Shortened Regimens for Drug-susceptible Pulmonary Tuberculosis

Sponsor

Beijing Chest Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02901288

Collaborator

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

3,900

Enrollment

Locations

Arms

Duration (Months)

111.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Pulmonary	Drug: Isoniazid Drug: Rifampicin Drug: Pyrazinamide Drug: Ethambutol Drug: Levofloxacin	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3900 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2018

Anticipated Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: experimental group1 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 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. Drug: Rifampicin Rifampicin is a widely used anti-tuberculosis medication. Drug: Pyrazinamide Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis. Drug: Ethambutol Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb. Drug: Levofloxacin 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. Other Names: Cravit
Experimental: experimental group2 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 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. Drug: Rifampicin Rifampicin is a widely used anti-tuberculosis medication. Drug: Pyrazinamide Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis. Drug: Ethambutol Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.
Active Comparator: Control regimen group 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 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. Drug: Rifampicin Rifampicin is a widely used anti-tuberculosis medication. Drug: Pyrazinamide Pyrazinamide is a commonly used medication for tuberculosis, with bactericidal effect against intracellular mycobacterium tuberculosis. Drug: Ethambutol Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.

Arm

Intervention/Treatment

Experimental: experimental group1

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

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.

Drug: Rifampicin

Rifampicin is a widely used anti-tuberculosis medication.

Drug: Pyrazinamide

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

Drug: Ethambutol

Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.

Drug: Levofloxacin

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.

Other Names:

Cravit

Experimental: experimental group2

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

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.

Drug: Rifampicin

Rifampicin is a widely used anti-tuberculosis medication.

Drug: Pyrazinamide

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

Drug: Ethambutol

Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.

Active Comparator: Control regimen group

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

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.

Drug: Rifampicin

Rifampicin is a widely used anti-tuberculosis medication.

Drug: Pyrazinamide

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

Drug: Ethambutol

Ethambutol is a widely used medicine in anti-TB regimens with bacteriostatic effect against M. tb.

Outcome Measures

Primary Outcome Measures

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

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.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anhui Chest Hospital	Hefei	Anhui	China	230000
2	Beijing Research Institute for Tuberculosis Control	Beijing	Beijing	China	100000
3	Beijing Chest Hospital,Capital Meical University	Beijing	Beijing	China	101149
4	Chongqing Infectious Disease Medical Center	Chongqing	Chongqing	China	500106
5	Pulmonary Hospital of Lanzhou	Lanzhou	Gansu	China	730000
6	Centre for Tuberculosis Control of Guangdong Province	Guangzhou	Guangdong	China	510000
7	Guangxi Center for Disease Prevention and Control	Nanning	Guangxi	China	530000
8	HeBei Province Center for Disease Prevention and Control	Shijiazhuang	Hebei	China	050000
9	Infectious Disease Prevention Hospital in Heilongjiang Province	Ha'erbin	Heilongjiang	China	150000
10	Heilongjiang Province center for tuberculosis Control and Prevention	Haerbin	Heilongjiang	China	150000
11	Harbin Chest Hospital	Harbin	Heilongjiang	China	150000
12	The Infectious Hospital of Hebi	Hebi	Henan	China	458000
13	Kaifeng Pulmonary Disease Hospital	Kaifeng	Henan	China	475000
14	Sixth People's Hospital of Nanyang City	Nanyang	Henan	China	473000
15	The First Affiliated Hospital of Xinxiang Medical University	Xianxiang	Henan	China	453100
16	Wuhan medical treatment center	Wuhan	Hubei	China	430000
17	Wuhan Institute For Tuberculosis Control	Wuhan	Hubei	China	430030
18	Hunan Institute For Tuberculosis Control	Changsha	Hunan	China	410000
19	The Sixth People's Hospital of Nantong	Nantong	Jiangsu	China	226000
20	The Fifth People's Hospital of Suzhou	Suzhou	Jiangsu	China	215000
21	The Third People's Hospital of Zenjiang	Zhenjiang	Jiangsu	China	212005
22	Changchun Infectious Disease Hospital	Changchun	Jilin	China	130000
23	Tuberculosis Hospital in Jilin Province	Jilin	Jilin	China	132000
24	China Shenyang Chest Hospital	Shenyang	Jilin	China	110000
25	The Fourth People's Hospital of Ningxia Autonomous Region	Yinchuan	Ningxia	China	750000
26	The 4th People's Hospital of Qinghai Province	Xining Shi	Qinghai	China	810000
27	The Infectious Disease Hospital of Wangkai Zaozhuang	Tengzhou	Shandong	China	277500
28	Shanghai Pulmonary Hospital	Shanghai	Shanghai	China	200000
29	Taiyuan Fourth People's Hospital	Taiyuan	Shanxi	China	030000
30	The Tuberculosis Prevention and Treatment Hospital of Shanxi Province	Xi'an	Shanxi	China	710100
31	Public Health Clinical Center of Chengdu	Chengdu	Sichuan	China	610061
32	Tianjin Haihe Hospital	Tianjin	Tianjin	China	300000
33	Tianjin centers for Disease Control and Prevention	Tianjin	Tianjin	China	300041
34	Chest of Hospital of Xinjiang Uygur Autonomous Region of the PRC	Wulumuqi	Xinjiang	China	830001
35	The Third People's Hospital of Kunming City	Kunming	Yunnan	China	650041