Clinical trial NCT02901288: Shortened Regimens for Drug-susceptible Pulmonary Tuberculosis
Official title: Shortened Regimens for First Diagnosed Smear Positive Drug Susceptible Pulmonary Tuberculosis: a Randomised Controlled Non-inferiority Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Tuberculosis, Pulmonary
Keywords: pulmonary tuberculosis
shortened regimen
clinical trial
Lead sponsor: Beijing Chest Hospital
Sponsor class: OTHER
Collaborators: name: Hubei Provincial Center for Disease Control and Prevention
name: Centre for Tuberculosis Control of Guangdong Province
name: Hunan Institute For Tuberculosis Control
name: Anhui Chest Hospital
name: Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control
name: Wuhan Institute for Tuberculosis Control
name: Shanghai Pulmonary Hospital, Shanghai, China
name: Shenyang Chest Hospital
name: Changchun Infectious Disease Hospital
name: First Affiliated Hospital of Xinjiang Medical University
name: Public Health Clinical Center of Chengdu
name: Taiyuan Fourth People's Hospital
name: The Sixth People's Hospital of Nantong
name: The Tuberculosis Prevention and Treatment Hospital of Shanxi Province
name: Beijing Research Institute for Tuberculosis Control
name: Infectious Disease Prevention Hospital in Heilongjiang Province
name: The Third People's Hospital of Zhenjiang
name: Tianjin centers for Disease Control and Prevention
name: Harbin Chest Hospital
name: Chest of Hospital of Xinjiang Uygur Autonomous Region of the PRC
name: Heilongjiang Province center for tuberculosis Control and Prevention
name: Tianjin Haihe Hospital
name: The Infectious Disease Hospital of Wangkai Zaozhuang
name: The Third People's Hospital of Kunming City
name: Kaifeng Central Hospital
name: The Infectious Hospital of Hebi
name: Pulmonary Hospital of Lanzhou
name: The Fourth People's Hospital of Ningxia Autonomous Region
name: The Fourth People's Hospital of Qinghai Province
name: The Fifth People's Hospital of Suzhou
name: Chongqing Infectious Disease Medical Center
name: Tuberculosis Hospital in Jilin Province
name: Sixth People's Hospital of Nanyang City
name: Wuhan Union Hospital, China
First posted: 2016-09-15
Enrollment: 3900
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 1. Design: The study is a multi-center, randomized,controlled non-inferiority trial.
2. Population: patients with newly diagnosed drug-susceptible pulmonary TB who fulfill the inclusion and exclusion criteria.
3. 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)..
4. 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.
5. 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.
6. Sample Size:

   Approximately 3900 participants will be enrolled and randomized with 1:1:1 ratio into either Experimental group1, Experimental group2 or control group.
7. Blinding:

   The study is an open-label study.
8. Assessment and follow-up:

All patients will be followed by to 2 years after completion of treatment.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. Is aged 18-65 years.
3. 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.
4. Newly diagnosed cases receiving anti-TB treatment for less than one month
5. Urine Human Chorionic Gonadotropin(U-HCG) negative and must agree to use effective contraception during the trial period.
6. 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:

1. Concomitant severe cardiovascular, liver, kidney, nervous system, hematopoietic system and other diseases, or concomitant neoplastic diseases. Or extensive lesion with respiratory insufficiency.
2. Uncontrolled diabetes mellitus.
3. Concomitant mental disorders.
4. Is HIV positive.
5. Is critically ill, and in the judgment of the investigator, not fit for the study or unlikely to complete the full course of study.
6. Is known to be pregnant or breast-feeding.
7. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule.
8. Is taking any medications contraindicated with the medicines in any trial regimen of the study.
9. Has a known allergy to any drug of treatment regimens.
10. Is currently taking part in another trial.
11. Has a QTc interval more than 480ms.

Primary outcomes:
measure: The percentage of participants with TB recurrence/relapse by 24 months after the end of treatment.
timeFrame: 24 months after treatment completion for all 3 groups
measure: Percentage of participants with treatment failure at either 4.5 months or 6 months after randomization.
timeFrame: 4.5 months after randomization for experimental group1 and 2; 6 months after randomization for control group
Secondary outcomes:
measure: Treatment adverse reactions occuring
timeFrame: 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.
measure: Time to sputum smear or culture conversion within intensive phase .
timeFrame: An avergae of 2-3 months after randomization.
measure: Sputum smear or culture conversion proportion at the treatment completion.
timeFrame: An average of 6 months for control group while 4.5 months for experimental group 1 and 2.
measure: Radiological manifestation change of TB lesion or cavity.
timeFrame: An average of 6 months during treatment and 24 months after treatment completion.
measure: Patiens adherence rate
timeFrame: An average of 6 months during treatment and 24 months after treatment completion.
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Chest Hospital
state: Anhui
city: Beijing
country: China
facility: Beijing Research Institute for Tuberculosis Control
state: Beijing
city: Beijing
country: China
facility: Beijing Chest Hospital,Capital Meical University
state: Beijing
city: Chongqing
country: China
facility: Chongqing Infectious Disease Medical Center
state: Chongqing
city: Lanzhou
country: China
facility: Pulmonary Hospital of Lanzhou
state: Gansu
city: Guangzhou
country: China
facility: Centre for Tuberculosis Control of Guangdong Province
state: Guangdong
city: Nanning
country: China
facility: Guangxi Center for Disease Prevention and Control
state: Guangxi
city: Shijiazhuang
country: China
facility: HeBei Province Center for Disease Prevention and Control
state: Hebei
city: Ha'erbin
country: China
facility: Infectious Disease Prevention Hospital in Heilongjiang Province
state: Heilongjiang
city: Haerbin
country: China
facility: Heilongjiang Province center for tuberculosis Control and Prevention
state: Heilongjiang
city: Harbin
country: China
facility: Harbin Chest Hospital
state: Heilongjiang
city: Hebi
country: China
facility: The Infectious Hospital of Hebi
state: Henan
city: Kaifeng
country: China
facility: Kaifeng Pulmonary Disease Hospital
state: Henan
city: Nanyang
country: China
facility: Sixth People's Hospital of Nanyang City
state: Henan
city: Xianxiang
country: China
facility: The First Affiliated Hospital of Xinxiang Medical University
state: Henan
city: Wuhan
country: China
facility: Wuhan medical treatment center
state: Hubei
city: Wuhan
country: China
facility: Wuhan Institute For Tuberculosis Control
state: Hubei
city: Changsha
country: China
facility: Hunan Institute For Tuberculosis Control
state: Hunan
city: Nantong
country: China
facility: The Sixth People's Hospital of Nantong
state: Jiangsu
city: Suzhou
country: China
facility: The Fifth People's Hospital of Suzhou
state: Jiangsu
city: Zhenjiang
country: China
facility: The Third People's Hospital of Zenjiang
state: Jiangsu
city: Changchun
country: China
facility: Changchun Infectious Disease Hospital
state: Jilin
city: Jilin
country: China
facility: Tuberculosis Hospital in Jilin Province
state: Jilin
city: Shenyang
country: China
facility: China Shenyang Chest Hospital
state: Jilin
city: Yinchuan
country: China
facility: The Fourth People's Hospital of Ningxia Autonomous Region
state: Ningxia
city: Xining Shi
country: China
facility: The 4th People's Hospital of Qinghai Province
state: Qinghai
city: Tengzhou
country: China
facility: The Infectious Disease Hospital of Wangkai Zaozhuang
state: Shandong
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
state: Shanghai
city: Taiyuan
country: China
facility: Taiyuan Fourth People's Hospital
state: Shanxi
city: Xi'an
country: China
facility: The Tuberculosis Prevention and Treatment Hospital of Shanxi Province
state: Shanxi
city: Chengdu
country: China
facility: Public Health Clinical Center of Chengdu
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Haihe Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin centers for Disease Control and Prevention
state: Tianjin
city: Wulumuqi
country: China
facility: Chest of Hospital of Xinjiang Uygur Autonomous Region of the PRC
state: Xinjiang
city: Kunming
country: China
facility: The Third People's Hospital of Kunming City
state: Yunnan
Study officials:
affiliation: Beijing Chest Hospital
name: Shenjie Tang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.