Sitafloxacin-containing Regimens for Shortening Tuberculosis Treatment

Study Overview
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Brief Summary
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This study is a clinical trial conducted to determine whether the sitafloxacin-containing three-month regimens are as effective as the standard six-month regimen and the four-month rifapentine and moxifloxacin regimen (substitution of rifapentine for rifampin and moxifloxacin for ethambutol) for treatment of pulmonary tuberculosis. The standard six-month regimen is two months of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by four months of isoniazid and rifampin. The four-month regimen consists of two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid rifapentine and moxifloxacin. The new three-month tuberculosis treatment regimens are six weeks of isoniazid, rifapentine, Sitafloxacin, and pyrazinamide, followed by seven weeks of isoniazid, rifapentine, and Sitafloxacin, or 13 weeks of isoniazid, rifapentine, Sitafloxacin, and pyrazinamide. The primary research question is to evaluate the efficacy and safety of the 3 month Sitafloxacin-containing regimen, and to determine if it can shorten the treatment of drug-susceptible pulmonary tuberculosis while achieving non-inferiority in treatment success with the current 6 month and 4 month treatment regimens. Safety, side effects of Sitafloxacin for participants in the clinical trial are also assessed. Rates of cure, treatment success, recurrence, and cure (cure without recurrence) are determined for subgroup analysis in the standard six-month regimen group, the four-month regimen group, and two three-month regimen groups.

Detailed Description
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TB disease-free survival at 13 weeks after study treatment assignment among participants in the three-month regimen group 1 and 2, the four-month regimen group, and the standard six-month regimen. The patients are AFB sputum smear negative or culture negative for M. tuberculosis, two assays are performed (each test is separated by at least seven days), eliminating the M. tuberculosis load from a pulmonary infection. Persons with positive culture results for M. tuberculosis or smear-positive sputum(spoligotyping isolates genetically identified as M. tuberculosis). Data collected pre-study included written informed consent; patients assessed for eligibility; height and weight; clinical symptoms of TB; adjunctive therapy; adverse drug reaction; blood and urine routine; liver and kidney function; acid-fast staining; single M. tuberculosis strain isolated from one patient with TB; GeneXpert MTB/RIF; chest CT scans Clinical symptoms of TB: cough, expectoration, hemoptysis, chest pain, fever, shortness of breath, weak. All patients should review for Xpert MTB/RIF assay in the second week. During treatment, clinical symptoms of TB and body weights takes weekly; blood and urine routine in weeks 1,2,4,8,13; Sputum smears and culture were routinely in weeks 1,2,4,8,13, and months 6 and 12. TB Disease-free Survival at six or twelve months after study treatment assignment as the secondary outcome measures. TB patients were identified through bacteriological confirmation (smear-positive and/or culture-positive). Pulmonary TB patients showed manifestation of tuberculosis by chest CT scans or X-ray. Adverse events of the treatment: neurological diseases, blood system diseases; diseases of the circulatory system; respiratory diseases; digestive diseases; extra-pulmonary TB; diabetes; arthralgia; mental disorders; hemoptysis and pneumothorax; pulmonary embolism; skin rash. Management of a participant with a positive sputum culture for M. tuberculosis at or after week 13: A second sputum sample was collected on the following day for a second culture. If M. tuberculosis is isolated in culture, drug susceptibility testing should be performed on one isolate. Patients will re-evaluate symptoms and chest CT scans; sputum was performed in triplicates and repeated for validation. These patients could restart the standard six-month regimen at any time. Patients follow up one week after the completion of treatment and 6,12,18 months after treatment is over. Patients undergo regular follow-up with sputum smear tests or imaging studies. Patients with positive TB symptom screen or suspected TB patients based on imaging tests are recommended with research staff.

Official Title
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A Randomized Controlled Non-Inferiority Study for Shortening Tuberculosis Treatment With Sitafloxacin-Containing Regimens

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: Sitafloxacin
* Drug: SMZ/TMP
* Drug: Rifampin
* Drug: Pyrazinamide
* Drug: Rifapentine
* Drug: Isoniazid
* Drug: Ethambutol
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years to 70. At least one sputum specimen is positive for acid-fast bacilli or positive results of sputum culture on smear microscopy(species identification as M. tuberculosis) or at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing. Phenotypic drug susceptibility testing indicates the patient's isolate is susceptible to rifampin, isoniazid, pyrazinamide, ethambutol, rifapentine, moxifloxacin, and Sitafloxacin. Patients have written informed consent. Exclusion Criteria: Extra-pulmonary or Disseminated TB. HIV-positive individuals, steroid-dependent and those on steroid treatment. Autoimmune diseases, severe hepatic or renal dysfunction, psychosis, hematological malignancies, cancer, diabetes individuals. Known allergy to one or more of the study drugs. Women who are currently pregnant or breast-feeding. Patients who received any investigational drug in the past three months. The patients refused treatment with medications Mycobacterium tuberculosis/nontuberculous mycobacterium co-infection. In the investigator's judgment, other medical conditions that are not in the individual's best interest to participate.

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: The three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin-containing regimen<br>Thirteen weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and Sitafloxacin. | Drug: Sitafloxacin<br>* In our Intervention group, sitafloxacin replace the ethambutol, 200mg/d<br>Drug: Pyrazinamide<br>* Pyrazinamide is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 2000mg (20-30mg/kg/d)<br>Drug: Rifapentine<br>* In our Intervention group, rifapentine replace rifampin, 600mg/d<br>Drug: Isoniazid<br>* Isoniazid is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 300mg (4-6mg/kg/d)<br>|
| Experimental: The three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin&SMZ/TMP-containing regimen<br>Six weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and Sitafloxacin, followed by seven weeks of daily treatment with rifapentine, isoniazid, ,SMZ/TMP and Sitafloxacin. | Drug: Sitafloxacin<br>* In our Intervention group, sitafloxacin replace the ethambutol, 200mg/d<br>Drug: SMZ/TMP<br>* In our The three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin&SMZ/TMP-containing regimen, Six weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and Sitafloxacin, followed by seven weeks of daily treatment with rifapentine, isoniazid, ,SMZ/TMP and Sitafloxacin, SMZ 80mg/kg/d, TMP16mg/kg/d<br>Drug: Pyrazinamide<br>* Pyrazinamide is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 2000mg (20-30mg/kg/d)<br>Drug: Rifapentine<br>* In our Intervention group, rifapentine replace rifampin, 600mg/d<br>Drug: Isoniazid<br>* Isoniazid is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 300mg (4-6mg/kg/d)<br>|
| Active Comparator: The six-month standard Rifampin&Isoniazid&Pyrazinamide&Ethambutol-containing regimen<br>Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by Eighteen weeks of daily treatment with rifampin and isoniazid. | Drug: Rifampin<br>* Rifampin is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, Rifampin 600mg (8-12mg/kg/d)<br>Drug: Pyrazinamide<br>* Pyrazinamide is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 2000mg (20-30mg/kg/d)<br>Drug: Isoniazid<br>* Isoniazid is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 300mg (4-6mg/kg/d)<br>Drug: Ethambutol<br>* Ethambutol is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 1200mg (15-25mg/kg/d)<br>|
| Active Comparator: The four-month Rifapentine&Isoniazid&Pyrazinamide&Moxifloxacin -containing regimen<br>Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin. | Drug: Rifapentine<br>* In our Intervention group, rifapentine replace rifampin, 600mg/d<br>Drug: Isoniazid<br>* Isoniazid is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 300mg (4-6mg/kg/d)<br>Drug: Ethambutol<br>* Ethambutol is a first-line antimicrobial agent against drug-susceptible tuberculosis in WHO guideline, 1200mg (15-25mg/kg/d)<br>Drug: Moxifloxacin<br>* Moxifloxacin is a fourth-generation fluoroquinolone with potent activity against M. tuberculosis in vitro and in vivo, 400mg (7.5-10mg/kg/d)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TB Disease-free Survival after the completion of the treatment cycle. | To evaluate the efficacy of a Sitafloxacin-containing regimen to determine whether the substitution of Sitafloxacin for moxifloxacin could shorten the treatment duration from 6 months to 3 months (13 weeks) for drug-susceptible pulmonary tuberculosis. Pathogen detection (including sputum smear and sputum culture) should complete in Week 13 in the three-month regimen group, Week 17 in the four-month regimen group, and Week 26 in the standard six-month regimen group. | Week 13 in the three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin-containing regimen and three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin&SMZ/TMP-containing regimen | 
| TB Disease-free Survival after the completion of the treatment cycle. | To evaluate the efficacy of a Sitafloxacin-containing regimen to determine whether the substitution of Sitafloxacin for moxifloxacin could shorten the treatment duration from 6 months to 3 months (13 weeks) for drug-susceptible pulmonary tuberculosis. Pathogen detection (including sputum smear and sputum culture) should complete in Week 13 in the three-month regimen group, Week 17 in the four-month regimen group, and Week 26 in the standard six-month regimen group. | Week 17 in the four-month Rifapentine&Isoniazid&Pyrazinamide&Moxifloxacin -containing regimen | 
| TB Disease-free Survival after the completion of the treatment cycle. | To evaluate the efficacy of a Sitafloxacin-containing regimen to determine whether the substitution of Sitafloxacin for moxifloxacin could shorten the treatment duration from 6 months to 3 months (13 weeks) for drug-susceptible pulmonary tuberculosis. Pathogen detection (including sputum smear and sputum culture) should complete in Week 13 in the three-month regimen group, Week 17 in the four-month regimen group, and Week 26 in the standard six-month regimen group. | Week 26 in the six-month standard Rifampin&Isoniazid&Pyrazinamide&Ethambutol-containing regimen | 
| Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen | To determine Grade 3 or higher adverse events in study participants during drug treatment in the standard six-month regimen, the four-month regimen, and the three-month regimen Sitafloxacin-containing and three-month Sitafloxacin&SMZ/TMP-containing regimen | Week 13 in the three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin-containing regimen and three-month Rifapentine&Isoniazid&Pyrazinamide&Sitafloxacin&SMZ/TMP-containing regimen | 
| Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen | To determine Grade 3 or higher adverse events in study participants during drug treatment in the standard six-month regimen, the four-month regimen, and the three-month regimen Sitafloxacin-containing and three-month Sitafloxacin&SMZ/TMP-containing regimen | Week 17 in the four-month Rifapentine&Isoniazid&Pyrazinamide&Moxifloxacin -containing regimen | 
| Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen | To determine Grade 3 or higher adverse events in study participants during drug treatment in the standard six-month regimen, the four-month regimen, and the three-month regimen Sitafloxacin-containing and three-month Sitafloxacin&SMZ/TMP-containing regimen | Week 26 in the six-month standard Rifampin&Isoniazid&Pyrazinamide&Ethambutol-containing regimen | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rates of negative sputum conversion | The rates of negative sputum conversion will be determined at the end of 2 months using the sputum smear and culture test. | two months | 
| TB disease-free survival at six and twelve months after study treatment assignment. | The rates of TB disease-free survival at six and twelve months | Twelve months |