shorter 18-month regimen containing 6 anti-TB drugs with MDR-TB patients,500 more patients will be enrolled and observed.

Detailed Description
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Design: the study is a multi-center,open, single arm trial. Population:patients with sputum culture positive and confirmed as MDR-TB via drug resistance of isoniazid(H),rifampicin(R),ethambutol(E)and pyrazinamide or patients with GeneXpert confirmed RR-TB. Investigational regimen:3Am-Mfx-PZA-X-Y-Z/3Am3-Mfx-PZA-X-Y-Z/12 Mfx-PZA-X-Y-Z.X、Y、Z are the drugs susceptible or possibly susceptible to mycobacterial bacilli(The candidated drugs to be selected are:Cs-Cycloserine,Pto-Protionamide,Clr-Clarithromycin,PAS-sodium para-aminosalicylate,E-ethambutol,Bdq-Bedaquiline,Cfz-Clofazimine,Lzd-linezolid).The abbreviation of the name of the 3 drugs in the regimen is explained as follows: PZA-pyrazinamide，Am-Amikacin，Mfx-moxifloxacin）and the total duration of the regimen is 18 months. Primary and secondary outcome measures: The primary outcome measures include 1.the treatment success rate.2. Death rate. The secondary outcome measures include 1.sputum conversion rate at the end of month 2, month 3,intensive phase of 6 months and treatment completion of all enrolled patients.2.Frequency of adverse drug reaction occurring during treatment.3.Radiological manifestation change of TB lesion or cavity during treatment. Sample size: 500 eligible patients will be enrolled.

Official Title
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The Effect of New MDR-TB Regimen With 18 Month Duration Containing 6 Anti-tuberculosis Drugs

Conditions
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Multi-drug Resistant Tuberculosis

Intervention / Treatment
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* Drug: 18-month regimen containing 6 anti-TB drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is willing and able to give informed consent to participate in the trial treatment and follow-up. Is aged between 18 years and 70 years. Has a positive sputum culture result or a positive GeneXpert result. Has evidence of RR-TB or MDR-TB either by GeneXpert or culture-based drug susceptibility testing (DST). Non pre-XDR-TB or XDR-TB. Is willing to use effective contraception of women at childbearing age. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB. Exclusion Criteria: pre-XDR-TB or XDR-TB. Has a known allergy to any drug of the regimen. Is currently taking or took part in another trial less than three months before the study initiation . Is HIV positive. Has abnormal ECG with QT prolongation over 430ms of men while 450 of women. Is critically ill, and in the judgment of the investigator, unlikely to take part in the study.Or has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe. Is known to be pregnant or breast-feeding. Has severe cardiovascular diseases, such as heart failure, hypertension (poor blood pressure control), arrhythmia or post-infarction status. Has severe concomitant severe disease such as respiratory failure or cardiac insufficiency or liver and kidney injury with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 2.5 times the upper limit of normal or with serum creatinine(Cr)more than 1.3 times the upper limit of normal. Has Karnofsky score less than 50%

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: investigational arm<br>the arm was given investigational regimen:3Am-Mfx-PZA-X-Y-Z/3Am3-Mfx-PZA-X-Y-Z/12 Mfx-PZA-X-Y-Z.X、Y、Z are the drugs susceptible or possibly susceptible to mycobacterial bacilli(The candidated drugs to be selected are:Cs-Cycloserine,Pto-Protionamide,Clr-Clarithromycin,PAS-sodium para-aminosalicylate,E-ethambutol,Bdq-Bedaquiline,Cfz-Clofazimine,Lzd-linezolid).The abbreviation of the name of each drug in the regimen is explained as follows: PZA-pyrazinamide，Am-Amikacin，Mfx-moxifloxacin）and the total duration of the regimen is 18 months. | Drug: 18-month regimen containing 6 anti-TB drugs<br>* Investigational regimen:3Am-Mfx-PZA-X-Y-Z/3Am3-Mfx-PZA-X-Y-Z/12 Mfx-PZA-X-Y-Z.X、Y、Z are the drugs susceptible or possibly susceptible to mycobacterial bacilli(The candidated drugs to be selected are:Cs-Cycloserine,Pto-Protionamide,Clr-Clarithromycin,PAS-sodium para-aminosalicylate,E-ethambutol,Bdq-Bedaquiline,Cfz-Clofazimine,Lzd-linezolid).The abbreviation of the name of each drug in the regimen is explained as follows: PZA-pyrazinamide，Am-Amikacin，Mfx-moxifloxacin）and the total duration of the regimen is 18 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the treatment success rate |  | at the end of treatment completion of all enrolled patients,an average of 18 months after the last patient enrolled | 
| death rate |  | at the end of treatment completion of all enrolled patients, an average of 18 months after the last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| sputum conversion rate at the end of month 2, month 3,intensive phase and treatment completion. |  | at the end of month 2, month 3,intensive phase of 6 months since treatment initiation and treatment completion of all enrolled patients, an average of 18 months after the last enrolled patient. | 
| Frequency of adverse drug reaction occurring during treatment. |  | at the end of treatment completion of all enrolled patients, an average of 18 months after the last enrolled patient. | 
| Radiological manifestation change of TB lesion or cavity at the end of month 2, month 3,intensive phase and treatment completion. | proportion of lung field the lesion accumulated taken up at different time points with the comparison to that at baseline. The number and size of cavities at different time points with comparison to that at baseline. | at the end of month 2, month 3,intensive phase of 6 months since treatment initiation and treatment completion of all enrolled patients, an average of 18 months after the last enrolled patient. |