Shortened Regimens for Drug-susceptible Pulmonary Tuberculosis

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and efficacy of two shortened regimens for newly diagnosed smear positive drug susceptible pulmonary tuberculosis in comparison to World Health Organization recommended standard 6-month regimen.

Detailed Description
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Design: The study is a multi-center, randomized,controlled non-inferiority trial. Population: patients with newly diagnosed drug-susceptible pulmonary TB who fulfill the inclusion and exclusion criteria. Investigational regimens: Experimental group 1 regimen consists of levofloxacin, isoniazid , rifampicin,ethambutol and pyrazinamide for 4.5 months. Experimental group 2 regimen consists of isoniazid, rifampicin, ethambutol and pyrazinamide for 4.5 months. The control group is WHO recommended regimen conmposed of isoniazid , rifampicin, ethambutol and pyrazinamide for 2 months, followed by isoniazid , rifampicin for 4 months. Dosage: isoniazid 300mg(given once daily), rifampin 450mg(less than 50kg,given once daily)or 600mg(more than 50kg,given once daily), pyrazinamide 1500mg(less than 50kg,given once daily)or 30mg/kg(more than 50kg,once daily), ethambutol 750mg (less than 50kg,once daily) or 1000mg (more than 50kg,once daily), levofloxacin 600mg(less than 50kg,given once daily) or 800mg(more than 50kg,once daily).. Trial objectives: to evaluate that shortened regimens is not inferior to standard treatment in terms of efficacy and safety for new smear positive pulmonary TB patients. Primary and Secondary outcome measures: The primary efficacy outcome measures include (a)the percentage of participants with TB recurrence/relapse by 24 months after the end of treatment;(b) percentage of participants with treatment failure at either 4.5 months or 6 months after randomization. (a) Time to sputum smear or culture conversion within intensive phase.(b) Sputum smear conversion proportion at the treatment completion. (c) Number of adverse drug reaction occurring during treatment or follow-up period. (d) Radiological manifestation change of TB lesion or cavity.(e) Patients adherence rate. Sample Size: Approximately 3900 participants will be enrolled and randomized with 1:1:1 ratio into either Experimental group1, Experimental group2 or control group. Blinding: The study is an open-label study. Assessment and follow-up: All patients will be followed by to 2 years after completion of treatment.

Official Title
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Shortened Regimens for First Diagnosed Smear Positive Drug Susceptible Pulmonary Tuberculosis: a Randomised Controlled Non-inferiority Trial

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: Isoniazid
* Drug: Rifampicin
* Drug: Pyrazinamide
* Drug: Ethambutol
* Drug: Levofloxacin


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 (signed or witnessed consent if the patient is illiterate). Is aged 18-65 years. Has twice positive acid-fast bacilli(AFB) sputum smear or positive sputum culture result, along with chest x-ray imaging consistent with active pulmonary tuberculosis. Newly diagnosed cases receiving anti-TB treatment for less than one month Urine Human Chorionic Gonadotropin(U-HCG) negative and must agree to use effective contraception during the trial period. Has Alanine aminotransferase（ALT）and Total bilirubin（TBil） less than 2 times the upper limit of normal ; has Creatinine clearance rate （CrCI） more than 30ml/min; has Hemoglobin more than 7.0g/dL; has Platelet（PLT）more than 50 x10^9/L before study entry. Exclusion Criteria: Concomitant severe cardiovascular, liver, kidney, nervous system, hematopoietic system and other diseases, or concomitant neoplastic diseases. Or extensive lesion with respiratory insufficiency. Uncontrolled diabetes mellitus. Concomitant mental disorders. Is HIV positive. Is critically ill, and in the judgment of the investigator, not fit for the study or unlikely to complete the full course of study. Is known to be pregnant or breast-feeding. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule. Is taking any medications contraindicated with the medicines in any trial regimen of the study. Has a known allergy to any drug of treatment regimens. Is currently taking part in another trial. Has a QTc interval more than 480ms.

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: experimental group1<br>The experimental group1 all oral regimen is consisted of isoniazid,rifampin, pyrazinamide, ethambutol and levofloxacin for 4.5 months. Dosage: isoniazid 300mg(given once daily), rifampin 450mg(less than 50kg,given once daily)or 600mg(more than 50kg,given once daily), pyrazinamide 1500mg((less than 50kg,given once daily)or 30mg/kg(more than 50kg,once daily), ethambutol 750mg (less than 50kg,once daily) or 1000mg (more than 50kg,once daily), levofloxacin 600mg(less than 50kg,given once daily) or 800mg(more than 50kg,once daily). | Drug: Isoniazid<br>* Isoniazid is a widely used anti-tuberculosis medication. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique components of mycobacterial cell wall.<br>Drug: Rifampicin<br>* Rifampicin is a widely used anti-tuberculosis medication.<br>Drug: Pyrazinamide<br>* Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis.<br>Drug: Ethambutol<br>* Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.<br>Drug: Levofloxacin<br>* Levofloxacin is a commonly used antimicrobial for TB and other infections, which acts on the DNA-DNA-gyrase complex and topoisomerase IV. It is the S (-) enantiomer of the racemic active substance ofloxacin.<br>* Other names: Cravit;|
| Experimental: experimental group2<br>The experimental group2 all oral regimen consisted of isoniazid,rifampin, pyrazinamide, and ethambutol for 4.5 months. The dosage of isoniazid,rifampin, pyrazinamide, and ethambutol is as same as that of control regimen. | Drug: Isoniazid<br>* Isoniazid is a widely used anti-tuberculosis medication. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique components of mycobacterial cell wall.<br>Drug: Rifampicin<br>* Rifampicin is a widely used anti-tuberculosis medication.<br>Drug: Pyrazinamide<br>* Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis.<br>Drug: Ethambutol<br>* Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.<br>|
| Active Comparator: Control regimen group<br>The control all oral regimen consisted of isoniazid,rifampin, pyrazinamide, and ethambutol during the intensive phase of treatment (2 months), followed by isoniazid and rifampin during the continuation phase (4 months). Dosage: isoniazid 300mg(given once daily), rifampin 450mg(less than 50kg,given once daily)or 600mg(more than 50kg,given once daily), pyrazinamide 1500mg((less than 50kg,given once daily)or 30mg/kg(more than 50kg,once daily), ethambutol 750mg (less than 50kg,once daily) or 1000mg (more than 50kg,once daily). . | Drug: Isoniazid<br>* Isoniazid is a widely used anti-tuberculosis medication. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique components of mycobacterial cell wall.<br>Drug: Rifampicin<br>* Rifampicin is a widely used anti-tuberculosis medication.<br>Drug: Pyrazinamide<br>* Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis.<br>Drug: Ethambutol<br>* Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants with TB recurrence/relapse by 24 months after the end of treatment. |  | 24 months after treatment completion for all 3 groups | 
| Percentage of participants with treatment failure at either 4.5 months or 6 months after randomization. |  | 4.5 months after randomization for experimental group1 and 2; 6 months after randomization for control group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment adverse reactions occuring |  | An average of 6 months for control group and 4.5 months for experimental group1 and 2 during treatment and 24 months after treatment completion. | 
| Time to sputum smear or culture conversion within intensive phase . |  | An avergae of 2-3 months after randomization. | 
| Sputum smear or culture conversion proportion at the treatment completion. |  | An average of 6 months for control group while 4.5 months for experimental group 1 and 2. | 
| Radiological manifestation change of TB lesion or cavity. |  | An average of 6 months during treatment and 24 months after treatment completion. | 
| Patiens adherence rate |  | An average of 6 months during treatment and 24 months after treatment completion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary tuberculosis, shortened regimen, clinical trial