Shortened Regimens for Drug-susceptible Pulmonary Tuberculosis

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

Hubei Provincial Center for Disease Control and Prevention, Centre for Tuberculosis Control of Guangdong Province, Hunan Institute For Tuberculosis Control, Anhui Chest Hospital, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Wuhan Institute for Tuberculosis Control, Shanghai Pulmonary Hospital, Shanghai, China, Shenyang Chest Hospital, Changchun Infectious Disease Hospital, First Affiliated Hospital of Xinjiang Medical University, Public Health Clinical Center of Chengdu, Taiyuan Fourth People's Hospital, The Sixth People's Hospital of Nantong, The Tuberculosis Prevention and Treatment Hospital of Shanxi Province, Beijing Research Institute for Tuberculosis Control, Infectious Disease Prevention Hospital in Heilongjiang Province, The Third People's Hospital of Zhenjiang, Tianjin centers for Disease Control and Prevention, Harbin Chest Hospital, Chest of Hospital of Xinjiang Uygur Autonomous Region of the PRC, Heilongjiang Province center for tuberculosis Control and Prevention, Tianjin Haihe Hospital, The Infectious Disease Hospital of Wangkai Zaozhuang, The Third People's Hospital of Kunming City, Kaifeng Central Hospital, The Infectious Hospital of Hebi, Pulmonary Hospital of Lanzhou, The Fourth People's Hospital of Ningxia Autonomous Region, The 4th People's Hospital of Qinghai Province, The Fifth People's Hospital of Suzhou, Chongqing Infectious Disease Medical Center, Tuberculosis Hospital in Jilin Province, Sixth People's Hospital of Nanyang City, Wuhan Union Hospital, China

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.

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.

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).

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.

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). .

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.

Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis.

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.

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

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.

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.

Gao M, Gao J, Du J, Liu Y, Zhang Y, Ma L, Mi F, Li L, Tang S; Trial Team. Efficacy of ultra-short course chemotherapy for new smear positive drug susceptible pulmonary tuberculosis: study protocol of a multicenter randomized controlled clinical trial. BMC Infect Dis. 2017 Jun 19;17(1):435. doi: 10.1186/s12879-017-2505-7.

Pease C, Hutton B, Yazdi F, Wolfe D, Hamel C, Quach P, Skidmore B, Moher D, Alvarez GG. Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses. BMC Infect Dis. 2017 Apr 11;17(1):265. doi: 10.1186/s12879-017-2377-x.