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

April 21, 2014 updated by: Wen-hong Zhang, Huashan Hospital
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Chongqing
      • Chongqing, Chongqing, China
        • Recruiting
        • Chongqing Pulmonary Hospital
        • Contact:
    • Henan
      • Zhengzhou, Henan, China
        • Recruiting
        • The Sixth People's Hospital of Zhengzhou
    • Jiangsu
      • Suzhou, Jiangsu, China
      • Wuxi, Jiangsu, China
        • Recruiting
        • The Fifth People's Hospital of Wuxi
        • Contact:
    • Xinjiang
      • Urumqi, Xinjiang, China
        • Active, not recruiting
        • Xinjiang Chest Hospital
    • Zhejiang
      • Hangzhou, Zhejiang, China
        • Recruiting
        • Hangzhou Red Cross Hospital
      • Hangzhou, Zhejiang, China
        • Active, not recruiting
        • The Affiliated Hospital of Hangzhou Normal University
      • Huzhou, Zhejiang, China
      • Taizhou, Zhejiang, China
        • Active, not recruiting
        • Wenling No.1 People's Hospital
      • Wenzhou, Zhejiang, China
        • Recruiting
        • Ruian People's Hospital
        • Contact:
      • Zhuji, Zhejiang, China
        • Recruiting
        • Zhuji People's Hospital of Zhejiang Province
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Pyrazinamide Sensitive Comparator

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
Drug: Pyrazinamide containing regimen
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.
Experimental: Pyrazinamide Resistant Comparator

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
Drug: Regimen without Pyrazinamide
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The Median Time to Sputum Culture Conversion
Time Frame: 24 months
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Percentage of treatment success
Time Frame: 24 months

Treatment success is defined as：

  1. During the last 12 months of treatment，participants have at least 5 sputum cultures negative taken at least 30 days apart.
  2. 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.
  3. Participants complete the treatment, but less than 5 culture results are available.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Huashan Hospital

Investigators

  • Principal Investigator: Wenhong Zhang, PhD,MD, Huashan Hospital of Fudan University, Shanghai, China
  • Principal Investigator: Ying Zhang, PhD, Huashan Hospital of Fudan University, Shanghai, China;Johns Hopkins University, Baltimore, Maryland, USA

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (Anticipated)

April 1, 2016

Study Completion (Anticipated)

April 1, 2016

Study Registration Dates

First Submitted

April 21, 2014

First Submitted That Met QC Criteria

April 21, 2014

First Posted (Estimate)

April 23, 2014

Study Record Updates

Last Update Posted (Estimate)

April 23, 2014

Last Update Submitted That Met QC Criteria

April 21, 2014

Last Verified

April 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KY2013-260
  • 2013ZX10003008-003 (Other Grant/Funding Number: National Major Science and Technology Special Project)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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