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Optimization of MDR-TB Treatment Regimen Based on the Molecular Drug Susceptibility Results of Pyrazinamide

Primary Purpose

Multidrug Resistant Tuberculosis

Status
Unknown status
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Pyrazinamide containing regimen
Regimen without Pyrazinamide
Sponsored by
Huashan Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multidrug Resistant Tuberculosis focused on measuring Multidrug Resistant Tuberculosis, Pyrazinamide

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients who are diagnosed with active tuberculosis
  • Patients who are smear positive and sputum culture positive for tuberculosis
  • History of active tuberculosis less than 3 years
  • With less than 2 times of previous antituberculous therapy
  • The patients should be voluntarily entering the study and willing to sign up the consent form after full knowledge of the risks, schedule, drug features of this study.
  • MDR-TB is defined as resistance to the following two drugs: Isoniazid and Rifampicin.
  • Extensively drug-resistant(XDR-TB) is defined as resistance to any flouroquinolones and any one of the three second-line antituberculous injections (capreomycin, kanamycin, amikacin)
  • The study enrolled MDR-TB subjects and excluded XDR-TB subjects. If MDR-TB subjects is also resistant to flouroquinolones or capreomycin( kanamycin, amikacin), the subjects is included in the study as pre-XDR TB patients.

Exclusion Criteria:

  • Known allergy or intolerance to the drugs in this study
  • Liver damage (Hepatic encephalopathy; ascites; prothrombin time prolonged 2 seconds compared with normal controls; blood bilirubin 3 times greater than the upper limit of the normal range)
  • Platelets <150x109 / L, WBC < 3x109 / L.
  • Abnormal ECG (Male patients with prolonged QT interval exceeding 430ms, Female patients with prolonged QT interval exceeding 450ms)
  • Serum creatinine 1.5 times higher than upper limit
  • Fasting blood-glucose higher than 8.0 mmol/L
  • Patients who are on medication that effect the results of the drugs in this study
  • Karnofsky score<50% (see appendix)
  • Women who are pregnant or breastfeeding
  • HIV positive
  • Participating in other clinical trials in the past three months
  • Patients with mental illness and severe neurosis
  • Patients who have poor compliances
  • Any special circumstances in which the research physicians believe that is not suitable for this study.

Sites / Locations

  • Chongqing Pulmonary HospitalRecruiting
  • The Sixth People's Hospital of ZhengzhouRecruiting
  • The Fifth People's Hospital of SuzhouRecruiting
  • The Fifth People's Hospital of WuxiRecruiting
  • Xinjiang Chest Hospital
  • Hangzhou Red Cross HospitalRecruiting
  • The Affiliated Hospital of Hangzhou Normal University
  • The Affiliated Hospital of Luzhou Medical CollegeRecruiting
  • Wenling No.1 People's Hospital
  • Ruian People's HospitalRecruiting
  • Zhuji People's Hospital of Zhejiang ProvinceRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Pyrazinamide Sensitive Comparator

Pyrazinamide Resistant Comparator

Arm Description

Pyrazinamide containing regimen: Regimen B1 - 6ZAmkLfxClrPto\6ZlfxClrPto Six months of chemotherapy with Pyrazinamide,Amikacin,Levofloxacin,Clarithromycin,plus Prothionamide,followed by Six months of Pyrazinamide,Levofloxacin,Clarithromycin,plus Prothionamide

Regimen without Pyrazinamide: Regimen B2 - 6HAmkLfxClrPto\18HlfxClrPto Six months of chemotherapy with Isoniazid,Amikacin,Levofloxacin,Clarithromycin,plus Prothionamide,followed by Eighteen months of Isoniazid,Levofloxacin,Clarithromycin,plus Prothionamide

Outcomes

Primary Outcome Measures

The Median Time to Sputum Culture Conversion

Secondary Outcome Measures

The Percentage of treatment success
Treatment success is defined as： During the last 12 months of treatment，participants have at least 5 sputum cultures negative taken at least 30 days apart. During the last 12 months of treatment，participants have only one sputum culture positive, followed by at least 3 consecutive sputum cultures negative taken at least 30 days apart, without symptoms progression. Participants complete the treatment, but less than 5 culture results are available.

Full Information

First Posted
April 21, 2014
Last Updated
April 21, 2014
Sponsor
Huashan Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02120638
Brief Title
Optimization of MDR-TB Treatment Regimen Based on the Molecular Drug Susceptibility Results of Pyrazinamide
Official Title
Optimization of MDR-TB Treatment Regimen Based on the Molecular Drug Susceptibility Results of Pyrazinamide
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Unknown status
Study Start Date
April 2014 (undefined)
Primary Completion Date
April 2016 (Anticipated)
Study Completion Date
April 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Huashan Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Multidrug resistant tuberculosis (MDR-TB) is difficult to treat and raises a great challenge to TB control program. That pyrazinamide can shorten the course of treatment and facilitate bacilli clearance has been proved recently. In 2011, WHO recommended to use pyrazinamide throughout the course of treatment for MDR-TB. However, pyrazinamide susceptibility testing has not been widely used in clinic. And the conventional testing is time-consuming and unreliable. In contrast, the detection of pncA and rpsA mutations with molecular methods can provide rapid results of pyrazinamide susceptibility. The purpose of this study is to evaluate the efficacy of the introduce the molecular testing of pyrazinamide susceptibility in optimizing the MDR-TB treatment regimen.
Detailed Description
This is a phase 3, open labeled, prospective cohort study to evaluate the molecular testing of pyrazinamide susceptibility in optimizing the MDR-TB treatment regimen. Approximately 100 participants will be given the molecular detection of pncA and rpsA mutations and divide into to the pyrazinamide sensitive comparator group and the pyrazinamide resistant group based on the susceptibility results. For the pyrazinamide sensitive group, the regimen contains six months of chemotherapy with pyrazinamide, amikacin, levofloxacin, plus prothionamide, followed by six months of pyrazinamide, levofloxacin, clarithromycin, plus prothionamide. For the pyrazinamide resistant group, the regimen contains six months of chemotherapy with isoniazid, amikacin, levofloxacin, plus prothionamide, followed by eighteen months of isoniazid, levofloxacin, clarithromycin, plus prothionamide. The participants will be followed up to 24 months after the start of the treatment. The primary outcome is the sputum culture conversion and the adverse events. Safety evaluations that will be performed are the routine lab tests, blood glucose, hearing , vital signs, ECG, reporting of adverse events, physical examinations and X-rays.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug Resistant Tuberculosis
Keywords
Multidrug Resistant Tuberculosis, Pyrazinamide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Pyrazinamide Sensitive Comparator
Arm Type
Active Comparator
Arm Description
Pyrazinamide containing regimen: Regimen B1 - 6ZAmkLfxClrPto\6ZlfxClrPto Six months of chemotherapy with Pyrazinamide,Amikacin,Levofloxacin,Clarithromycin,plus Prothionamide,followed by Six months of Pyrazinamide,Levofloxacin,Clarithromycin,plus Prothionamide
Arm Title
Pyrazinamide Resistant Comparator
Arm Type
Experimental
Arm Description
Regimen without Pyrazinamide: Regimen B2 - 6HAmkLfxClrPto\18HlfxClrPto Six months of chemotherapy with Isoniazid,Amikacin,Levofloxacin,Clarithromycin,plus Prothionamide,followed by Eighteen months of Isoniazid,Levofloxacin,Clarithromycin,plus Prothionamide
Intervention Type
Drug
Intervention Name(s)
Pyrazinamide containing regimen
Intervention Description
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, >70kg 2000-2500mg daily Amikacin 600mg daily Levofloxacin 33-70kg 750 mg daily, >70kg 1000 mg daily Clarithromycin 33-50kg 500 mg daily, >50kg 1000 mg daily Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, >70kg 1000 mg daily All treatment is taken daily, for a duration of up to 12 months depending on treatment arm.
Intervention Type
Drug
Intervention Name(s)
Regimen without Pyrazinamide
Intervention Description
Isoniazid 600mg daily Amikacin 600mg daily Levofloxacin 33-70kg 750 mg daily, >70kg 1000 mg daily Clarithromycin 33-50kg 500 mg daily, >50kg 1000 mg daily Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, >70kg 1000 mg daily All treatment is taken daily, for a duration of up to 18 months depending on treatment arm.
Primary Outcome Measure Information:
Title
The Median Time to Sputum Culture Conversion
Time Frame
24 months
Secondary Outcome Measure Information:
Title
The Percentage of treatment success
Description
Treatment success is defined as： During the last 12 months of treatment，participants have at least 5 sputum cultures negative taken at least 30 days apart. During the last 12 months of treatment，participants have only one sputum culture positive, followed by at least 3 consecutive sputum cultures negative taken at least 30 days apart, without symptoms progression. Participants complete the treatment, but less than 5 culture results are available.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients who are diagnosed with active tuberculosis Patients who are smear positive and sputum culture positive for tuberculosis History of active tuberculosis less than 3 years With less than 2 times of previous antituberculous therapy The patients should be voluntarily entering the study and willing to sign up the consent form after full knowledge of the risks, schedule, drug features of this study. MDR-TB is defined as resistance to the following two drugs: Isoniazid and Rifampicin. Extensively drug-resistant(XDR-TB) is defined as resistance to any flouroquinolones and any one of the three second-line antituberculous injections (capreomycin, kanamycin, amikacin) The study enrolled MDR-TB subjects and excluded XDR-TB subjects. If MDR-TB subjects is also resistant to flouroquinolones or capreomycin( kanamycin, amikacin), the subjects is included in the study as pre-XDR TB patients. Exclusion Criteria: Known allergy or intolerance to the drugs in this study Liver damage (Hepatic encephalopathy; ascites; prothrombin time prolonged 2 seconds compared with normal controls; blood bilirubin 3 times greater than the upper limit of the normal range) Platelets <150x109 / L, WBC < 3x109 / L. Abnormal ECG (Male patients with prolonged QT interval exceeding 430ms, Female patients with prolonged QT interval exceeding 450ms) Serum creatinine 1.5 times higher than upper limit Fasting blood-glucose higher than 8.0 mmol/L Patients who are on medication that effect the results of the drugs in this study Karnofsky score<50% (see appendix) Women who are pregnant or breastfeeding HIV positive Participating in other clinical trials in the past three months Patients with mental illness and severe neurosis Patients who have poor compliances Any special circumstances in which the research physicians believe that is not suitable for this study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wenhong Zhang, PhD,MD
Phone
+86 21 52889999
Ext
8123
Email
zhangwenhong@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ying Zhang, PhD
Organizational Affiliation
Huashan Hospital of Fudan University, Shanghai, China;Johns Hopkins University, Baltimore, Maryland, USA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Wenhong Zhang, PhD,MD
Organizational Affiliation
Huashan Hospital of Fudan University, Shanghai, China
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chongqing Pulmonary Hospital
City
Chongqing
State/Province
Chongqing
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiyan Zhang
Email
593189393@qq.com
Facility Name
The Sixth People's Hospital of Zhengzhou
City
Zhengzhou
State/Province
Henan
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yu Chen
Email
chenyuhnzz@163.com
Facility Name
The Fifth People's Hospital of Suzhou
City
Suzhou
State/Province
Jiangsu
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peijun Tang
Email
tangpeipei001@163.com
Facility Name
The Fifth People's Hospital of Wuxi
City
Wuxi
State/Province
Jiangsu
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qinlao Ou
Email
oqinfang@163.com
Facility Name
Xinjiang Chest Hospital
City
Urumqi
State/Province
Xinjiang
Country
China
Individual Site Status
Active, not recruiting
Facility Name
Hangzhou Red Cross Hospital
City
Hangzhou
State/Province
Zhejiang
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yunfeng Sheng
Email
shengyf617@163.com
Facility Name
The Affiliated Hospital of Hangzhou Normal University
City
Hangzhou
State/Province
Zhejiang
Country
China
Individual Site Status
Active, not recruiting
Facility Name
The Affiliated Hospital of Luzhou Medical College
City
Huzhou
State/Province
Zhejiang
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fuli Huang
Email
10111220006@fudan.edu.cn
Facility Name
Wenling No.1 People's Hospital
City
Taizhou
State/Province
Zhejiang
Country
China
Individual Site Status
Active, not recruiting
Facility Name
Ruian People's Hospital
City
Wenzhou
State/Province
Zhejiang
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dong Zhang
Email
418022491@qq.com
Facility Name
Zhuji People's Hospital of Zhejiang Province
City
Zhuji
State/Province
Zhejiang
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heqing Huang
Email
zjganran@163.com

12. IPD Sharing Statement

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Optimization of MDR-TB Treatment Regimen Based on the Molecular Drug Susceptibility Results of Pyrazinamide

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